# projects

application_id: 10248407
project_number: 5R01AA028503-02
project_title: Sex Differences in Risk for Alcohol Use Disorder: Neural and Hormonal Influences
administering_ic: NIAAA
award_notice_date: 2021-07-21
opportunity_number: PA-19-091
application_type: 5
activity_code: R01
ic: AA
serial_number: 028503
program_official: MATOCHIK, JOHN A
project_start_date: 2020-09-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-BDCN-C(90)S]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe sex gap in alcohol consumption is closing rapidly due to alarming increases in alcohol consumptionamong young women. As such there is an urgent need to determine the factors underlying sex differences inrisk for AUD. Current addiction models propose three neurofunctional domains that drive problematic alcoholuse and therefore serve as candidate sex-specific risk factors: executive function negative emotionality andincentive salience. Data from our lab and others suggest that poor inhibitory control a key component ofexecutive function is a stronger risk factor for women than for men. Moreover we have preliminary evidencethat female drinkers show less engagement of neural circuitry underlying inhibitory control and that this sexdifference is influenced by circulating levels of estradiol. However the degree to which hormonally-moderatedsex differences in executive function extend to the negative emotionality and incentive salience domains andhow these sex differences influence current and future drinking is unknown. Here we will determine: 1) theneurobiological factors contributing to sex-specific risk for AUD in each of these three addiction domains and 2)the degree to which sex differences in each domain influence current and prospective drinking. Femaledrinkers will undergo fMRI to assess neural correlates of inhibitory control (i.e. executive function) negativeemotionality and alcohol cue reactivity (i.e. incentive salience) at three phases of their menstrual cycle: earlyfollicular phase (low estradiol low progesterone) late follicular phase (high estradiol low progesterone) andmid-luteal phase (moderate estradiol high progesterone). Male drinkers will undergo three fMRI scans atmatched intervals. Immediately following each scan participants will complete a session of free-accessintravenous alcohol self-administration. We will then follow participants for 18 months to longitudinally assesschanges in drinking patterns. We hypothesize that hormonally-moderated neural function underlying inhibitorycontrol and negative emotionality will be stronger predictors of current and future alcohol consumption inwomen compared to men whereas neural alcohol cue reactivity will be a stronger predictor for men. Theproject capitalizes on the unique skill sets of the PI (an Early Career Investigator) and a strong collaborativeinvestigative team. The innovative design will provide essential information regarding neural factors influencingdevelopment and maintenance of AUD and critically how this risk is influenced by sex and fluctuations in sexhormones. Ultimately this proposal is a crucial step in a line of research that will lead to the development ofsex-specific prevention and treatment efforts for AUD.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohols;Amygdaloid structure;Anterior;Area;Base of the Brain;Biologic Development;Biological;Brain;Corpus striatum structure;Data;Development;Emotional;Estradiol;Female;Functional Magnetic Resonance Imaging;Future;Goals;Gonadal Steroid Hormones;Heavy Drinking;Hormonal;Inferior frontal gyrus;Insula of Reil;Intervention;Intravenous;Laboratories;Link;Luteal Phase;Maintenance;Measures;Medial;Menstrual cycle;Modeling;Motor;Negative Finding;Neurobiology;Neurophysiology - biologic function;Participant;Patient Self-Report;Pattern;Pharmacotherapy;Phase;Prefrontal Cortex;Prevention;Progesterone;Research;Research Personnel;Risk;Risk Factors;Scanning;Self Administration;Sex Differences;Signal Transduction;Smoker;Transcranial magnetic stimulation;Woman;addiction;alcohol abuse therapy;alcohol cue;alcohol intervention;alcohol risk;alcohol use disorder;base;career;cingulate cortex;cue reactivity;design;disorder risk;drinking;executive function;follow-up;functional MRI scan;hazardous drinking;incentive salience;innovation;male;men;negative affect;neural circuit;neural correlate;novel;proliferative phase Menstrual cycle;prospective;relating to nervous system;sex;skills;young woman

public_health_relevance:
PROJECT NARRATIVEThe findings from this project will determine sex differences and the influence of sex hormones on neuralfunction underlying risk for Alcohol Use Disorder (AUD) as well as how sex differences in neural functioninfluence current and future alcohol consumption. The results will identify novel brain-based targets for sex-specific prevention and treatment efforts for AUD and will provide information on the optimal timing ofintervention for women based on fluctuating sex hormones. As such the project is a critical step towards thedevelopment of biologically-based sex-specific interventions for AUD.


application_id: 10248371
project_number: 5R35ES028373-05
project_title: Environmental Liver Disease
administering_ic: NIEHS
award_notice_date: 2021-08-09
opportunity_number: RFA-ES-16-008
application_type: 5
activity_code: R35
ic: ES
serial_number: 028373
program_official: SCHUG, THADDEUS
project_start_date: 2017-09-15
project_end_date: 2025-08-31
study_section: ZES1-LWJ-K(R)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Academia;Address;Adolescent;Adult;Affect;Animal Model;Area;Cardiovascular Diseases;Cessation of life;Chemical Exposure;Chemicals;Child;Cirrhosis;Collaborations;Data;Development;Diabetes Mellitus;Endocrine;Environment;Environmental Health;Epidemiologist;Exposure to;Fatty Liver;Goals;Government Agencies;Health;Hepatocyte;Industry;Lipids;Liver;Liver diseases;Malignant neoplasm of liver;Medical Societies;Metabolism;Methods;Mission;National Institute of Environmental Health Sciences;Nutrient;Obesity;Physicians;Poison;Policies;Polychlorinated Biphenyls;Population;Practice Guidelines;Reproducibility;Research;Resources;Scientist;Strategic Planning;Time;Training and Education;Transplantation;Vinyl Chloride;Vision;Work;chronic liver disease;diagnostic biomarker;disease registry;environmental chemical;global health;human subject;innovation;next generation;programs;sex


application_id: 10247852
project_number: 3R01HL139047-03S1
project_title: Remote Hind Limb Ischemia Mechanism of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2020-12-10
opportunity_number: PA-20-222
application_type: 3
activity_code: R01
ic: HL
serial_number: 139047
suffix: S1
program_official: SCHWARTZ, LISA
project_start_date: 2020-12-01
project_end_date: 2022-06-30
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Although hind limb remote ischemic conditioning (RIC) is cardioprotective the mechanism isunknown. The long-term goal of this project is to understand the mechanism of protection by remotehind-limb ischemia. The central hypothesis of this proposal is that transient ischemic episodes awayfrom the myocardial infarction (MI) contribute to the recovery through secretion of beneficialexosomes from skeletal muscle endocrine improving mitochondrial metabolism hydrogen sulfide(H2S an anti-oxidant anti-inflammatory anti-apoptotic vasoactive gas) and mobilization of bonemarrow stem cells (BMSC) to the site of injury (Figure 1). It is known that DNA hypermethylation byepigenetic modification inhibits the gene and produces homocysteine (Hcy) leading tohyperhomocysteinemia (HHcy) that decreases H2S. Interestingly increase in cystathione  synthase(CBS) and cystathionine  lyase (CSE) enzymes increases H2S and decreases Hcy. Our preliminarydata suggests that RIC induced musclin (a skeletal muscle hormone) attenuated myocardial muscledamage and dysfunction. The central hypothesis will be tested by the following three specific aims:Specific Aim 1: To determine whether the RIC releases exosomes induces musclin and reversescompromised skeletal and cardiac muscle function during MI and diabetes. Specific Aim 2: Todetermine whether the RIC enhances H2S production by increasing CBS and CSE expression andepigenetic hypomethylation and gene induction during MI and diabetes. Specific Aim 3: To determinewhether the RIC instigates BMSC mobilization to the site of myocardial injury and mitigates muscledamage by regeneration after MI during diabetes.

project_terms:
Address;Anti-Inflammatory Agents;Antioxidants;Apoptotic;Attenuated;Bone Marrow Stem Cell;Coronary heart disease;Cystathionine;DNA;Data;Diabetes Mellitus;Endocrine;Enzymes;Epigenetic Process;Functional disorder;Gases;Genes;Goals;Heart;Hematopoietic Stem Cell Mobilization;Hindlimb;Homocysteine;Hormones;Hydrogen Sulfide;Hyperhomocysteinemia;Hypermethylation;Incidence;Injury;Ischemia;Limb structure;Lyase;Modification;Muscle;Muscle function;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Production;Recovery;Risk;Site;Skeletal Muscle;Testing;cardioprotection;diabetic;effective therapy;exosome;gene induction;improved;ischemic conditioning;limb ischemia;mitochondrial metabolism;myocardial injury

public_health_relevance:
Narrative:The incidence of coronary heart disease (CHD) in diabetics is robust and this proposal addresses theissue of remote ischemia can create beneficial effects on ischemic insult in the heart. There must bea strategy to restore lost ischemic tolerance capacity in diabetes to counter the risk. Our proposalfocuses on this aspect and evaluates mechanisms of remote ischemic condition (RIC) in effectivetreatment of myocardial infarction (MI).


application_id: 10247700
project_number: 5R01CA230758-04
project_title: Characterize the role of EBF1 in breast cancer progression
administering_ic: NCI
award_notice_date: 2022-09-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 230758
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2018-09-01
project_end_date: 2024-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 11716117
contact_pi: WU, YADI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Basal-like breast cancer (BLBC) is a devastating form with limited therapeutic options. Duringtumor progression and metastasis tumor cells rewire their metabolism which results in anenhanced nutrient uptake to supply the energetic and biosynthetic pathway under the hypoxiccondition. It is important for tumor cells to activate mitochondrial selective autophagy (mitophagy)to avoid metabolic crisis and maintain the mitochondrial homeostasis. The means by which BLBCcells fine-tune mitochondrial biogenesis and mitophagy to maintain metabolic and mitochondrialhomeostasis in order to adapt the hypoxic microenvironment remain elusive. We found that EBF1is highly expressed in BLBC. Knockdown of EBF1 induced extensive mitophagy and eventualcell death. Interestingly silencing HIF1 blocked the EBF1 deficiency-induced mitophagy and celldeath in BLBC. In addition we found that HIF1 induced EBF1 expression and that EBF1interacted with HIF1 and inhibited HIF1 activity. Based on these preliminary data we speculatethat EBF1 functions as a safeguard to ensure metabolic homeostasis through a regulation ofHIF1 activity which when compromised can contribute to imbalanced mitochondria andmassive mitophagy in BLBC. Our strategy will be to first delineate the role of EBF1 in BLBC (Aim1); then determine the molecular interplay between EBF1 and HIF1 (Aim 2); and to characterizethe role of EBF1 in vivo in human samples as well as in several mouse models (Aim 3). Theknowledge gained from these studies will increase our fundamental understanding about biologicrelationship between metabolic reprogramming and mitochondrial homeostasis particular duringhypoxia. Our work also reveals a pivotal function for the EBF1 in BLBC and suggests that targetingthis pathway may offer alternative treatment strategies for this aggressive subtype of breastcancer.

project_terms:
Address;Affect;Attenuated;Autophagocytosis;B-Lymphocytes;Biogenesis;Bioinformatics;Biological;Brain;Breast Cancer Cell;Breast Cancer cell line;Cell Death;Cells;Cessation of life;Clinical;Data;Disease;EP300 gene;Early identification;Ensure;Environment;Event;Feedback;Genes;Genetic Transcription;Goals;Growth;HIF1A gene;Homeostasis;Human;Hypoxia;Hypoxia Inducible Factor;Immunocompetent;Interruption;Intrinsic factor;Knockout Mice;Knowledge;Luciferases;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;NCI-Designated Cancer Center;Neoplasm Metastasis;Nutrient;Oxygen;Pathogenesis;Pathologist;Pathway interactions;Patients;Play;Process;Prognosis;Reaction;Reagent;Regulation;Research;Response Elements;Role;Sampling;Signal Transduction;Specimen;Stress;System;Talents;Testing;Therapeutic;Tumorigenicity;Work;alternative treatment;base;breast cancer progression;cancer initiation;conditional knockout;druggable target;in vivo;inhibitor;innovation;insight;interest;knock-down;malignant breast neoplasm;mouse model;multidisciplinary;neoplastic cell;novel;overexpression;prevent;programs;response;targeted treatment;transcription factor;treatment strategy;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;uptake

public_health_relevance:
Despite immense interest in metabolic reprogramming related to tumor progression we still havelittle knowledge about how this process is balanced to maintain catabolic homeostasis particularlyduring conditions of stress. By defining the role of EBF1 in regulation of HIF1 activity this projectwill provide unique and new insight into how HIF1-mediated metabolic reprogramming isregulated through EBF1.


application_id: 10247633
project_number: 5DP5OD028155-04
project_title: Histamine in homes: Exposure risks and health effects
administering_ic: OD
award_notice_date: 2021-08-20
opportunity_number: RFA-RM-18-010
application_type: 5
activity_code: DP5
ic: OD
serial_number: 028155
program_official: MILLER, BECKY
project_start_date: 2019-09-16
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-PSE-H(70)]
contact_pi_person_id: 15186293
contact_pi: DEVRIES, ZACHARY
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Exposure to indoor environmental contaminants is a major health risk factor particularly in relation to allergic disease andasthma. In the United States alone over 50 million people suffer from allergies each year with an estimated annual costof over $18 billion. Although numerous contaminants have been identified indoors mitigation in most cases is possiblebecause their sources chemical characteristics dissemination and health effects have been identified. Contaminants thattend to be particularly challenging to manage are those that either remain un-identified or that we do not fully understand.Bed bugs have resurged globally during the last 20 years severely affecting the quality of life in disadvantagedcommunities. I recently discovered and quantified large amounts of histamine in bed bug-infested homes. Althoughhistamine has been extensively investigated as a food contaminant in fish and alcoholic beverages chronic exposure tohistamine has not been considered because histamine has never been detected as a contaminant in homes. Histamine isa downstream modulator in the mammalian immune response and it is routinely used in provocation tests includingbronchial challenge and skin tests. The presence of large histamine deposits in household dust and its multiple clinicaleffects (e.g. vasodilation inflammation neuromodulation) predict that dermal and respiratory exposure to histaminecould constitute a serious health risk. I therefore hypothesize that histamine is ubiquitous in bed bug infested homesparticularly in inner-city low-income residences and chronic exposure to histamine poses serious health risks to humans.I propose an integrated and interdisciplinary approach to understand the contribution of bed bugs to histamine residuesin homes the pervasiveness and spatial distribution of histamine in the indoor environment and the effects of histamineon human health. If successful this project will identify a new environmental contaminant that has gone undetected andunabated for almost two decades. To this end I will address the following specific aims:1. Quantify bed bug histamine production and determine the extent of histamine production in other arthropods.2. Characterize the spatial distribution of histamine in bed bug infested homes.3. Correlate environmental histamine with the bed bug resurgence and adverse health outcomes4. Determine the bioactivity and clinical relevance of bed bug derived histaminePresently no programs offer the opportunity to conduct cutting edge research at the intersection of indoor entomologyand public health. Therefore to address the problems outlined above I require research independence. This awardsupported by significant commitments from my host institution will provide me with the infrastructure and mentoring torapidly develop into an independent researcher. I am well-prepared to bypass the traditional post-doctoral phase becauseof my experience working on projects that span several levels of biological organization my leadership in internationalcollaborative projects mentorship of several undergraduate students strong publication record and my proven ability tocoordinate large-scale multi-disciplinary studies. The experience I have gained and my productivity during my graduatetraining surpasses what many scientists achieve during the first 35 years of post-doctoral training.

project_terms:
Address;Adjuvant;Affect;Alcoholic Beverages;Allergens;Allergic Disease;Archives;Arthropods;Asthma;Atopic Dermatitis;Award;Bacteria;Bedbugs;Beds;Behavior;Biological;Biology;Biotechnology;Blood;Bypass;Canis familiaris;Cell Culture Techniques;Characteristics;Chemicals;Chronic;Communities;Defecation;Deposition;Dermal;Development;Disadvantaged;Dust;Educational process of instructing;Eligibility Determination;Entomology;Environmental Health;Environmental Pollution;Environmental Risk Factor;Epidemiology;Exposure to;Extrinsic asthma;Faculty;Fecal analysis procedure;Feces;Fishes;Food;Funding;Health;Health Care Costs;Histamine;Histamine Production;Home;House Dust;Human;Hygiene;Hypersensitivity;Hypersensitivity skin testing;Immune response;Indoor environment;Inflammation;Infrastructure;Ingestion;Institution;International;Leadership;Life;Location;Low income;Mass Fragmentography;Mentors;Mentorship;Microbe;Mus;National Institute of Environmental Health Sciences;Outcome;Personal Satisfaction;Phase;Postdoctoral Fellow;Prevalence;Productivity;Pruritus;Public Health;Publications;Quality of life;Reaction;Research;Research Personnel;Research Support;Risk;Risk Factors;Sampling;Science;Scientist;Skin;Source;Spatial Distribution;Testing;Training;United States;United States National Institutes of Health;Universities;Vasodilation;Wages;air sampling;allergic response;asthmatic;career;clinical effect;clinically relevant;cohort;cost;dermal exposure;environmental toxicology;experience;exposed human population;feeding;gut microbiome;inner city;innovation;interdisciplinary approach;multidisciplinary;neuroregulation;post-doctoral training;programs;residence;respiratory;rho;stem;undergraduate student

public_health_relevance:
Allergies affect more than 50 million people in the United States with estimates of health costs exceeding$18 billion annually. Central to combatting allergic disease and asthma are efforts to understand theenvironmental risk factors that induce allergic responses. This project stemming from my recentdiscovery that bed bugs disseminate large amounts of histamine in their feces will comprehensivelydocument the prevalence and distribution of histamine in homes infested with bed bugs and determinethe risks of exogenous histamine exposure to human health both of which are critical to promote humanhealth and well-being in the indoor environment.


application_id: 10246871
project_number: 5U01AA026225-05
project_title: 2/2 Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV)
administering_ic: NIAAA
award_notice_date: 2021-09-03
opportunity_number: RFA-AA-17-014
application_type: 5
activity_code: U01
ic: AA
serial_number: 026225
program_official: WANG, JOE
project_start_date: 2017-09-22
project_end_date: 2022-08-31
study_section: ZAA1-DD(14)V
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COOK, ROBERT L
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Heavy alcohol drinking and HIV-1 infection are independently associated with the development ofabnormalities in the brain function and cognition and increasing evidence indicates that the combinatorialeffects of HIV infection and alcohol are likely to worsen these abnormalities. Significantly both HIV- 1 infectionand chronic alcohol abuse cause alterations in gut microbiome (dysbiosis) and increase intestinal permeabilityand microbial translocation (MT) which are major pathogenic factors driving local and systemic inflammation.The dysbiosis is characterized by loss of gut bacterial biodiversity a reduction in beneficial bacteria and/or anexpansion of harmful or pro-inflammatory bacteria. However there is limited understanding of (i) the interactiveeffects of heavy alcohol drinking and HIV-1 infection on gut dysbiosis and (ii) the longitudinal qualitative(microbial membership) and quantitative (relevant abundance) determinants of dysbiosis. The current proposaladdresses these gaps with an overall goal to promote the development of rational therapies targeting gutdysbiosis. Accordingly we pursue a unifying hypothesis that in HIV-infected individuals heavy alcohol usecompounds gut dysbiosis and consequent peripheral immune inflammation leading to exacerbation of neuro-inflammation and cognitive dysfunction. To test these hypotheses we will enroll 100 HIV+ participants from30-to-90-day challenge Florida SHARC study (AA020797). This is a funded prospective cohort study in whichenrolled heavy drinkers are challenged to stop drinking for 30 to 90 days assisted by contingencymanagement (CM) payments and motivational interviewing. This application Alcohol associatedComorbidities and Microbiome Evaluation in HIV (ACME HIV 2/2) leverages the existing resources of30-to-90-day challenge Florida SHARC study: participant recruitment measures of alcohol consumptionbiospecimen and biomarker collection; expertise in alcohol HIV and neuroimaging. New data include:longitudinal changes in gut dysbiosis correlative changes in peripheral inflammation and measures ofcognition and neuroinflammation. In response to RFA-AA-17-014 we will partner with the St. PETER HIVstudy (ACME HIV 1/2) to corroborate our findings in Aims 1 and 2 and to conduct combined cross-cohortanalyses. We will complete the following Specific Aims among HIV+ heavy drinkers: AIM 1: To assesslongitudinal qualitative and quantitative changes in the gut microbiome (dysbiosis) associated with very heavyalcohol consumption. AIM 2: To determine the impact of HIV infection and alcohol abuse induced gut dysbiosison intestinal permeability microbial translocation (MT) and resultant peripheral endotoxemia immuneactivation and inflammation. AIM 3: To investigate the impact of dysbiosis and peripheral inflammation ondevelopment of neuro-inflammation and cognitive function. Completion of these aims will lay groundwork for anintervention targeting alcohol-associated dysbiosis which could profoundly reduce inflammation and improvecognitive functions in HIV+ heavy drinkers.

project_terms:
16S ribosomal RNA sequencing;Address;Adverse effects;Alcohol abuse;Alcohol consumption;Alcoholic beverage heavy drinker;Alcohols;Automobile Driving;Bacteria;Bacterial Genes;Behavior assessment;Biodiversity;Biological Markers;Brain;Chronic;Clinical Research;Cognition;Cognitive;Cohort Analysis;Cohort Studies;Collection;Data;Development;Endotoxemia;Enrollment;Evaluation;Evaluation Studies;Florida;Functional disorder;Funding;Goals;HIV;HIV Infections;HIV-1;Heavy Drinking;Immune;Impaired cognition;Impairment;Individual;Infection;Inflammation;Inflammatory;Intervention;Intestinal permeability;Link;Longitudinal Studies;Measures;Neurobiology;Neurocognitive;Neurocognitive Deficit;Outcome;Participant;Pathogenesis;Pathogenicity;Pathologic;Patient Recruitments;Peripheral;Phylogeny;Prospective cohort study;Research;Resolution;Resources;Role;Sample Size;Shotguns;Structure;Taxonomy;Testing;Virulence Factors;alcohol effect;alcohol measurement;alcohol research;clinically relevant;cognitive function;cognitive performance;cognitive testing;combinatorial;comorbidity;contingency management;cooking;drinking;dysbiosis;gut dysbiosis;gut microbiome;gut microbiota;gut-brain axis;immune activation;improved;metagenomic sequencing;microbial;microbial community;microbiome;microbiome alteration;microbiota;motivational enhancement therapy;neuroimaging;neuroinflammation;outcome prediction;payment;preclinical study;prospective;relating to nervous system;response;systemic inflammatory response;targeted treatment;whole genome

public_health_relevance:
The goal of this proposal is to investigate the effects of heavy alcohol drinking on intestinal microbiota and gutbarrier dysfunction with consequent peripheral inflammation which ultimately worsen neurocognitive functionsin HIV-1 infected individuals.


application_id: 10246154
project_number: 5T03OH010637-08
project_title: The Environmental Health Science Program at Western Kentucky University
administering_ic: NIOSH
award_notice_date: 2021-06-01
opportunity_number: PAR-15-352
application_type: 5
activity_code: T03
ic: OH
serial_number: 010637
program_official: MAPLES, ELIZABETH
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: ZOH1-NXT(02)
contact_pi_person_id: 14375391
contact_pi: TAYLOR, RITCHIE DON
other_pis: Not Applicable
congressional_district: 02
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe Environmental Health Science (EHS) degree program at Western Kentucky University (WKU) is acomprehensive program built upon education and training in basic and applied sciences. The overalleducational objective is to provide students the opportunity to develop a comprehensive understanding of thechemical biological physical and social factors or stressors in the occupational and natural environments thatimpact public health. Because of the interdisciplinary nature of the program the core EHS faculty collaborateon research within the program and with other academic disciplines departments and programs both within theinstitution and externally. A core component of the program is engagement of faculty and students in researchand/or practice experiences with an environmental and occupational health science focus.The courses offered are designed to meet the general requirements for evaluating workplace andenvironmental hazards by anticipating recognizing evaluating and controlling stressors or factors that mayaffect the health comfort or productivity of workers and the general public. This program responds to needsidentified by our advisory committee members area industries consultants and administrators and isconsistent with the existing inventory of classroom courses and laboratory courses offered at WKU. Thesuccess of graduates employed as occupational safety and health specialists environmental health and safetyspecialists industrial hygienists and in closely related fields has established the credibility of the institution tooffer this curriculum.The National Institute for Occupational Safety and Health (NIOSH) Training Project Grant (TPG) at WKU hasspecific objectives to enhance occupational safety and health and related training through the EHS degreeprogram. Primary long-term objectives are to support recruitment of students provide training andprofessional development opportunities advance the environmental and occupational health science field inKentucky and beyond and enhance the diversity of students in the program.Specifically the program will provide stipends in the form of tuition scholarships to train six (6) students ormore each project annum for the 5 year project period. Training though the EHS curriculum will allow studentsin the TPG to graduate with an environmental and occupational health degree. A broad goal of the TPG is toattract and retain minority students. The EHS program has seen an increase in minority student enrollmentsboth African American and Hispanic students; however the relative percentage of minority students in theprogram is low. The administrators of WKUs TPG believe that it is important to continue to be diligent andinnovative in expanding opportunities for minorities to enter the EHS field. NIOSH TPG sponsorship of theWKU EHS Program will ensure opportunities and training that will promote expertise in the EHS field for thepeople of Kentucky and this region so they may be adequately represented in local state and national jobs.

public_health_relevance:
Public Health Relevance StatementThe Environmental Health Science (EHS) program prepares students with a strong foundation in appliedphysics chemistry biology and mathematics that lead to the development of skills that can be utilized in avariety of public health settings. EHS program graduates have become environmental and occupational healthscience professionals protecting public health across Kentucky the region and the nation.


application_id: 10245119
project_number: 5UH3CA233282-04
project_title: (ACCSIS) Accelerating Colorectal Cancer Screening through Implementation Science in Appalachia
administering_ic: NCI
award_notice_date: 2021-08-19
opportunity_number: RFA-CA-17-038
application_type: 5
activity_code: UH3
ic: CA
serial_number: 233282
program_official: GRIMES, GENEVIEVE M
project_start_date: 2018-09-19
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-N(52)R]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: PASKETT, ELECTRA D.
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Modified Project Summary/Abstract SectionThis multi-site project aims to increase screening and follow-up for colorectal cancer (CRC) in central Appalachia a medically underserved region recognized as one of three distinct hotspots for CRC mortality. Specifically the Appalachian Regional Commission classifies 32 eastern Ohio (OH) counties and the 54 counties in eastern Kentucky (KY) as north central and central Appalachia respectively. CRC incidence and mortality rates in the area are among the highest in the nation and neither state meets the national target of 80% of eligible residents screened for CRC. There have been few randomized intervention trials addressing multiple levels of influence on CRC screening behaviors and outcomes in this region. To address this gap investigators at the University of Kentucky and The Ohio State University will build on a 12-year collaborative history strong relationships with Appalachian communities and health clinics and extensive experience with community-based cancer prevention and control intervention research to develop implement and evaluate a multilevel intervention (MLI)  adapted from evidence-based interventions that include components targeting clinics and providers (in-reach) and the community (outreach)  to increase CRC screening follow-up and referral-to-care among patients age 50-74 in 12 counties in Appalachian KY and OH. The overall goals of this project are to contribute to the evidence-base for a MLI that increases rates of CRC screening follow-up and referral-to-care particularly in rural medically underserved populations and help showcase best practices for how MLIs can be scaled-up to reduce the burden of CRC in the U.S. For the Planning-Exploratory Phase (UG3) in Year 1 our specific aims are to: 1) Pilot test measure and refine a MLI to increase rates of CRC screening follow-up and referral-to-care in Appalachian OH and Appalachian KY; and 2) Provide evidence supporting transition to the Implementation Phase (UH3) [per NCI approval]. For the Implementation Phase (UH4) in Years 2-5 our specific aims are to: 1) Test the revised MLI in a group randomized trial delayed intervention to assess the impact of the MLI on increasing rates of CRC screening follow-up and referral-to-care among Appalachian KY and Appalachian OH populations; and 2) Assess dissemination and sustainability of the intervention. The project will be implemented in collaboration with community and clinical partners in 12 counties 6 in Ohio and 6 in Kentucky. Counties will be randomized to early or delayed intervention after baseline data collection. The main outcome will be CRC screening as defined by US Preventive Services Task Force guidelines and measured by clinic electronic health records and county- level behavioral assessments using random digit dialed telephone surveys similar to CDCs Behavioral Risk Factor Surveillance System. Our work will be accomplished through collaboration with the ACCSIS Coordinating Center other ACCSIS Research Projects ACCSIS Steering Committee and Workgroups NCI and community partners. If effective this MLI will be disseminated to our clinical and community partners throughout Appalachia.

project_terms:
Address;Administrator;Advisory Committees;Age;Appalachian Region;Area;Area Health Education Centers;Behavior assessment;Behavioral Risk Factor Surveillance System;Cancer Control;Caring;Centers for Disease Control and Prevention (U.S.);Characteristics;Clinic;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Health;Community Health Systems;Community Outreach;County;Data Collection;Digit structure;Disease;Electronic Health Record;Evidence based intervention;Fright;Geography;Goals;Guidelines;Health;Health Care Costs;Health Personnel;Incidence;Intervention;Intervention Studies;Intervention Trial;Kentucky;Knowledge;Life;Link;Localized Malignant Neoplasm;Low Income Population;Measures;National Cancer Institute;Neighborhood Health Center;Ohio;Outcome;Patients;Phase;Play;Population;Poverty;Preventive care;Preventive service;Provider;Public Health;Randomized;Recording of previous events;Research;Research Personnel;Research Project Grants;Role;Rural;Rural Appalachia;Rural Community;Savings;Site;Source;Surveys;System;Telephone;Testing;Trust;Underserved Population;United States;Universities;Work;base;behavioral outcome;cancer education;cancer health disparity;cancer prevention;colorectal cancer screening;community clinic;community organizations;effective intervention;evidence base;experience;follow-up;health care availability;health care delivery;implementation science;improved;interest;medically underserved;medically underserved population;mortality;randomized trial;safety net;scale up;screening;underserved area;uptake


application_id: 10242785
project_number: 5F30HL143943-03
project_title: Mechanisms of renin angiotensin modulation in thoracic aortic aneurysms
administering_ic: NHLBI
award_notice_date: 2021-08-18
opportunity_number: PA-18-673
application_type: 5
activity_code: F30
ic: HL
serial_number: 143943
program_official: MEADOWS, TAWANNA
project_start_date: 2019-09-01
project_end_date: 2022-05-14
study_section: Special Emphasis Panel[ZRG1-F10A-R(20)L]
contact_pi_person_id: 14923219
contact_pi: CHEN, JEFF ZHEYING
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Thoracic aortic aneurysms (TAAs) are a common clinically-silent dilatation of the aorta. Howevercomplications of this disease - such as aortic dissection and rupture - are sudden and deadly. Because there iscurrently no validated medical therapy to prevent or reverse aortic dilation all patients with thoracic aorticaneurysms will eventually need surgical repair. Marfan syndrome is caused by mutations in fibrillin-1 a large extracellular matrix protein responsible forelastin structure and aortic integrity. Our project proposes the use of Marfan syndrome model mice toinvestigate the pathogenesis of TAAs. We have shown that TAAs occur in an angiotensin receptor (AT1areceptor) dependent manner. How AT1a receptors are activated in Marfan syndrome is a gap in currentknowledge. AT1a receptors are canonically activated by its main effector peptide angiotensin II. It can also beactivated in a ligand independent manner. We hypothesize that AT1a receptors in Marfan syndrome areactivated in an AngII dependent manner. Furthermore we hypothesize that depletion of endogenous AngIIsufficiently attenuates TAA development in Marfan syndrome through inhibition of AT1a receptor activity. To test this hypothesis we will determine if AngII depletion by angiotensinogen antisenseoligonucleotide administration attenuates aortic dilation aortic medial remodeling and aortic AT1a receptoractivity. We will also perform a retrospective clinical study using a large electronic health record dataset todetermine if inhibition of AngII formation angiotensin receptor blockade or beta-blockade are associated withprotection against TAA in Marfan syndrome patients. Altogether completion of this project will provide a better understanding of the molecular mechanismbehind Marfan syndrome associated thoracic aortic aneurysm pathogenesis.

project_terms:
3-Dimensional;Angiotensin II;Angiotensin Receptor;Angiotensin Type 1a Receptor;Angiotensin-Converting Enzyme Inhibitors;Angiotensinogen;Angiotensins;Antisense Oligonucleotides;Aorta;Aortic Rupture;Attenuated;Binding;Bioinformatics;Breeding;Cardiomyopathies;Clinical;Clinical Research;Collagen;Communication Research;Confocal Microscopy;Data;Data Set;Databases;Deposition;Development;Dilatation - action;Dilated Cardiomyopathy;Dimensions;Disease;Dissection;Elastin;Electron Microscopy;Electronic Health Record;Enzyme Inhibition;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;FBN1;Genetic;Goals;Growth;Half-Life;Health;Hemorrhage;Human;Knowledge;Ligands;Losartan;MADH2 gene;MAPK3 gene;Marfan Syndrome;Matrix Metalloproteinases;Measurement;Measures;Mechanics;Medial;Medical;Modeling;Molecular;Mus;Mutation;Nitric Oxide;Operative Surgical Procedures;Pathogenesis;Patients;Peptides;Peptidyl-Dipeptidase A;Pharmaceutical Preparations;Pharmacology;Phosphorylation;Plant Roots;Process;Production;Publishing;RNA Interference;Receptor Activation;Renin;Reporting;Research Ethics;Risk;Rupture;Signal Transduction;Specificity;Stretching;Structure;Sudden Death;Testing;Thoracic Aortic Aneurysm;Training;Transforming Growth Factor beta;Ultrasonography;Vascular Smooth Muscle;Visualization;base;extracellular;inhibitor/antagonist;mortality;mouse model;prevent;protective effect;receptor;repaired;transdifferentiation

public_health_relevance:
PROJECT NARRATIVEThoracic aortic aneurysms greatly increase the risk of sudden death by aortic rupture followed with rapidinternal bleeding. Currently there is no validated medical therapy to treat thoracic aortic aneurysms.Uncovering the key processes which drive thoracic aortic aneurysm formation is critical for identifying targetsthat can modulate this disease.


application_id: 10242747
project_number: 5R21EY030225-02
project_title: Novel function of beta-catenin in regulation of RPE basal membrane
administering_ic: NEI
award_notice_date: 2021-08-18
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: EY
serial_number: 030225
program_official: NEUHOLD, LISA
project_start_date: 2020-09-01
project_end_date: 2022-08-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 8875628
contact_pi: LU, QINGXIAN
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe RPE acts as a blood outer retinal barrier transporting nutrients from the choroid circulation to adjacentphotoreceptors. Apical microvilli on the RPE are critical for interdigitating interaction with photoreceptor outersegments. The basal membrane of the RPE differentiates into a heavily folded plasma membrane system toform a specialized organelle called basal infolding. These infoldings dramatically increases the surface area toenhance diffusion and transporter-assisted flux of solutes factors nutrients and metabolites. How the infoldingarises and its potential relevance to RPE biology has not been explored. In preliminary results we demonstratethat this infolding is mediated by -catenin in a complex with N- and P-cadherins/-catenin and cytoplasmic -catenin is required for the integrity of basal membrane infolding. We hypothesize that the increase in surfacearea resulting from membrane infolding is critical for efficient nutrient transport. Similar membrane infoldingincreases surface area at the blood brain barrier the intestinal lumen and kidney tubules that serve as a blood-urine barrier. Consistent with functional inhibition of nutrient transport mouse -catenin mutants showshortening of adjacent photoreceptor outer segments which depend upon nutrients transported through theRPE. In this proposal we will test whether the -catenin/cadherin complex stabilizes the RPE basal infoldingsfor maintaining the basal infolding integrity and ensuring efficient transport of nutrients and metabolites acrossthe RPE barrier. Inadequate metabolic support from RPE has been linked to several aspects of age-relatedmacular degeneration as have mutations in P-cadherin and -catenin. As such the -catenin conditionalknockout mouse represents an important model to study the etiology and pathogenesis of RPE dystrophy andretinal degeneration. Our study will provide a novel mechanism for the integrity of RPE basal infoldings and itsrelevance to RPE function which may give insight into the pathogenesis of RPE dystrophy and AMD evensome of renal diseases.

project_terms:
Active Biological Transport;Adhesions;Adolescent;Adult;Affect;Age related macular degeneration;Aging;Animals;Antibodies;Antibody Specificity;Apical;Area;Basal lamina;Biology;Blood;Blood - brain barrier anatomy;Blood Circulation;Bruch's basal membrane structure;Butterflies;Cadherins;Cell membrane;Cell-Matrix Junction;Cells;Choroid;Complex;Data;Defect;Diffusion;Disease;Ectodermal Dysplasia;Electron Microscopy;Electroretinography;Ensure;Epithelial Cells;Etiology;Eye diseases;Face;Functional disorder;Glucose;Glucose Transporter;Histologic;Human;Hypotrichosis;Intestines;Iron;Kidney Diseases;Knock-out;Knockout Mice;Lateral;Lead;Link;Liquid substance;Mediating;Membrane;Metabolic;Modeling;Molecular;Morphology;Mus;Mutation;N-Cadherin;Nutrient;Organelles;P-Cadherin;Pathogenesis;Pathogenicity;Pathology;Pathway interactions;Patients;Pattern;Phenotype;Photoreceptors;Pigments;Play;Regulation;Renal tubule structure;Retina;Retinal Degeneration;Retinitis Pigmentosa;Role;SHFM1 gene;SLC2A1 gene;Source;Stains;Stratum Basale;Surface;Swelling;Symptoms;Syndrome;System;Testing;Time;Tissues;Urine;Vision;Work;alpha catenin;base;beta catenin;cell type;cellular microvillus;conditional knockout;corneal epithelium;glucose uptake;innovation;insight;macular dystrophy;mutant;novel;null mutation;receptor;recruit;renal epithelium;solute

public_health_relevance:
NARRATIVERPE polarity and integrity are essential for retina tissue organization and visual function. Deletion of -cateninfrom adult RPE disrupts RPE basal infolding and cell-matrix adhesions causing RPE detachment fromunderlying basal lamina. This innovating work allows us developing a model for further studying etiology andpathogenic mechanisms for many types of RPE dysfunction related eye diseases.


application_id: 10242623
project_number: 5R01AG061065-04
project_title: Role of Gut Microbial Dysbiosis and Aging on HIV-associated neurocognitive and brain dysfunction
administering_ic: NIA
award_notice_date: 2021-05-25
opportunity_number: RFA-AG-18-023
application_type: 5
activity_code: R01
ic: AG
serial_number: 061065
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2018-09-30
project_end_date: 2023-05-31
study_section: ZAG1-ZIJ-U(A1)
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COHEN, RONALD A;COOK, ROBERT L
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Although AIDS-defining illnesses have decreased the prevalence of HIV-associated non-AIDS conditions suchas HIV-Associated Neurocognitive Disorders (HAND) remains high and is estimated to be over 50%particularly in aging individuals with long-standing HIV infection. However the pathophysiology of HAND inaging HIV+ adults remains unresolved. Current evidence and our preliminary data suggest that interactionsof altered gut microbiome (dysbiosis) gut-derived microbial translocation and systemic inflammationcontribute to neurodegenerative processes. It is becoming increasingly evident that in both HIV-1 infection andaging alterations in gut microbiome (dysbiosis) and ensuing increase in intestinal permeability and microbialtranslocation (MT) are major pathogenic drivers of local and systemic inflammation. Importantly aging-associated microbiota changes are shown to be connected to immunosenescence and inflammaging.Preclinical/clinical studies using bacterial 16S ribosomal RNA (rRNA) gene sequencing indicate that microbialdysbiosis associated with HIV-1 infection or aging has several common pathogenic features. However thesestudies were largely hypothesis-generating with limited sample sizes and were not adequately powered toaddress microbiome endpoints after correction for multiple testing and did not reveal the functional potential ofthe microbiota (pathogenic or beneficial) or yield bacterial resolution to species or strain level. The currentproposal will address these limitations by using an adequately powered longitudinal study and will conduct 16SrRNA gene and Whole Genome Shotgun (WGS) metagenomic sequencing that will determine bacterialcomposition and diversity provide identification at the species and strain level and enable the functionalcharacterization of the bacterial genes. Our overarching hypothesis is that the interactive effects of agingand HIV-1 infection at the level of gut dysbiosis and permeability and ensuing local and systemicinflammation play a major pathogenic role in driving HIV infection and aging-associatedneuroinflammation and cognitive dysfunction. To test these hypotheses we will leverage and utilize HIV+and healthy aging populations from ongoing NIH-sponsored longitudinal studies at the Universities of Louisville(UofL) and Florida (UF) with the following specific aims: Aim 1: To assess longitudinal qualitative andquantitative changes in the gut microbiome (dysbiosis) in older persons living with HIV-1 infection.Aim 2: To determine the impact of HIV-1 infection and age associated gut dysbiosis on (A) intestinalpermeability and microbial translocation (MT) and resultant peripheral endotoxemia andinflammation; and (B) multimodal MRI/MRS measures of neuroinflammation and cerebral metabolicdisturbance. Aim 3: To investigate the impact of gut dysbiosis and peripheral and neuroinflammationand cerebral metabolic disturbance on cognitive dysfunction and functional brain abnormalities (FMRI)relative to age and HIV status.

project_terms:
16S ribosomal RNA sequencing;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Automobile Driving;Bacterial Genes;Brain;Cerebrum;Clinical Research;Cognitive aging;Data;Diffusion Magnetic Resonance Imaging;Elderly;Endotoxemia;Florida;Functional disorder;Goals;HIV;HIV Infections;HIV-1;HIV-associated neurocognitive disorder;Impaired cognition;Individual;Infection;Inflammaging;Inflammation;Intestinal permeability;Longitudinal Studies;Magnetic Resonance;Magnetic Resonance Imaging;Measures;Metabolic;Nerve Degeneration;Neurocognitive;Neuropathogenesis;Pathogenicity;Peripheral;Phylogeny;Play;Population;Prevalence;Process;Resolution;Rest;Role;Sample Size;Serum;Severities;Shotguns;Structure;Taxonomy;Testing;United States National Institutes of Health;Universities;White Matter Hyperintensity;age effect;alcohol research;base;brain abnormalities;brain dysfunction;cognitive function;cooking;cytokine;dysbiosis;gut dysbiosis;gut microbiome;gut-brain axis;healthy aging;immune activation;immunosenescence;metagenomic sequencing;microbial;microbial community;microbiome;microbiome alteration;microbiota;multimodality;neuroinflammation;pre-clinical;rRNA Genes;systemic inflammatory response;white matter;whole genome

public_health_relevance:
The goal of this proposal is to conduct collaborative studies to understand the gut-brain relationship in olderpersons living with HIV-1 infection. The study will examine the role of gut-driven mechanisms on HIV-associated Neurocognitive Disorders (HAND) in the aging HIV+ population.


application_id: 10241542
project_number: 5UG1OD024954-04
project_title: The Kentucky ECHO Pediatric IDeA Research Center (KE-PIRC)
administering_ic: OD
award_notice_date: 2021-08-24
opportunity_number: RFA-OD-19-026
application_type: 5
activity_code: UG1
ic: OD
serial_number: 024954
program_official: RAJU, TONSE N
project_start_date: 2016-09-23
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-J(51)R]
contact_pi_person_id: 14437890
contact_pi: WATSON, SARA E
other_pis: DEVLIN-PHINNEY, LORI ANN
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Academic Medical Centers;Address;Adolescent;Adult;Airway Disease;Alcohol consumption;Appalachian Region;Area;Child;Child Health;Child health care;Childhood;Chronic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Development;Diabetes Mellitus;Disease;Drug abuse;Education;Educational Status;Environmental Health;Etiology;Faculty;Family;Family Physicians;Feedback;Fetal Development;Funding;Generations;Goals;Health;Health Benefit;Healthcare;Heart Diseases;High Prevalence;Individual;Infant;Institution;Intervention;Kentucky;Leadership;Malignant neoplasm of lung;Mentors;Mentorship;Multi-Institutional Clinical Trial;Neonatal;Neurologist;Obesity;Outcome;Participant;Patients;Pediatric Hospitals;Physicians;Population;Population Heterogeneity;Preventive;Primary Health Care;Process;Provider;Refugees;Research;Research Infrastructure;Research Personnel;Resources;Rural;Rural Community;Rural Population;Scientist;Site;Smoking;Stroke;System;Talents;Teacher Professional Development;Time;Training;Training and Education;Underrepresented Minority;Underserved Population;United States National Institutes of Health;Universities;Urban Community;Vulnerable Populations;Work;Workplace;autism spectrum disorder;biomedical referral center;care outcomes;career;cohort;community engagement;community partnership;ethnic minority population;fetal;improved;innovation;member;next generation;novel strategies;nutrition;outreach program;patient population;pediatrician;postnatal;programs;racial minority;recruit;rural area;rural underserved;senior faculty;skills;success;underserved area;urban underserved


application_id: 10241441
project_number: 5R00ES028748-05
project_title: Phthalate-Induced Ovulatory Dysfunction in Women
administering_ic: NIEHS
award_notice_date: 2021-08-19
opportunity_number: PA-16-193
application_type: 5
activity_code: R00
ic: ES
serial_number: 028748
program_official: SCHUG, THADDEUS
project_start_date: 2019-09-02
project_end_date: 2023-08-31
study_section: NSS
contact_pi_person_id: 12252020
contact_pi: HANNON, PATRICK RYAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThis K99/R00 award will prepare Dr. Patrick Hannon for an independent research career with the main goal ofproviding Dr. Hannon all the necessary technical and professional skills to transition into a career in academiaand become a leader in the field of reproductive toxicology. Dr. Hannon has extensive training in elucidatingthe effects of environmental toxicants on the ovary in rodent models but in this K99/R00 he will expand hisresearch training and translate these findings into human health and fertility. These goals will be accomplishedwith the support of Dr. Hannon's enthusiastic and exceptional mentoring team led by Drs. Thomas Curry andHumphrey Yao. The research proposal and career development plan created by Dr. Hannon with the guidanceof his mentoring team will provide Dr. Hannon with new experimental techniques and skills needed to establishan independent research program. In the research training component Dr. Hannon will elucidate the effectsand mechanisms by which phthalates a class of endocrine-disrupting chemicals impair ovulation and fertilityin humans and rodents. Women of reproductive age are exposed to phthalates on a daily basis becausephthalates are incorporated in a myriad of common consumer medical building and personal care products.However little is known about the effects of environmentally relevant levels of phthalates on ovulationespecially in humans. This is concerning because defects in ovulation are the leading cause of infertility inwomen. Preliminary data for this proposal are the first to show that an environmentally relevant phthalatemixture inhibits progesterone (P4) production and alters the mRNA levels of P4 receptor (PGR) prostaglandin-endoperoxide synthase 2 (PTGS2) and amphiregulin (AREG) following human chorionic gonadotropintreatment (hCG; analogous to the midcycle luteinizing hormone surge) in human and mouse ovarian cells. P4PGR PTGS2 and AREG are known mediators of ovulation. Thus these findings suggest that phthalateexposure may disrupt ovulation contributing to infertility. A primary human granulosa cell model and mice willbe utilized to test the hypothesis that phthalates adversely impact ovulatory processes by altering the levels ofovulatory mediators leading to impaired ovulation and fertility. Specific Aim 1 (Mentored Phase) will determinewhich ovulatory events are impaired by phthalate exposure. Specific Aim 2 (Mentored and IndependentPhases) will elucidate the mechanisms by which phthalates impair these ovulatory processes. Specific Aim 3(Independent Phase) will establish that phthalate exposure causes impaired ovulation and infertility in vivo.These findings will establish the impact of phthalates on female fertility and reproductive health while providingDr. Hannon the necessary research and professional skills for his academic career. Further the attainment ofa greater understanding of the mechanisms of action of phthalates in human samples will begin to provideavenues to intervene on phthalate-induced reproductive dysfunction and infertility.

project_terms:
Academia;Academic skills;Address;Age;Amphiregulin;Animal Model;Area;Award;Biological Assay;Cell model;Cells;Cosmetics;Data;Defect;Development Plans;Endocrine;Endocrine Disruptors;Event;Excipients;Exposure to;Female;Female infertility;Fertility;Fertility Disorders;Functional disorder;Gene Expression;Gene Proteins;Goals;Granulosa-Lutein Cells;Health;Healthcare;Human;Human Chorionic Gonadotropin;Impairment;In Vitro;Infertility;Intervention;Lead;Leukocytes;Literature;Luteinizing Hormone;Measurement;Mediating;Mediator of activation protein;Medical;Mentors;Messenger RNA;Methods;Modeling;Mus;Ovarian;Ovary;Ovulation;Phase;Plasticizers;Pregnant Women;Prevalence;Process;Production;Progesterone;Prostaglandin Production;Protein Analysis;Proteins;Public Health;Quality of life;Reproductive Health;Research;Research Proposals;Research Training;Rodent;Rodent Model;Sampling;Societies;Solvents;Techniques;Testing;Time;Tissues;Toxic Environmental Substances;Toxic effect;Toxicology;Training;Translating;Woman;analog;angiogenesis;base;career;career development;chemical group;cost;cyclooxygenase 2;exposed human population;female fertility;granulosa cell;human model;human tissue;in vivo;insight;migration;mouse model;novel;ovarian dysfunction;personal care products;phthalates;programs;receptor;reproductive;response;skills;urinary

public_health_relevance:
PROJECT NARRATIVEExposure to endocrine-disrupting chemicals is increasingly being recognized as a contributing factor to theprevalence of infertility in which defects in ovulation are the leading cause of infertility in women. Theproposed research will address this public health concern by providing a more complete understanding of howphthalates a class of endocrine-disrupting chemicals that humans are exposed to on a daily basis disruptovulation and fertility in humans. These findings will begin to establish novel treatment targets and interventionmethods for phthalate-induced reproductive dysfunction and infertility.


application_id: 10241254
project_number: 5UH3DA044798-05
project_title: Kentucky Communities and Researchers Engaging to Halt the Opioid Epidemic (CARE2HOPE)
administering_ic: NIDA
award_notice_date: 2021-07-22
opportunity_number: RFA-DA-17-014
application_type: 5
activity_code: UH3
ic: DA
serial_number: 044798
program_official: LEE-WINN, ANGELA EUNJI
project_start_date: 2017-08-15
project_end_date: 2024-07-31
study_section: ZDA1-HXO-H(18)R
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: COOPER, HANNAH LF
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: The proposed project will build evidence-based community-rooted public health responses to theepidemics of non-medical prescription opioid (NMPO) and heroin injecting overdoses (ODs) and HCV and toimminent HIV outbreaks in 12 rural Appalachian Kentucky counties at the epicenter of these intertwinednational crises. 10 counties rank in the top 5% for HIV/HCV vulnerability. Rates of HCV injection drug use(IDU) and ODs are high in these counties and most are in coal country an RFA priority. Unfortunately these counties exemplify an extreme version of the implementation chasm a chasmdividing scientific knowledge from action. Evidence-based public health responses to these epidemics exist(e.g. syringe service programs [SSPs]) and are often deployed in cities. In these 12 rural counties thoughscarcities of resources and of providers conspire with drug-related stigma to constrain public health responses.The counties' public health infrastructures are weak their harm reduction infrastructures virtually non-existent. This project will bridge the implementation chasm in these 12 counties and recognizes that bridging thischasm requires more than simply importing SSPs and other evidence-based community response projects(EB-CRPs) from cities. Guided by harm reduction principles the Risk Environment Model and Community/Academic Partnerships (CAPs) in the UG3 we will: (1) Assess and enhance each county's readiness toimprove the local risk environment. (2) Examine the strengths resources needs and gaps of each county'srisk environment. We will conduct a multi-method Community Assessment of the Risk Environment thatintegrates innovative rigorous epidemiology (e.g. modeling); policy assessment; and best practices incommunity-based research (e.g. CAPs). (3) Select a package of EB-CRPs that responds to local needs andstrengths using elements of Intervention Mapping. Go/no go milestone: Each CAP will have created an EB-CRP package that (1) addresses targets common across all counties (e.g. opioid injection OD HCV HIV)and (2) is tailored to local needs resources and readiness. In the UH3 we will: (4) Tailor selected EB-CRPs toeach county's context using ADAPT-ITT. (5) Analyze the effectiveness and cost-effectiveness of each county'sEB-CRP package using an innovative stepped-wedge community randomized trial and mathematical models.We will use continuous quality improvement to enhance each EB-CRP's fidelity reach immediate effects andoutcomes. To inform interventions advanced network analyses will overlay risk networks with GHOSTphylogenetic transmission data to show where HCV has been and predict where it is going. We draw strengthfrom our collaborations. CAPs will meld residents' local knowledge with researchers' scientific expertise. Multi-PIs Young and Cooper have assembled an academic team with unsurpassed expertise in key substancetheories and methods and in multisite studies. The combination of a rigorous innovative design (e.g. step-wedge community trials) strong theories and a stellar team with community roots will ensure high impact.

project_terms:
Address;Appalachian Region;Area;Behavioral;Caring;Centers for Disease Control and Prevention (U.S.);Cities;Coal;Collaborations;Communities;Community Trial;Country;County;Disease Outbreaks;Drug user;Effectiveness;Elements;Ensure;Environment;Epidemic;Epidemiologic Methods;Epidemiology;Evidence based intervention;General Population;HIV;HIV/HCV;Harm Reduction;Health;Health Services;Hepatitis C virus;Heroin;Incidence;Infrastructure;Injecting drug user;Injections;Intervention;Kentucky;Knowledge;Laws;Letters;Methods;Modeling;Naloxone;National Institute of Drug Abuse;Needle-Exchange Programs;Outcome;Overdose;Pathway Analysis;Pharmaceutical Preparations;Phylogenetic Analysis;Plant Roots;Policies;Prescription opioid overdose;Provider;Public Health;Qualitative Research;Readiness;Research Infrastructure;Research Personnel;Resources;Risk;Risk Assessment;Rivers;Rural;Rural Appalachia;Services;Site;Substance Use Disorder;Testing;United States Substance Abuse and Mental Health Services Administration;Unsafe Sex;Work;base;combat;community based research;cost effectiveness;data exchange;design;evidence base;implementation science;improved;infectious disease treatment;injection drug use;innovation;intervention mapping;mathematical model;member;misuse of prescription only drugs;opioid epidemic;opioid injection;prescription opioid;randomized trial;response;rural counties;social stigma;theories;virtual

public_health_relevance:
Narrative: The proposed project will employ community/academic partnerships to build effective evidence-based community-grounded public health responses to combat the intertwined epidemics of heroin and non-medical prescription opioid injecting overdoses and HCV and imminent HIV outbreaks in 12 of the hardesthit rural counties in the US. Located in Central Appalachian Kentucky 10 of the 12 counties are in the top 5%for HIV/HCV vulnerability in the US. Most counties are in coal country an RFA priority area.


application_id: 10240750
project_number: 5R01AI141889-04
project_title: Influenza D Virus Entry and Tissue Tropism
administering_ic: NIAID
award_notice_date: 2021-08-20
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 141889
program_official: BOZICK, BROOKE ALLISON
project_start_date: 2018-09-21
project_end_date: 2023-08-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8527363
contact_pi: LI, FENG
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Novel influenza D virus (IDV) utilizes bovines as a primary reservoir with periodical spillover toother mammalian hosts including pigs and horses. Of greater public health importance serologicalevidence of IDV infections in humans has been demonstrated. Preliminary investigations have revealedthat IDV binds to human 9-O-acetylated N-acetylneuraminic acid (Neu59Ac2) the receptor of humaninfluenza C virus (ICV) and non-human N-glycolylneuraminic acid (Neu5Gc9Ac) and likely utilizesthem for viral entry. Further functional studies indicate that IDV is more efficient in recognizing bothhuman Neu59Ac2- and non-human Neu5Gc9Ac-containing glycans than ICV and ICV seems topreferentially bind to human Neu59Ac2 over non-human Neu5Gc9Ac. In agreement with this ICV hasa limited host range with humans as a reservoir. These results suggest that IDV and ICV diverge incommunicating with sialic acids (SA) for infection. The hypothesis is that subtle differences in thesequence and structure of the receptor-binding pocket residing in the hemagglutinin-esterase-fusion(HEF) protein between IDV and ICV cause substantial differences in the virus-receptor interactionwhich can expand or reduce or change tissue and species tropisms. Furthermore the recentobservation on the extracellular resistance of IDV to low pH inactivation versus the intracellularrequirement of low pH for viral entry suggests a novel entry/fusion mechanism by which IDV employsto deliver its genome into the target cell. Three aims are proposed to address these hypotheses in thisR01 application which involve a comparative study of IDV and ICV. Aim 1 will elucidate the entrymechanism of IDV while Aim 2 will define the molecular basis of the HEF receptor binding affinity andspecificity and its impact on IDV tropism. Aim 3 is deigned to address how two IDV lineages swine andbovine read the glycan receptors differentially and how this information is transduced to differenttissue and species tropisms between these two groups of IDVs. In summary this proposal leverages theteam's expertise in IDV research and novel aspects of IDV-receptor interaction and entry to elucidatethe cross-species transmission mechanism of IDVs. Understanding molecular details of virus-receptorinteraction may lead to development of novel strategies for the control and prevention of IDV and ICVinfections in humans.

project_terms:
Acids;Address;Affinity;Agreement;Animals;Antiviral Agents;Asia;Binding;Biological;Carbon;Cattle;Cavia;Cells;Chimeric Proteins;Comparative Study;Data;Dependence;Development;Disease;Disease Outbreaks;Distant;Endocytosis;Equus caballus;Europe;Family suidae;Ferrets;Genetic;Genome;Health;Human;Immunity;Infection;Influenza;Influenza A virus;Influenza C Virus;Influenza D Virus;Influenza prevention;Investigation;Lead;Light;Membrane Fusion;Molecular;Mutation;N-Acetylneuraminic Acid;N-glycolylneuraminic acid;Oklahoma;Pathway interactions;Periodicals;Polysaccharides;Positioning Attribute;Public Health;Research;Research Priority;Resistance;Ruminants;Serology;Sialic Acids;Specificity;Structure;Tissues;Tropism;Vaccines;Viral;Viral Genome;Virus;Virus Diseases;Virus Receptors;Work;Zoonoses;base;chemical group;cross-species transmission;extracellular;hemagglutinin esterase;influenzavirus;insight;novel;novel strategies;preference;receptor;receptor binding;sialic acid receptor;tissue tropism;trait;virus tropism

public_health_relevance:
Project Narrative Influenza D is a new type of influenza virus with bovines as a primaryreservoir that infects and causes influenza diseases in multiple mammalianspecies including swine and cattle. This proposal aims to understand the virus-receptor interaction and to address how this interaction impacts viralentry/fusion pathways and tissue/species tropism. The successful completion ofproposed work will offer novel insights to the cross-species transmissionmechanism of these newly discovered influenza D viruses from zoonoticreservoirs that will be critical to develop effective antiviral and vaccine strategiesagainst influenza D virus infection in humans and animals.


application_id: 10239531
project_number: 3OT2OD024898-01S4
administering_ic: OD
award_notice_date: 2020-09-10
opportunity_number: RFA-RM-15-018
application_type: 3
activity_code: OT2
ic: OD
serial_number: 024898
suffix: S4
program_official: QASHU, FELICIA M
project_start_date: 2017-09-20
project_end_date: 2021-08-31
study_section: Anatomical and Functional Mapping of the Innervation of Marjor Internal Organs[AFMI(53)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Functional Mapping with Lumbosacral Epidural Stimulation for Restoration of Bladder Function After Spinal Cord Injury

project_abstract:
The overall objective of this functional bladder mapping study is to identify the spinal cord epiduralstimulation (scES) configurations (anode/cathode selection amplitude frequency and pulse width) at thelumbosacral level that can promote neural control of bladder storage (capacity) and voiding efficiency afterspinal cord injury (SCI). This comprehensive functional mapping study in both humans and animals in parallelinvolves a novel clinical application of a marketed Medtronic device for bladder dysfunction after SCI. Themapping (human and animal) and training (human) experiments address several specific objectives of theSPARC Program initiative per RFA-RM-15-018 including neural circuit maps regarding functional connectivity(Aim 1) neural plasticity related to stimulation (bladder training experiments  Aim 2) variability (animal-to-animal and patient-to-patient) and research on what organ functions results from different types of stimulation(storage vs voiding and identifying any additional effects on bowel and/or sexual function). The long-term reduction in the cost to the health care system care givers and society would bedramatic. SCI results in impairments of locomotor sensory and autonomic functions severely affecting overallhealth and quality of life. Proper bladder management post-SCI is necessary to decrease the risk of upperurinary tract disease a major source of morbidity. Life-long urologic care is required for SCI individuals yetmost efforts treat symptoms but do not improve intrinsic function. Current therapies for bladder managementafter SCI include catheterization pharmacologic and surgical interventions functional electrical stimulation(peripheral) and urethral stents but all have deleterious effects. We have exciting data from multipleindividuals with severe injuries (AIS A and B) indicating improved bladder function after undergoing a widelyimplemented activity-based rehabilitation locomotor training (LT) which includes stepping using body weightsupport on a treadmill with manual facilitation. In addition we have intriguing preliminary data from severalcompletely paralyzed individuals receiving scES in combination with task specific training that recoveredstanding and voluntary movement and showed improvements in both bladder capacity and voiding efficiency.Our most recent pilot data also indicate an immediate benefit of scES alone on bladder function. Thus wepropose to determine the functional gains that can be achieved in the storage and voiding phases of lowerurinary tract function as a result of activation of spinal circuits with scES in humans with SCI and in a clinically-relevant rodent SCI model. We will test the general hypothesis that bladder capacity and voiding efficiencyincreases with scES post-SCI and to an even greater extent with scES bladder training over time. This proposal involves the collaboration of clinicians and scientists with extensive experience in animaland human SCI models. Our unique approach will utilize the expertise of a multi-disciplinary team (expertise inbladder function neuromodulation rehabilitation engineering and statistics) to 1) determine the optimalstimulation parameters for storage and voiding in SCI research participants already implanted with the scESMedtronic device (16-electrode array from L1-S1); 2) quantify the long-term effects of daily bladder trainingusing optimal stimulation parameters (all the same research participants); 3) measurement of secondarybenefits (bladder medication usage susceptibility to urinary tract infections indirect cardiovascular bowel andsexual function benefits) of long-term bladder training; and 4) address with a small animal model the impact oflocation lesion severity chronicity and gender. Our innovative approach and novel application of thisMedtronic Specify 5-6-5 device will allow us to determine specific types of scES needed for bladder functionwhich will lay the groundwork for expedient translation of this promising technique to larger numbers ofindividuals with SCI in the next phase of the SPARC initiative with additional refinement in parallel using alarge animal SCI model (pig) that is currently under development within the Kentucky Spinal Cord ResearchCenter.

project_terms:
Address;Affect;Animal Model;Animals;Anodes;Anti-Cholinergics;Anus;Autonomic Dysreflexia;Bladder;Bladder Control;Bladder Dysfunction;Body Weight;Cardiovascular system;Caregivers;Caring;Catheterization;Catheters;Cathodes;Chronic;Clinic;Clinical;Collaborations;Country;Data;Dependence;Development;Devices;Disease;Electrodes;Engineering;Family suidae;Feasibility Studies;Female;Foundations;Frequencies;Future;Gender;Goals;Health;Healthcare Systems;Human;Impairment;Implant;Increased frequency of micturition;Individual;Injury;Intervention;Intestines;Kentucky;Knowledge;Lead;Lesion;Life;Location;Locomotor training;Long-Term Effects;Lower urinary tract;Manometry;Manuals;Maps;Measurable;Measurement;Measures;Modeling;Morbidity - disease rate;Motor;Movement;Neuronal Plasticity;Operative Surgical Procedures;Organ;Paralysed;Participant;Patients;Peripheral;Pharmaceutical Preparations;Pharmacology;Phase;Physiologic pulse;Pilot Projects;Predisposition;Publications;Quality of life;Questionnaires;Rattus;Rehabilitation therapy;Research;Residual volume;Risk;Rodent;Safety;Scientific Advances and Accomplishments;Scientist;Sensory;Severities;Sex Functioning;Societies;Source;Specific qualifier value;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Stents;Techniques;Technology;Testing;Therapeutic;Time;Training;Translating;Translations;United States;Urethra;Urinalysis;Urinary tract infection;Urination;Urologic Diseases;Width;base;clinical application;clinically relevant;cohort;cost;diaries;dosage;experience;experimental study;functional electrical stimulation;functional gain;improved;innovation;life time cost;male;multidisciplinary;neural circuit;neuroregulation;novel;pressure;prevent;programs;restoration;severe injury;side effect;statistics;symptom treatment;treadmill;urinary;urologic;voltage;white matter

public_health_relevance:
Spinal cord injury (SCI) results in devastating effects on overall health and quality of life. TheChristopher and Dana Reeve Foundation have recently estimated that 1275000 people areliving with paralysis from SCI in the United States alone. This country could save an estimated$400 billion on direct and indirect lifetime costs if we can find ways to treat and prevent SCI.Bladder dysfunction affects daily life reduces quality of life and results in numerous life-longhealth complications. Improvements in bladder function have been recently discovered in SCIsubjects while they are undergoing an efficacious rehabilitation intervention activity-basedlocomotor training (LT). In addition multiple individuals with motor complete SCI who havereceived epidural stimulation in combination with LT also have significant improvements inbladder function. This proposal is an early feasibility study in a small number of subjects for anovel clinical application (bladder dysfunction after SCI) of a marketed Medtronic device (initialclinical safety and device functionality study). A parallel animal study will also be done. Theoverall objective of this study is to demonstrate that lumbosacral epidural stimulation may be aviable therapeutic strategy for improving storage (continence) and urination (voiding) after SCI.The knowledge gained from our innovative application of an existing stimulation device maylead to the translation and immediate application to a larger cohort of SCI individuals andprovide immense improvements in quality of life.


application_id: 10239310
project_number: 3R01DA033862-08S1
project_title: Assessing Care in the Context of an HIV Outbreak among PWID in Appalachia
administering_ic: NIDA
award_notice_date: 2021-08-12
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: DA
serial_number: 033862
suffix: S1
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2012-09-01
project_end_date: 2022-11-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT FROM PARENT AWARDThe overarching goal of this renewal application (R01DA033862) is to determine the influence of structuralinterventions on engagement in risk reduction and health promotion activities among rural Appalachian drugusers. Results from the three-year R01 that the investigators seek to continue reveal an ever-changinglandscape of prescription drug abuse; an epidemic that is still in its infancy. Unlike many rural and suburbanareas there is little evidence for the transition to heroin abuse. In this cohort there has been a marked shiftfrom abuse of OxyContin (extended-release oxycodone) to immediate release oxycodone to more recentlybuprenorphine and gabapentin-containing products. In addition rates of HCV prevalence and incidence arehigh especially given the population density of rural Appalachia. Given the syndemic of opioid abuse andinfectious disease transmission two structural interventions are particularly relevant to this population of ruralpeople who use drugs (PWUD). Medicaid (MC) expansion (under the Affordable Care Act [ACA]) and syringeaccess programs (SAP) are two structural interventions that may allow for increased engagement in healthpromotion among PWUD but are likely heavily influenced by individual network and community-level factors.Utilizing Latkins Dynamic Social Systems model and leveraging the extant highly successful cohort of ruralPWUD the aims include: 1) examining how dynamic factors of these structural interventions influencelongitudinal trends in illicit and prescription drug abuse; 2) determining the influence of these structuralinterventions on HIV/HCV incidence and engagement in risk reduction; and 3) assessing the influence of thesestructural interventions on uptake of substance abuse treatment. This study is highly significant given thatunderstanding the mechanisms by which these specific structural interventions influence health promotion iskey to improving public health in rural Appalachia. Substance abuse and HCV are two of the most important ifnot the most important health issues facing this region already plagued with marked health disparities. Usinginnovative measures of network and geospatial risk as well as conjoint analysis and multilevel longitudinalstatistical models results will not only inform development of interventions that optimize uptake and utilizationof risk reduction services such as SAP and substance abuse treatment but may inform policies surroundingfurther implementation of health promotion programs in the rural U.S.

project_terms:
Address;Adherence;Affordable Care Act;Appalachian Region;Area;Award;Biological Models;Biological Testing;Buprenorphine;Caring;Categories;Clinical;Code;Cohort Studies;Communicable Diseases;Communities;County;Data;Data Collection;Development;Disease;Disease Outbreaks;Disease Outcome;Drug usage;Drug user;Epidemic;Goals;HIV;HIV Seropositivity;HIV risk;HIV/HCV;Health;Health Personnel;Health Promotion;Health Resources;Health Services Accessibility;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C virus;Heroin Abuse;Human Resources;Human immunodeficiency virus test;Individual;Informed Consent;Injecting drug user;Interest Group;Intervention;Interview;Kentucky;Laboratories;Longitudinal Studies;Longitudinal trends;Measures;Medicaid;Medical;Methods;Ohio;Outcome;Oxycodone;Parents;Participant;Patients;Policies;Population Density;Positioning Attribute;Positive Test Result;Public Health;Research;Research Design;Research Personnel;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Appalachia;Rural Population;Scheme;Services;Site;Specialist;Statistical Models;Structure;Substance abuse problem;Surveys;Syringes;Testing;Viral;Visit;West Virginia;Work;barrier to care;base;care delivery;cohort;design;disease transmission;experience;gabapentin;health care model;health disparity;improved;infancy;innovation;opioid abuse;prescription drug abuse;programs;recruit;response;social;sociodemographics;statistics;substance abuse treatment;suburb;therapy development;treatment group;uptake;willingness

public_health_relevance:
PROJECT NARRATIVE FROM PARENT AWARDBoth MC expansion and SAPs have great potential to improve substance abuse and infectious diseaseoutcomes among rural PWUD/PWID; however first we must understand the mechanisms by which these SIsare influencing outcomes. Therefore results may inform ways in which to optimize uptake and utilization ofstructural interventions as well as to inform policies surrounding further implementation of SIs that will improvepublic health outcomes in rural Appalachia.


application_id: 10238097
project_number: 5K23MH111977-05
project_title: Enhancement of extinction learning using transcranial direct current stimunation
administering_ic: NIMH
award_notice_date: 2021-08-13
opportunity_number: PA-16-198
application_type: 5
activity_code: K23
ic: MH
serial_number: 111977
program_official: CHAVEZ, MARK RAY
project_start_date: 2017-09-11
project_end_date: 2023-08-31
study_section: Adult Psychopathology and Disorders of Aging Study Section[APDA]
contact_pi_person_id: 10570976
contact_pi: ADAMS, THOMAS G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThis application for a mentored patient-oriented research career development award will provide the applicant a clinical psychologist with a strong background in experimental psychopathology and cognitive-behavioraltherapy and growing expertise in non-invasive brain stimulation  with advanced training mentored researchexperience and protected research time. This will facilitate the applicant's long-term goal: to reduce the mentalhealth burden associated with pathological fear and anxiety by developing novel treatments and augmentationstrategies. The candidate proposes: 1) a training plan to gain expertise in translational clinical neuroscience: I)neurobiology and cognitive neuroscience II) neuroimaging and III) non-invasive brain stimulation; 2) amentoring and consultation team with expertise in these three areas; 3) two mentored research projects thatwill test whether transcranial direct current stimulation (tDCS) can enhance neural and cognitivemechanisms underlying exposure-based treatments for pathological fear and anxiety.The negative valence systems of acute threat (fear) potential threat (anxiety) and sustained threat are amongthe most clinically important research domain constructs. Psychiatric disorders characterized by pathologicalfear and anxiety are common and often disabling. Despite their limitations exposure therapies are among themost efficacious treatments for these disorders. Extinction learning is thought to be a core mechanism oftherapeutic exposure. Extinction learning is mediated by a well-defined circuit encompassing the medialprefrontal cortex amygdala and hippocampus. This raises the exciting possibility that direct engagement of thiscircuitry might enhance the response to therapeutic exposure. tDCS is a neuromodulation technology that canaugment synaptic plasticity learning and memory. The proposed studies will employ an experimentaltherapeutics framework to assay mechanisms of action behind therapeutic exposure and evaluate whether tDCSengages these mechanisms.Study 1 will enroll 62 healthy volunteers to test whether tDCS applied to the mPFC can augment spontaneousmPFC activity (Aim 1) functional engagement of extinction circuitry during extinction learning and recall (Aim 2)and classically-conditioned extinction learning (Aim 3). Study 2 will enroll 32 patients diagnosed with obsessive-compulsive disorder (OCD) who will complete a novel behavioral paradigm that encapsulates the core featuresof exposure therapy for OCD to test whether tDCS applied to the mPFC enhances exposure-relevant extinctionlearning (Aim 4).Pathological fear and anxiety directly affect more than one out of every four Americans. Existing treatments arefrequently inadequate and need to be improved. The proposed studies will evaluate the ability of tDCS to engageneural and cognitive targets that underpin therapeutic exposure for disordered anxiety. This synergy mayimprove treatment outcomes for individuals suffering from pathological fear and anxiety.

project_terms:
Acute;Affect;American;Amygdaloid structure;Anxiety;Anxiety Disorders;Area;Base of the Brain;Behavioral Paradigm;Biological Assay;Brain;Clinical;Cognitive;Cognitive Therapy;Consultations;Data;Development;Diagnosis;Disease;Distress;Encapsulated;Enrollment;Exercise;Exposure to;Extinction (Psychology);Frequencies;Fright;Functional Magnetic Resonance Imaging;Future;Galvanic Skin Response;Goals;Hippocampus (Brain);Individual;Intervention;Investigational Therapies;Knowledge;Lead;Learning;Measures;Medial;Mediating;Membrane Potentials;Memory;Mental Health;Mental disorders;Mentored Patient-Oriented Research Career Development Award;Mentors;Methods;Minority;Monitor;Mood Disorders;Negative Valence;Neurobiology;Neurosciences;Obsessive-Compulsive Disorder;Pathologic;Patients;Population;Post-Traumatic Stress Disorders;Prefrontal Cortex;Prevention;Procedures;Psychologist;Psychopathology;Psychotherapy;Refractory;Research;Research Project Grants;Rest;Ritual compulsion;Scanning;Signal Transduction;Stimulus;Symptoms;Synaptic plasticity;System;Technology;Testing;Therapeutic;Time;Training;Treatment outcome;anxious;base;behavior test;clinical efficacy;cognitive neuroscience;conditioned fear;conditioning;efficacious treatment;experience;functional MRI scan;healthy volunteer;improved;improved outcome;in vivo;indexing;learning extinction;neuroimaging;neuroregulation;noninvasive brain stimulation;novel;partial response;recruit;relating to nervous system;response;symptomatology;synergism;treatment of anxiety disorders

public_health_relevance:
PROJECT NARRATIVE The proposed studies aim to use transcranial direct current stimulation (tDCS)  a non-invasiveneuromodulatory technology  to augment resting brain activity and plasticity within fear extinction circuitryenhance extinction of classically-conditioned fear and improve learning within the context of therapeuticexposure. Results from these studies may lead toward the development of novel methods that can improve theefficacy and efficiency of therapeutic exposure for multiple forms of disordered fear and anxiety includingobsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).


application_id: 10237137
project_number: 5R03DE029547-02
project_title: Adhesion Screening of Dental Implant Materials Using Laser-Driven Acoustic Waves
administering_ic: NIDCR
award_notice_date: 2021-07-19
opportunity_number: PAR-16-409
application_type: 5
activity_code: R03
ic: DE
serial_number: 029547
program_official: LOPEZ, ORLANDO
project_start_date: 2020-08-12
project_end_date: 2023-07-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14741591
contact_pi: GRADY, MARTHA
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Bacteria accumulation on implants and devices within the oral cavity puts a patient at serious risk for infection.Eradication of established biofilm-forming infections remains difficult in part because the accumulated bacteriaare physiologically and metabolically distinct from the planktonic cells of the same organism. Despite intenseefforts in the field biofilm level response to treatments and changes in environment has been hindered by thelack of robust quantitative and accurate biofilm characterization techniques that can be directly correlated toimplant surfaces. Accurate biofilm adhesion measurement techniques are necessary because strong biofilmadhesion contributes to biofilm persistence on medical device surfaces. In order to more accurately assess thecharacteristics and contribution of biofilm adhesion on implant infections an appropriate film adhesionmeasurement technique must be developed for evaluation of low cohesive strength-high adhesive strengthbiofilm-substrate interfaces. The proposed investigation is designed to overcome current limitations in biofilm adhesion measurementtechniques by harnessing laser-induced acoustic waves. We recently discovered a new technique that generatesstress waves from a pulsed laser is capable of separating a biofilm from a surface. This discovery is especiallyimportant for biofilms with low cohesive strengths because existing measurement techniques perform poorly onthese biofilms whereas our newly discovered technique is well-suited for characterizing these types of biofilms.Controlling the amplitude of the generated stress waves from a pulsed laser enables a direct comparison of thestress required for biofilm detachment. We will assess and optimize the laser spallation technique for quantitativebiofilm adhesion strength measurement evaluate changes in adhesion due to surface treatments (e.g.roughness polymer coating). Successful completion of this research results in new tools for quantitativeadhesion measurement of biofilm-surface interfaces. Implementation of this technology will enable rationalselection of implant materials for reduced biofilm adhesion and improved clinical outcomes.

project_terms:
Acoustics;Adhesions;Adhesives;Antibiotics;Area;Atomic Force Microscopy;Bacteria;Bacterial Adhesion;Basic Science;Biocompatible Materials;Biological;Biological Testing;Calibration;Cell Adhesion;Cell Count;Cells;Characteristics;Clinical;Clinical Sciences;Collaborations;Communities;Data;Dental Implants;Disease;Engineering;Environment;Evaluation;Film;Future;Goals;Growth;Human;Implant;Infection;Investigation;Kentucky;Lasers;Light;Maintenance;Mammalian Cell;Measurement;Measures;Mechanics;Medical;Medical Device;Medical Technology;Metabolic;Methods;Microbial Biofilms;Modification;Molecular;Oral;Oral cavity;Organism;Osseointegration;Osteoblasts;Outcome;Patients;Physiologic pulse;Physiological;Polymers;Population;Procedures;Protocols documentation;Recurrence;Reporting;Research;Resolution;Safety;Saliva;Scheme;Scientist;Side;Streptococcus;Streptococcus gordonii;Streptococcus mutans;Streptococcus oralis;Streptococcus sanguis;Stress;Sucrose;Surface;System;Techniques;Testing;Titanium;Translational Research;Universities;Work;absorption;base;clinical center;cohesion;design;implant material;implantable device;improved;indexing;infection risk;innovation;innovative technologies;interest;interfacial;nanoscale;nanosecond;novel;oral microbial community;peri-implantitis;preclinical evaluation;promoter;screening;stem;technology validation;tool;translational physician;treatment response

public_health_relevance:
PROJECT NARRATIVEA key aspect of peri-implantitis is the oral microbiota that accumulate into biofilms on the implant surface. Thisproject develops and implements novel laser-based quantitative methods for measurement of biofilm adhesionto implant surfaces. Successful implementation of this technology will enable rational selection of implantmaterials for reduced biofilm adhesion and improved clinical outcomes.


application_id: 10237038
project_number: 1R56AI152597-01
administering_ic: NIAID
award_notice_date: 2020-08-25
opportunity_number: PA-19-056
application_type: 1
activity_code: R56
ic: AI
serial_number: 152597
program_official: MO, ANNIE X Y
project_start_date: 2020-09-01
project_end_date: 2022-08-31
study_section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-01
project_title:
Key sentinel roles of IFN-gamma production by microglia to orchestrate the innate and T cell-mediated protective immunity to prevent reactivation of cerebral Toxoplasma infection

project_abstract:
Reactivation of chronic infection with Toxoplasma gondii in immunocompromised individuals results in thedevelopment of life-threatening toxoplasmic encephalitis (TE). To improve prevention and treatment ofTE it is critical to define the mechanisms of the protective immunity to control T. gondii in the brain. Our recentstudy using bone marrow chimeric mice uncovered that IFN- production by brain-resident cells is crucial foractivating the protective innate immunity to limit T. gondii growth and for recruiting and activating immune Tcells in the brain to prevent reactivation of the infection. Our studies also identified that microglia (residentmacrophages in the brain parenchyma) produce IFN- in response to T. gondii growth in the brain. Theseevidences led us to hypothesize that IFN- production by microglia is a key sentinel mechanism of the brain toprovide the early stage innate defense and promptly activate T cell-mediated protective immunity to preventreactivation of T. gondii infection. In Aim 1 we will employ mice deficient in IFN- only in the microglia amongbrain-resident cells and reveal the key sentinel role of microglial IFN- to activate the cerebral innate immunityto limit reactivation of T. gondii infection. We will also determine the role of dense granule protein 6 of T. gondiias a major target of microglia to detect tachyzoite proliferation in the brain and activate their IFN- production.Aim 2 is to illustrate the crucial protective role of microglial IFN- to induce cerebral expression of CXCL9 tofacilitate recruitment of immune T cells into the brain. We will also identify the importance of microglial IFN- toupregulate an expression of MHC class I and II molecules in brain-resident cell populations which is requiredfor presenting T. gondii antigens to the T cells recruited into the brain for their activation. In regard to the T cellpopulation to prevent TE we previously showed that CD8+ T cells alone in combination with cerebral innateIFN- production are able to prevent reactivation of T. gondii infection. CD8+ T cells recognize target antigenspresented by the MHC class I molecules and different MHC class I molecules present different antigenepitopes to CD8+ T cells. Therefore T. gondii antigens that efficiently activate the protective CD8+ T cells mostlikely differ depending on the MHC class I molecules expressed in each individual. There are three MHC classclass I supermotifs HLA-A2 -A3 and -B7 which encompass 90% of the human population. Aim 3 is toidentify the T. gondii molecules that most efficiently stimulate IFN--producing CD8+ T cells capable ofpreventing TE specifically for each of these three MHC class I supermotifs. We will also confirm an efficiencyof the immunization with the identified T. gondii molecules to activate CD8+ T cells capable of preventing TEusing transgenic mice expressing these human MHC molecules. These studies will uncover the criticalcerebral immune system coordinated by microglial IFN- and shed light on the molecular mechanisms involvedin the immune coordination and T cell activation. The studies will also provide the basis for precision vaccinesfor each of the three MHC class I supermotifs to activate the protective CD8+ T cells to prevent TE.

project_terms:
Acquired Immunodeficiency Syndrome;Antigen Presentation;Antigen Targeting;Antigens;Bone Marrow;Brain;CD4 Lymphocyte Count;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCL9 gene;Cell Count;Cells;Cellular Immunity;Cerebrum;Cytoplasmic Granules;Development;Epitopes;Foundations;Goals;Growth;HIV Infections;HLA-A2 Antigen;Histocompatibility Antigens Class I;Host Defense;Human;Immune;Immune system;Immunity;Immunization;Immunocompromised Host;In Vitro;Individual;Infection;Interferon Type II;Life;Light;MHC Class I Genes;Mediating;Microglia;Modeling;Molecular;Mus;Natural Immunity;Parasites;Patients;Population;Prevention;Production;Proteins;Role;Sentinel;Surface;T-Cell Activation;T-Lymphocyte;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Transgenic Mice;Vaccines;adaptive immunity;brain parenchyma;chemokine;chronic infection;humanized mouse;improved;in vivo;macrophage;microbial;mutant;prevent;recruit;response;toxoplasmic encephalitis;vaccine development

public_health_relevance:
Reactivation of chronic infection with Toxoplasma gondii causes life-threatening toxoplasmicencephalitis (TE) in immunocompromised individuals such as those with AIDS. The proposedstudies aim to elucidate the mechanisms by which IFN- produced by microglia (one of thebrain-resident cell population) coordinates the protective immunity to prevent TE and to identifythe T. gondii molecules that most efficiently activate the microglial IFN- production and theprotective CD8+ T cells capable of preventing TE respectively. These studies will generate theinformation crucial for understanding the mechanisms of the protective immunity to prevent TEand for developing a vaccine to activate the protective CD8+ T cells capable of preventing TEeven when CD4+ T cell counts become low due to AIDS.


application_id: 10236293
project_number: 5F30HD103319-02
administering_ic: NICHD
award_notice_date: 2021-08-02
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: HD
serial_number: 103319
program_official: CHINN, JUANITA JEANNE
project_start_date: 2020-08-02
project_end_date: 2024-08-01
study_section: Special Emphasis Panel[ZRG1-F18-Z(20)]
contact_pi_person_id: 16164179
contact_pi: HANSEN, ANNA
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-08-02
project_title:
Social and biological determinants of pregnancy-related mortality and morbidity among rural underserved women

project_abstract:
ABSTRACT Over the past two decades the number of women dying from pregnancy-related causes in the UnitedStates has nearly doubled and cases of severe maternal morbidity have nearly tripled.2 3 Researchconcerning the factors influencing pregnancy-related mortality (PRM) and severe maternal morbidity (SMM)has previously neglected women in Central Appalachia despite the risk profile of this health disparatepopulation. This study utilizes a rigorous mixed methods approach guided by the conceptual framework foraction on the social determinants of health adopted by the World Health Organization to identify structural andintermediary determinants influencing Central Appalachian women's risk for SMM and PRM.1 4 This study is highly innovative in that it is the first study nationally outside the National Center for HealthStatistics (NCHS) to utilize a new database from the NCHS which links morbidity and mortality data.Furthermore it is the first known study to focus on SMM and PRM in women living in Central Appalachia andmay yield critical intervention insights for this underserved health disparate population. The following aims will:(1) Identify predictors of PRM and SMM in Central Appalachia. This aim will perform hierarchical logisticregressions on nation-wide data from the NCHS to determine risk and protective factors influencing women'srisk of SMM and PRM at delivery and one year postpartum.(2) Elucidate healthcare providers' and patients' perspectives on underlying mechanisms of PRM and SMM inCentral Appalachia. In-depth semi-structured interviews will be conducted with: (1) 10 patients who haveexperienced SMM and (2) 10 healthcare providers and 10 EMTs in Central Appalachia who have providedcare for patients experiencing SMM and PRM. The PI will leverage resources and expertise from the University of Kentucky's Center for Health EquityResearch Research Data Center and a highly supportive interdisciplinary mentorship team who are expertsin rural health disparities implementation science and maternal-fetal medicine. Mentorship by team memberswill provide the PI with ample training concerning the implementation of mixed methods studies projectmanagement responsible conduct of research and the dissemination of findings. This training will provide thePI with the skillset necessary to carry out the specific aims and lay the foundation for the PI to become anindependent physician-scientist with an extramurally supported research portfolio in the field of maternalhealth. Results from this study will produce essential knowledge concerning predictors of SMM and PRM in anat-risk population and identify factors influencing poor maternal outcomes which may be targeted by futureinterventions. Findings may also inform development of future empirical investigations into in other ruralpopulations.

project_terms:
Address;Adopted;Alaska Native;American;Appalachian Region;Biological;Caring;Cessation of life;Chronic Disease;County;Data;Data Set;Databases;Death Records;Detection;Development;Diabetes Mellitus;Diagnosis;Discipline of obstetrics;Disease;Distress;Emergency Medical Technicians;Epidemiology;Etiology;Evaluation;Evidence based intervention;Extramural Activities;Female of child bearing age;Foundations;Future;Health;Health Personnel;Healthcare;High Prevalence;Home;Hospitalization;Hypertension;Intervention;Interview;Investigation;Kentucky;Knowledge;Link;Location;Logistic Regressions;Maternal Health;Maternal-fetal medicine;Medical;Mentors;Mentorship;Methods;Mississippi;Morbidity - disease rate;Mothers;Native Americans;Organ;Outcome;Participant;Patient Care;Patients;Pattern;Physicians;Policies;Population;Populations at Risk;Postnatal Care;Postpartum Period;Postpartum Women;Poverty;Pregnancy;Pregnancy Complications;Pregnancy Outcome;Pregnant Women;Prevalence;Prevention;Provider;Regression Analysis;Research;Research Support;Residencies;Resources;Risk;Risk Factors;Rural;Rural Appalachia;Rural Population;Scientist;Structure;Sum;Training;United States;United States National Center for Health Statistics;United States National Institutes of Health;Universities;Validity of Results;Woman;World Health Organization;black women;burden of illness;cultural competence;data centers;evidence base;experience;health care availability;health disparity populations;health equity;health inequalities;implementation science;innovation;insight;maternal outcome;member;mortality;mortality risk;neglect;obstetric care;predictive modeling;prepregnancy;protective factors;research data dissemination;residence;responsible research conduct;rural area;rural health disparities;rural setting;rural underserved;secondary analysis;severe maternal morbidity;social;social determinants;social health determinants;sociodemographic factors

public_health_relevance:
This study elucidates social and medical determinants underlying death and severe morbidity attributable topregnancy in an underserved health disparate population namely rural Appalachian women. Findings mayinform the development of evidence-based culturally competent interventions among this population. Resultsmay inform development of future empirical investigations in other underserved rural populations (e.g. ruralwomen in the Mississippi Delta region and rural Native American women)..


application_id: 10236243
project_number: 3R44AA025804-03S1
project_title: Novel modulators of the dopamine transporter for alcohol and nicotine use disorders
administering_ic: NIAAA
award_notice_date: 2020-09-04
opportunity_number: PA-18-935
application_type: 3
activity_code: R44
ic: AA
serial_number: 025804
suffix: S1
program_official: FERTIG, JOANNE
project_start_date: 2016-09-22
project_end_date: 2023-03-31
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe parent award is to develop novel medications for alcohol and nicotine use disorders. Thesedisorders have increased during COVID19 [e.g. Clay and Parker 2020] and are associated withincreased susceptibility to and severity of infection. This supplemental proposal is focused onhow mechanisms of COVID-19 infection and neurotoxicity are influenced by alcohol and nicotineand how these novel medications interact with these mechanisms. The applicants have previouslyused organotypic hippocampal neuronal cultures to study interactions between nicotine alcoholwithdrawal and viral protein neurotoxicity and these cultures will be used here. First nicotine hasbeen reported to up-regulate the viral receptor angiotensin converting enzyme 2 (ACE2) onneurons providing a mechanism for increased SARS CoV2 infectivity and neurotoxicity insmokers and vapers [see Kabbani & Olds 2020]. The nicotinic receptor partial agonists(lobinaline N-oxides) from the parent award should inhibit this effect of nicotine and this will betested in the first specific aim using immunohistochemistry to evaluate ACE2 expression inorganotypic cultures. Once CNS infection has occurred coronaviruses cause excitotoxicity thatis inhibited by inhibitors of neuronal glutamate /NMDA receptors (NMDARs) [Hasanagic &Serdeveric 2020]. This is similar to alcohol withdrawal (AWD) [Stepanyan et al 2008] and soshould be ameliorated by drugs that prevent neurotoxicity in AWD. Once again the nicotinicactivity of lobinaline N-oxides may be valuable but another medication under development by thecompany for alcohol use disorder the aryliminoguanidine JR220 is even more directly relevantbecause it is an inhibitory modulator of the NMDAR [Barron et al 2012] The neuroprotectivepossibilities for these drugs will be evaluated against viral protein neurotoxicity in organotypiccultures in specific aim 2. The hypothesis is therefore that coronavirus infectivity and neurotoxicityare enhanced in patients with nicotine and alcohol use disorders and that both the disorders andthe COVID19 consequences should be inhibited by the medications under development. Thesenovel therapeutic targets for lobinaline N-oxides and JR220 in COVID-19 infection will stronglysupport the therapeutic and commercial value of products from the parent award.

project_terms:
2019-nCoV;Affect;Agonist;Alcohol consumption;Alcohol withdrawal syndrome;Alcohols;Angiotensin Receptor;Animal Model;Award;Binding Proteins;COVID-19;COVID-19 pandemic;Cell surface;Cells;Central Nervous System Infections;Chronic;Clinical;Complex;Computer software;Coronavirus;Development;Disease;Disease Outbreaks;Exposure to;Fluorescence Microscopy;Future;Glutamates;HIV;HIV tat Protein;Heavy Drinking;Hippocampus (Brain);Hospitalization;Image;Immunohistochemistry;In Vitro;Infection;Lung;Mediating;Memantine;Microscopy;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Neurologic;Neurons;Nicotine;Nicotine Use Disorder;Nicotinic Receptors;Outcome;Oxides;Parents;Patients;Peptidyl-Dipeptidase A;Pharmaceutical Preparations;Phenotype;Predisposition;Preparation;Proteins;Pulmonary Pathology;Rattus;Reporting;Respiratory Signs and Symptoms;Route;Severities;Signs and Symptoms;Site;Smoker;Smoking;Stains;Testing;Therapeutic;Toxic effect;Up-Regulation;Viral;Viral Proteins;Virus Receptors;alcohol abuse therapy;alcohol availability;alcohol exposure;alcohol use disorder;clay;commercialization;dopamine transporter;excitotoxicity;inhibitor/antagonist;neuroinflammation;neurotoxic;neurotoxicity;new therapeutic target;nicotine inhalation;nicotine use;novel;prevent;receptor;respiratory virus;therapeutic candidate;vaper;vaping

public_health_relevance:
Project NarrativeThe drugs that are being developed for the treatment of alcohol use disorder Lobinaline N-oxidesand JR220 also have implications for coronavirus treatment. Because nicotine and alcohol affectcoronaviruses infectivity and neurotoxicity these treatments have direct and indirect effects on theCOVID 19 pandemic.


application_id: 10233816
project_number: 5R35GM131807-03
project_title: Hedgehog Signaling in Development and Metabolism
administering_ic: NIGMS
award_notice_date: 2021-08-20
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 131807
program_official: XU, JIANHUA
project_start_date: 2019-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Hedgehog (Hh) signaling plays critical roles in pattern formation and cell growth control and is also involved inmetabolic control. Further aberrant Hh signaling causes diverse types of cancers. Transduction of the Hhsignal requires the G protein-coupled receptor (GPCR) family protein Smoothened (Smo) in both insects andmammals. While many components in the Hh pathway have been identified how the Hh signal is transducedthrough the 12-span transmembrane protein Patched (Ptc) to Smo is still unclear. This team has discovered 1)that Smo undergoes phosphorylation by multiple kinases which leads to Smo cell surface accumulation andsignaling activity; 2) that sumoylation induced by Hh promotes Smo activation; and 3) that ubiquitinationdownregulates Smo cell surface accumulation by promoting Smo endocytosis. Results from these studiessuggest that in response to Hh stimulation multiple steps occur in Smo regulation. However despitesignificant progress key questions persist regarding the mechanism controlling Smo protein expression andactivation: 1) How is Smo transcription specifically regulated? 2) Whether and how does Hh regulate lipolysis?3) How does cholesterol activate Smo? and 4) Whether and how is the sodium pump involved in Ptc and Smoregulation? Recent discoveries by this group that Smo transcription is specifically regulated in adipose tissuethat an alternative cholesterol biosynthesis pathway regulates Smo accumulation and activation and that thesodium pump plays a positive role in activating Smo likely by regulating cholesterol on the plasma membraneare critical foundations to answering those questions. The overarching goal of this research program is tounderstand how Hh signals are sensed and transmitted to control downstream biological events that ultimatelygovern cell growth and patterning. Drosophila fat body and oenocyte have emerged as attractive models tostudy lipid metabolism and circulation. Published and preliminary findings in these models have indicated thatlipid accumulation is regulated by highly conserved signaling pathways and that Hh signaling controls not onlylipogenesis but also lipolysis by regulating specific genes. These studies provide new tools and hypotheses forinvestigating the mechanisms of Smo signaling and the role of Hh/Smo signaling in regulating lipid metabolismwhich particular relevance to such cancers as basal cell carcinoma and medulloblastoma. The proposed five-year program of studies uses a combination of genetic and biochemical approaches to build on priorcontributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study willprovide novel insights into mechanisms surrounding Smo suppression by Ptc and activation by cholesterol. Inaddition expected outcomes will provide novel insights into human developmental disorders and promotedevelopment of diagnostic tools and novel therapeutic approaches to oppose Smo drug resistance usingmetabolism as a platform to transform current concepts of Hh signaling in cancer obesity and metabolicdiseases.

project_terms:
Adipose tissue;Basal cell carcinoma;Biochemical;Biological;Blood Circulation;Cell membrane;Cell surface;Cholesterol;Development;Diagnostic;Drosophila genus;Drug resistance;Embryonic Development;Endocytosis;Erinaceidae;Event;Fat Body;Foundations;G-Protein-Coupled Receptors;Genes;Genetic;Genetic Transcription;Goals;Human;Insecta;Integral Membrane Protein;Investigation;Knowledge;Lipids;Lipolysis;Malignant Neoplasms;Mammals;Metabolic Control;Metabolic Diseases;Metabolism;Modeling;Mutation;Na(+)-K(+)-Exchanging ATPase;Obesity;Outcome;Pathway interactions;Pattern;Pattern Formation;Phosphorylation;Phosphotransferases;Play;Process;Protein Family;Proteins;Publishing;Regulation;Research;Role;Signal Pathway;Signal Transduction;Sumoylation Pathway;System;Ubiquitination;cancer type;cell growth;cholesterol biosynthesis;developmental disease;hedgehog signal transduction;human disease;insight;lipid biosynthesis;lipid metabolism;medulloblastoma;novel;novel therapeutic intervention;patched protein;programs;protein activation;protein expression;public health relevance;response;smoothened signaling pathway;tool


application_id: 10233581
project_number: 1F30AG072770-01
project_title: Characterizing the role of glutamate transporter 1 on astrocyte physiology in Alzheimer's disease
administering_ic: NIA
award_notice_date: 2021-04-07
opportunity_number: PA-20-245
application_type: 1
activity_code: F30
ic: AG
serial_number: 072770
program_official: DIBATTISTA, AMANDA
project_start_date: 2021-07-01
project_end_date: 2021-10-12
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 16028135
contact_pi: FARR, NATHAN DREW
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYContact PI / Project Leader: FARR NATHAN DREWTitle: CHARACTERIZING THE ROLE OF ASTROCYTIC GLUTAMATE TRANSPORTER 1 ON ASTROCYTEPHYSIOLOGY IN ALZHEIMERS DISEASEAwardee Organization: UNIVERSITY OF KENTUCKYAbstract Text:Alzheimers disease (AD) inflicts significant private community and societal burdens by impairing cognitivefunction. The likely foundation for cognitive dysfunction in AD is synaptic impairment characterized in part byglutamate-dependent hyperexcitability. Astrocytes lose capacity to regulate glutamate in AD including by areduction and/or dysfunction of the astrocytic glutamate transporter EAAT2/Glt-1. Glt-1 removes glutamate fromthe extracellular milieu providing a primary defense against excitotoxicity while also driving electrochemicalgradients that promote glycolysis and lactate release. Normalization of Glt-1 such as by treatment withpharmacological agents that increase Glt-1 expression has been shown to protect synaptic proteins improvebasal synaptic strength and improve cognition. However the sufficiency of astrocytic Glt-1 to independentlyrestore neuronal function has not been shown. Furthermore the effect of Glt-1 on the astrocyte-neuron lactateshuttle in AD is unknown despite a clear mechanistic link between the two processes. Therefore Aim 1 will testthe hypothesis that normalization of Glt-1 using an astrocyte-specific AAV vector will restore astrocyte-neuroncoupling. In addition to the effect of Glt-1 on neurons Glt-1 may also ameliorate excitotoxic damage to thestructural barrier between vascular endothelium and perivascular astrocyte endfeet. Although excitotoxicity hasbeen shown to damage astrocyte-vessel function including via neuronal calcium dysregulation the role of Glt-1is unknown. To investigate the potentially protective role of Glt-1 on astrocyte-vessel interactions Aim 2 will testthe hypothesis that normalization of Glt-1 will restore cerebral blood flow neurovascular coupling and blood-brain barrier leakiness. Aim 3 will establish the sufficiency of astrocytic Glt-1 to ameliorate neuronalhyperexcitability and to restore neuronal network connectivity synchronicity and neural density by alteringcalcium signaling. The objectives of the research will be to explicate the physiologic mechanism of astrocytic Glt-1 and to spur development of astrocyte-directed approaches to treat Alzheimers disease. The primary goal ofthe fellowship will be to equip the trainee with skills necessary for further research training and for a successfulindependent research career measuring similar endpoints using basic and translational neuroimagingtechniques. Execution of that goal will be achieved through a comprehensive training plan and a mentoring teamof world-renowned experts from the Sanders-Brown Center on Aging. The trainee will develop expertise incommunication of research results and networking complex data analyses rigorous research design andcutting-edge techniques such as electrochemistry electrophysiology and intravital imaging in the mouse. Atailored training and career development plan will facilitate the trainees ultimate translation of those skills tosolve vital research questions in the neurodegeneration field. These skills and excellent mentorship thereforerepresent an outstanding opportunity to develop the trainee towards alleviating dementia as an independentphysician-scientist.

project_terms:
Acids;Affect;Aging;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Amino Acid Transporter;Astrocytes;Automobile Driving;Autopsy;Blood - brain barrier anatomy;Brain;Brain region;Calcium;Calcium Signaling;Caliber;Cell physiology;Cells;Cerebrovascular Circulation;Characteristics;Chemicals;Cognition;Communication;Communication Research;Communities;Coupling;Custom;Data Analyses;Dementia;Development;Development Plans;Dextrans;Electrochemistry;Electrophysiology (science);Environment;Excitatory Amino Acids;Fellowship;Foundations;Functional disorder;Genetic;Glial Fibrillary Acidic Protein;Glucose;Glutamate Transporter;Glutamates;Glycolysis;Goals;Homologous Gene;Impaired cognition;Impairment;Injections;Knowledge;Lactate Transporter;Laser Speckle Imaging;Lead;Life;Link;Measures;Mediating;Memory;Mentors;Mentorship;Metabolic;Metabolism;Microelectrodes;Molecular Profiling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotransmitters;Pathology;Pharmacology;Physicians;Physiological;Physiology;Privatization;Process;Production;Proteins;Research;Research Design;Research Training;Resources;Rodent;Role;Science;Scientist;Senile Plaques;Signal Transduction;Slice;Structure;Synapses;Techniques;Technology;Testing;Text;Thinking;Training;Translations;Up-Regulation;Vascular Endothelium;Vibrissae;adeno-associated viral vector;barrel cortex;base;brain cell;calcium indicator;career;career development;cognitive function;cohort;complex data;density;design;effective therapy;excitotoxicity;experience;experimental study;extracellular;improved;in vivo;intravital imaging;mouse model;multiphoton microscopy;neuroimaging;neurovascular;neurovascular coupling;novel;overexpression;patch clamp;promoter;relating to nervous system;response;skills;treatment strategy;uptake

public_health_relevance:
PROJECT NARRATIVECommunication between brain cells via chemical messengers termed neurotransmitters areaffected by dementia which causes decline in memory and thinking severe enough to interferewith daily life. This study will focus on one neurotransmitter glutamate in a model of Alzheimersdisease. Understanding these cellular processes could lead to novel treatment strategies fordementia.


application_id: 10232953
project_number: 1F31AT011472-01
administering_ic: NCCIH
award_notice_date: 2021-04-01
opportunity_number: PA-20-246
application_type: 1
activity_code: F31
ic: AT
serial_number: 011472
program_official: SABRI, MERAV
project_start_date: 2021-04-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZAT1 JM (11)]
contact_pi_person_id: 15833935
contact_pi: HETTINGER, ZACHARY
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-04-01
project_title:
Skeletal muscle extracellular matrix remodeling through cyclic compressive loading in old rats recovering from disuse atrophy

project_abstract:
PROJECT SUMMARY/ABSTRACTThe control of muscle mass is impaired in older adults and is exacerbated by periods of muscle disusecommon to lengthy hospital stays immobilization and physical inactivity. The recovery following disuseatrophy is incomplete in older adults which contributes to functional decline. During the recovery of musclemass in older adults there is an accumulation of intramuscular collagen which contributes to functionaldeficits. Lost strength following disuse atrophy in older adults is clinically important due to its tight correlationwith morbidity and loss of independence which combined with the rising population of older adults equates toa large burden on the United States healthcare system. Therefore it is critical therapies be made available toregulate excessive collagen deposition in muscles from older adults. We propose massage in the form of cycliccompressive loading may present as a useful alternative in regulating collagen deposition in muscles fromolder adults as it is a well-tolerated clinical tool. Using a rat model and our laboratory's custom-built roboticmassage device we show massage is able to initiate the turnover of collagen in muscles of old ratsundergoing muscle regrowth. However it is currently unclear how massage initiates collagen turnover or howaging affects collagen regulation during the recovery of muscle mass in older adults. Therefore the purpose ofthis application is to (1) determine if massage impacts collagen remodeling by using isotope tracer methodsand mass spectroscopy and (2) identify how aging and massage impact the gene expression of collagen-remodeling cell populations using single cell RNA sequencing. Results from the proposed experiments willdefine the use of massage as a complementary health intervention for mitigating excessive collagen depositionduring the recovery period following disuse atrophy in older adults. Apart from assessing gaps in knowledge ofcollagen regulation during muscle regrowth in old rats this proposal is an excellent training platform toaccomplish my long-term career goals of becoming an independent scientist. The innovative research planprepared for this application is overseen by experts in the field of skeletal muscle aging who have eachcommitted their time in training me to accomplish the goals set out in this application. Combining principles ofbiomechanics and molecular biology this is a unique training plan that not only benefits my training but alsoidentifies massage as a complementary health intervention for older adults recovering from disuse atrophy.The combination of innovative research mentorship and research environment each contribute towardstraining to become an independent scientist in the field of skeletal muscle aging.

project_terms:
Address;Affect;Age;Aging;Area;Bioinformatics;Biomechanics;Cells;Clinical;Collagen;Complementary Health;Connective Tissue;Custom;Data;Deposition;Deuterium Oxide;Devices;Disuse Atrophy;Elderly;Environment;Extracellular Matrix;Fibroblasts;Gastrocnemius Muscle;Gene Expression;Goals;Healthcare Systems;Immobilization;Impairment;Intervention;Intramuscular;Isotopes;Knowledge;Laboratories;Length of Stay;Mass Spectrum Analysis;Massage;Measurement;Measures;Mentorship;Methods;Modeling;Molecular;Molecular Biology;Mononuclear;Morbidity - disease rate;Muscle;Muscular Atrophy;Older Population;Peptide Hydrolases;Periodicity;Population;Rattus;Recovery;Regulation;Research;Risk;Robotics;Scientist;Skeletal Muscle;Therapeutic Studies;Time;Tracer;Training;United States;age related;career;cell type;experimental study;functional decline;human old age (65+);in vivo;in vivo evaluation;innovation;macrophage;mechanical load;mechanical properties;mimetics;muscle aging;muscle form;muscle stiffness;muscle strength;physical inactivity;prevent;response;robotic device;satellite cell;single-cell RNA sequencing;stem cells;tool;young adult

public_health_relevance:
PROJECT NARRATIVEMuscle strength is compromised in old age and is made worse by excess connective tissue accumulationduring muscle wasting which occurs during lengthy hospital stays immobilization and physical inactivity. Thisproject will investigate how massage in the form of cyclic compressive loading can enhance the remodeling ofconnective tissue during the recovery period after muscle wasting in older adults.


application_id: 10232646
project_number: 3U01DK074007-15S1
project_title: University of Louisvilles Clinical Center in Gastroparesis Clinical Research Consortium
administering_ic: NIDDK
award_notice_date: 2020-09-01
opportunity_number: PA-18-591
application_type: 3
activity_code: U01
ic: DK
serial_number: 074007
suffix: S1
program_official: SERRANO, JOSE
project_start_date: 2006-04-15
project_end_date: 2022-08-31
study_section: ZDK1(O2)-S
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Gastroparesis is a disorder of gastric function characterized by delay in gastric emptying frequently associatedwith chronic nausea and vomiting early satiety postprandial fullness abdominal pain and malnutrition thatmay require nutritional support. Gastroparesis has a devastating impact on quality of life and predominantlyaffects younger women. In the past 5 years the Gastroparesis Clinical Research Consortium (GpCRC) hasmade a series of important contributions (see below) to improve our understanding of this disorder andadvancing the goals of patients physicians and the NIH for management of gastroparesis. Yet much remainsto be learned about its etiology natural history treatment strategies and clinical course whichis the rationale behind our response to the Continuation of the Gastroparesis Consortium RFA-DK-10-502. Thebiggest barrier to effective therapeutic approaches to gastroparesis is our lack of knowledge about either itspathogenesis or its pathophysiology. Further the correlation between the major symptoms such as nauseavomiting pain and current methods to measure change in gastric function (electrical motor activity mealemptying times) is poor at best. Finally we do not understand the long-term outcomes of these patients andwhether outcomes differ on the basis of etiology symptom severity and degree of emptying abnormalities.Consequently our approach to these patients is erratic and treatment has been empirical and only partiallyeffective if at all in relieving the major symptoms. The mission of the GpCRC is completely aligned with therecommendations of the National Commission on Digestive Diseases;5 specifically Research Goal 2.6 relatesto gastroparesis and states: "Understand the noxious visceral signaling causing nausea and vomiting related togastric neuro-electrical and/or motor dysfunction and the bi-directional brain-gut interactions. Gastroparesisprovides an archetypal disease for investigative inquiry. Chronic vomiting a debilitating and socially isolatingdigestive symptom creates potentially life-threatening disruptions in fluid and electrolyte homeostasis andcompromises nutritional status. Chronic nausea remains a significant hidden disability. Nausea and vomitingusually occur in tandem and overlay with other Gl symptoms as well as presenting in numerous digestivediseases. More effective treatments for nausea and vomiting would improve quality of life and physicalfunctioning in a vast array of illnesses. A paucity of research exists for defining peripheral noxious signaling ofnausea and vomiting related to primary Gl motor/sensory disturbances."The Specific Aims of this proposal are to: 1. Complete the current GpCRC registry; 2. To continue the GpCRCcore lab responsible for anatomic and related studies on tissue sample of patients with Gp syndromes; 3.Continue pharmacologic studies on patients with Gp syndromes; 4. Continue device studies for patients withthe Gp syndromes; and 5. A new multicenter study based on several GpCRC ancillary studies and other pilotdata.

project_terms:
Abdominal Pain;Affect;Anatomy;Ancillary Study;Chronic;Clinical;Clinical Research;Data;Devices;Digestive System Disorders;Disease;Electrolytes;Etiology;Functional disorder;Gastric Emptying;Gastroparesis;Goals;Homeostasis;Knowledge;Life;Liquid substance;Malnutrition;Measures;Methods;Mission;Motor;Motor Activity;Multicenter Studies;Natural History;Nausea;Nausea and Vomiting;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmacology Study;Physical Function;Physicians;Quality of life;Recommendation;Registries;Research;Sensory;Series;Severities;Signal Transduction;Stomach;Symptoms;Syndrome;Time;Tissue Sample;Treatment Efficacy;United States National Institutes of Health;Universities;Visceral;Vomiting;base;clinical center;disability;early satiety;effective therapy;gut-brain axis;improved;motor disorder;response;social;treatment strategy;young woman

public_health_relevance:
This proposal aims to gather a better understanding of gastroparesis which is a devastating disorder inpredominantaly younger women. This is a continuation of the Gastroparesis Clinical Research Consortium(GpCRC). The GpCRC has made a series of important contributions to improve our understanding of thisdisorder and advancing the goals of patients physicians and the NIH for management of gastroparesis. Thisproposal continues the mission of the GpCRC to better understand and treat this disorder.


application_id: 10232422
project_number: 5R01CA218068-05
project_title: Randomized Trial of a Social Media-Delivered Intervention Targeting Indoor Tanning Users
administering_ic: NCI
award_notice_date: 2021-06-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 218068
program_official: PERNA, FRANK
project_start_date: 2017-07-15
project_end_date: 2023-05-31
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 10885868
contact_pi: STAPLETON, JEROD L
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe number of U.S. adults treated annually for melanoma the most deadly form of skin cancer has nearlydoubled in the past 15 years and the incidence rate is projected to again double by 2030. This growth is partlyattributed to the popularity of artificial ultraviolet-emitting indoor tanning beds. Despite recognition by numerousnational and international health organizations as being carcinogenic to humans nearly 10 million Americansuse indoor tanning beds each year. An estimated 1 in 10 of all new U.S. cases of melanoma and 400000annual cases of non-melanoma skin cancer are directly attributable to indoor tanning. Most concerning nearly1 in 5 young adult white females engage in high-risk indoor tanning defined as using indoor tanning beds atleast ten times a year which is associated with a substantially increased risk of melanoma. As indoor tanninggained popularity among young women over the past two decades melanoma has recently become one of themost common cancers among this population. The 2014 Surgeon General's Call to Action to Prevent SkinCancer identified a critical research gap related to an absence of interventions that target high risk indoortanners and address underlying motives for tanning including the desire to look attractive and healthy and toconform to societal beauty standards. The purpose of this application is to implement and test an interventiondesigned to encourage indoor tanning cessation among high-risk tanners. The intervention is unique in usingpersuasive techniques and content to reduce perceived pressure to be tan reduce the value placed on tanningand promote positive body image rather than focusing on information about the risks of tanning. Theintervention will be delivered via the social media site Facebook through the secret groups feature. The useof Facebook groups will allow group-based interactions among participants which can facilitate strongerchanges in attitudes and behaviors and provides a platform to embed the intervention into individuals' normalroutines. The first proposed aim is to refine the existing intervention content from our preliminary interventionstudies with user-generated feedback. The second aim is to conduct a randomized controlled trial of theintervention in a sample of 400 young women engaged in high-risk tanning. Our primary hypothesis is thatparticipants who receive the intervention will report less indoor tanning at a 6-month follow-up compared tothose who participate in a control Facebook group. Our third aim will examine hypothesized psychosocialmediators of the intervention effects. The intervention has strong potential for cost-effective widespreaddissemination and targets a group at high-risk for future cancer development. If effective the intervention hasthe potential to significantly reduce the growing burden of melanoma and other skin cancers.

project_terms:
Address;Adopted;Adult;American;Appearance;Attitude;Beauty;Behavior;Behavior Therapy;Belief;Body Image;Cognitive Dissonance;Collaborations;Conflict (Psychology);Control Groups;Development;Eating Behavior;Eating Disorders;Facebook;Feedback;Female;Funding;Future;Grant;Growth;Human;Incidence;Individual;Intervention;Intervention Studies;Intervention Trial;Lead;Malignant Neoplasms;Mediating;Mediator of activation protein;Participant;Population;Process;Randomized Controlled Trials;Recording of previous events;Reporting;Research;Research Personnel;Risk;Sampling;Site;Skin;Skin Cancer;Skin Carcinoma;Skin tanning;Surgeon;Techniques;Testing;Time;Treatment Efficacy;Woman;Work;base;behavior change;body dissatisfaction;carcinogenicity;college;cost effective;design;eHealth;efficacy evaluation;experience;follow-up;high risk;implementation intervention;implementation study;innovation;international health organization;intervention effect;melanoma;novel;pressure;primary outcome;programs;psychosocial;randomized trial;skin cancer prevention;social culture;social media;success;tanning booths;theories;therapy design;trend;ultraviolet;usability;web site;young adult;young woman

public_health_relevance:
PROJECT NARRATIVEThe use of artificial ultraviolet indoor tanning beds is associated with an increased risk of skin cancer includingthe deadly melanoma. This project involves developing and testing a novel behavioral intervention deliveredvia the social media site Facebook that is designed to reduce high-risk indoor tanning behaviors among youngadult women. If effective the intervention may be widely disseminated and has the potential to help reverseconcerning melanoma trends observed among young women.


application_id: 10232400
project_number: 5R01NS114404-02
project_title: BMAL1/ARNTL plays a critical non-circadian role in secondary tissue damage after contusive SCI
administering_ic: NINDS
award_notice_date: 2021-06-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 114404
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-08-15
project_end_date: 2025-05-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: SARASWAT, SUJATA OHRI;WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ARNTL gene;Acute;Affect;Agonist;Antioxidants;Apoptosis;Apoptotic;Atherosclerosis;Biological Process;Blood;Blood coagulation;Brain;Cardiovascular Diseases;Cell Count;Cell Proliferation;Cells;Cervical spinal cord injury;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical;Complex;Contusions;Cues;Down-Regulation;Drug Targeting;Endothelial Cells;Endothelium;Enhancers;Extravasation;Feedback;Functional disorder;Gene Expression;Genes;Genetic Transcription;Genetic Translation;Health;Hemoglobin;Hemorrhage;Homeostasis;Human;Impairment;Inflammation;Injury;Intervention;Knock-out;Light;Locomotor Recovery;Longevity;Malignant Neoplasms;Mediating;Mediator of activation protein;Mental Depression;Metabolic syndrome;Microglia;Modeling;Molecular;Mus;Mutant Strains Mice;Natural Immunity;Nerve Degeneration;Oligodendroglia;Organ;Outcome;Pathogenesis;Pathology;Periodicity;Permeability;Pharmacology;Phosphorylation;Play;Protein Kinase;Proteins;Proteolipids;Recovery;Recovery of Function;Regulation;Regulator Genes;Reporting;Research;RiboTag;Role;Secondary to;Signal Transduction;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;TNFRSF10B gene;Technology;Testing;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Transcription Repressor;Vascular Diseases;adaptive immunity;angiogenesis;biological adaptation to stress;cadherin 5;cancer cell;cell type;circadian;cytotoxic;effective therapy;endoplasmic reticulum stress;experimental study;feeding;improved;improved outcome;inhibitor/antagonist;insight;loss of function;macrophage;neuroinflammation;new therapeutic target;novel;selective expression;systemic inflammatory response;tissue injury;transcription factor;transcription factor CHOP;transcriptome sequencing;translation factor;white matter;white matter damage


application_id: 10232098
project_number: 5F31AA028725-02
project_title: Probiotic and intestinal miR194 regulation of bile acid metabolism in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2021-07-22
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: AA
serial_number: 028725
program_official: WANG, JOE
project_start_date: 2020-08-01
project_end_date: 2022-03-01
study_section: ZAA1-GG(32)
contact_pi_person_id: 15957958
contact_pi: JIANG, MENGWEI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Patients with alcoholic liver disease (ALD) often exhibit manifestations of cholestasis a liver pathology definedby accumulation of hepatic bile acids (BAs) which are toxic and an important causative factor in hepatocytedeath and liver injury in ALD. Excess hepatic BA concentration is a result of increased BA de novo synthesisand decreased BA secretion to bile. BA metabolism is regulated by farnesoid X receptor (FXR) signaling inintestine and liver. Previous study suggests that intestinal FXR is likely a major player to regulate hepatic BAsynthesis. Intestinal FXR activation is regulated by gut lumen BA species and concentration. Primary BAchenodeoxycholic acid (CDCA) is an agonist of FXR which is antagonized by taurine--murine cholic acid(TMCA). Previous studies have demonstrated that gut BA is dysregulated in ALD patients and in experimentalALD mice. Modulation of dysregulated BA signaling in the intestine improves experimental ALD. Interestinglyour preliminary data showed that in the NIAAA binge-on-chronic alcohol feeding model intestinal FXR mRNAwas markedly reduced along with decreased intestinal fibroblast growth factor (FGF) 15/19 (mouse/humans)and increased hepatic Cyp7a1 expression elevated BA concentration and liver injury. Targeting intestinal FXRboth in transcription and in activation may be a plausible strategy for inhibiting ALD. FXR transcription isregulated by microRNA194 (miR194) which is highly expressed in the intestine. Our preliminary data showedthat alcohol feeding significantly increased intestinal miR194. Interestingly miR194 is suppressed by taurineupregulated gene 1(TUG1) a long non-coding RNA regulated by taurine concentration. Therefore it is likely thatalcohol-induced miR194 causes a reduction of intestinal FXR in ALD. Supplementation of probiotic Lactobacillusrhamnosus GG (LGG) is protective against experimental ALD through multiple mechanisms. Our preliminarystudy showed that LGG suppressed alcohol-increased miR194 and -decreased FXR in the intestine. Theseprevious and preliminary studies strongly suggest that LGG may exert its function in hepatic BA synthesisthrough modulation of intestinal miR194-FXR signaling. We thus hypothesize that alcohol exposure increasesintestinal miR194 and suppresses FXR and FGF15 leading an increase in hepatic de novo BA synthesis andliver injury; and LGG supplementation inhibits intestinal miR194 and suppresses hepatic BA synthesis and liverinjury in mice. To test our hypothesis we design following specific aims: Aim 1 will determine the role of miR194in the regulation of intestinal FXR signaling and hepatic BA homeostasis in ALD. Aim 2 will determine the role ofintestinal miR194-FXR-FGF15 signaling in the protective effects of LGG on ALD. Aim 3 will identify themechanism(s) of miR194 regulation in ALD. Collectively the training and research proposed here will not onlyfill a significant need for the development of ALD treatments but will also foster my development from a youngscientist to a successful independent investigator in the field of alcohol-induced organ disease.

project_terms:
Agonist;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Bile Acid Biosynthesis Pathway;Bile Acids;Bile fluid;Caco-2 Cells;Cessation of life;Chenodeoxycholic Acid;Cholestasis;Cholic Acids;Chronic;Clinical Trials;Data;Development;Disease;Endocrine;Enzymes;Epithelial;Epithelial Cells;Exhibits;FDA approved;FGF19 gene;Fibroblast Growth Factor;Fostering;Genes;Genetic Transcription;Hepatic;Hepatocyte;Homeostasis;Hormones;Human;Intestines;Knockout Mice;Lactobacillus casei rhamnosus;Liver;Liver diseases;Mediating;Messenger RNA;Modeling;Mus;National Institute on Alcohol Abuse and Alcoholism;Organ;Pathology;Patients;Probiotics;Production;Receptor Activation;Receptor Inhibition;Receptor Signaling;Regulation;Research;Research Personnel;Role;Scientist;Signal Transduction;Supplementation;Taurine;Testing;Training;Untranslated RNA;alcohol exposure;bile acid metabolism;design;dietary;disorder prevention;feeding;gut microbiota;improved;intestinal epithelium;liver injury;mouse model;non-alcoholic fatty liver disease;probiotic supplementation;protective effect;receptor

public_health_relevance:
Alcoholic liver disease (ALD) is responsible for nearly half of liver disease deaths yet there are no FDA-approved therapies available for the treatment of any stage of its progression. LGG has been used in clinicaltrial for mild alcoholic hepatitis. Elucidating the mechanisms of probiotic action on hepatic bile acid synthesiswill further support an optimization of probiotic usage alone and/or with other strategy targeting bile acidhomeostasis in the ALD prevention/treatment.


application_id: 10231714
project_number: 7R01AI141889-03
project_title: Influenza D Virus Entry and Tissue Tropism
administering_ic: NIAID
award_notice_date: 2020-08-17
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: AI
serial_number: 141889
program_official: BOZICK, BROOKE ALLISON
project_start_date: 2018-09-21
project_end_date: 2023-08-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8527363
contact_pi: LI, FENG
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Novel influenza D virus (IDV) utilizes bovines as a primary reservoir with periodical spillover toother mammalian hosts including pigs and horses. Of greater public health importance serologicalevidence of IDV infections in humans has been demonstrated. Preliminary investigations have revealedthat IDV binds to human 9-O-acetylated N-acetylneuraminic acid (Neu59Ac2) the receptor of humaninfluenza C virus (ICV) and non-human N-glycolylneuraminic acid (Neu5Gc9Ac) and likely utilizesthem for viral entry. Further functional studies indicate that IDV is more efficient in recognizing bothhuman Neu59Ac2- and non-human Neu5Gc9Ac-containing glycans than ICV and ICV seems topreferentially bind to human Neu59Ac2 over non-human Neu5Gc9Ac. In agreement with this ICV hasa limited host range with humans as a reservoir. These results suggest that IDV and ICV diverge incommunicating with sialic acids (SA) for infection. The hypothesis is that subtle differences in thesequence and structure of the receptor-binding pocket residing in the hemagglutinin-esterase-fusion(HEF) protein between IDV and ICV cause substantial differences in the virus-receptor interactionwhich can expand or reduce or change tissue and species tropisms. Furthermore the recentobservation on the extracellular resistance of IDV to low pH inactivation versus the intracellularrequirement of low pH for viral entry suggests a novel entry/fusion mechanism by which IDV employsto deliver its genome into the target cell. Three aims are proposed to address these hypotheses in thisR01 application which involve a comparative study of IDV and ICV. Aim 1 will elucidate the entrymechanism of IDV while Aim 2 will define the molecular basis of the HEF receptor binding affinity andspecificity and its impact on IDV tropism. Aim 3 is deigned to address how two IDV lineages swine andbovine read the glycan receptors differentially and how this information is transduced to differenttissue and species tropisms between these two groups of IDVs. In summary this proposal leverages theteam's expertise in IDV research and novel aspects of IDV-receptor interaction and entry to elucidatethe cross-species transmission mechanism of IDVs. Understanding molecular details of virus-receptorinteraction may lead to development of novel strategies for the control and prevention of IDV and ICVinfections in humans.

project_terms:
Acids;Address;Affinity;Agreement;Animals;Antiviral Agents;Asia;Binding;Biological;Carbon;Cattle;Cavia;Cells;Chimeric Proteins;Comparative Study;Data;Dependence;Development;Disease;Disease Outbreaks;Distant;Endocytosis;Equus caballus;Europe;Family suidae;Ferrets;Genetic;Genome;Health;Human;Immunity;Infection;Influenza;Influenza A virus;Influenza C Virus;Influenza prevention;Investigation;Lead;Light;Membrane Fusion;Molecular;Mutation;N-Acetylneuraminic Acid;N-glycolylneuraminic acid;Oklahoma;Pathway interactions;Periodicals;Polysaccharides;Positioning Attribute;Public Health;Research;Research Priority;Resistance;Ruminants;Sendai virus;Serological;Sialic Acids;Specificity;Structure;Tissues;Tropism;Vaccines;Viral;Viral Genome;Virus;Virus Diseases;Virus Receptors;Work;Zoonoses;base;chemical group;cross-species transmission;extracellular;hemagglutinin esterase;influenzavirus;insight;novel;novel strategies;preference;receptor;receptor binding;sialic acid receptor;tissue tropism;trait;virus tropism

public_health_relevance:
Project Narrative Influenza D is a new type of influenza virus with bovines as a primaryreservoir that infects and causes influenza diseases in multiple mammalianspecies including swine and cattle. This proposal aims to understand the virus-receptor interaction and to address how this interaction impacts viralentry/fusion pathways and tissue/species tropism. The successful completion ofproposed work will offer novel insights to the cross-species transmissionmechanism of these newly discovered influenza D viruses from zoonoticreservoirs that will be critical to develop effective antiviral and vaccine strategiesagainst influenza D virus infection in humans and animals.


application_id: 10231514
project_number: 1RF1AG072728-01
project_title: Emerging Role of Tau Citrullination During Alzheimers disease and Tauopathies
administering_ic: NIA
award_notice_date: 2021-04-29
opportunity_number: PA-20-185
application_type: 1
activity_code: RF1
ic: AG
serial_number: 072728
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2021-05-01
project_end_date: 2024-04-30
study_section: Special Emphasis Panel[ZRG1 MDCN-R (03)]
contact_pi_person_id: 9300523
contact_pi: LEE, DANIEL CARL
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Emerging Role of Tau Citrullination During Alzheimers disease and TauopathiesHuman tauopathies are a group of neurological disorders including Alzheimers disease (AD) for which nodisease modifying therapies exist. Tau proteinopathic phenotypes show a spectrum of pathological hallmarksand clinical syndromes. There is increasing recognition that post-translational modifications (PTMs) promotestrain or conformational assemblies that contribute to tauopathies signifying a need to understand how novelPTMs contribute to tauopathy risk. Protein citrullination (citR) induced by peptidyl arginine deiminases (PADs)leads to an irreversible PTM that alters protein structure/ function by neutralizing positively charged arginineresidues within proteins. We discovered that aberrant tau activates PAD4 in neurons (protein PAD4 genePADi4); tau is client of PAD4 and is citrullinated at 14 arginine residues and those changes are associated withreduced tau fibrillization; citR prevents tau phosphorylation of key epitopes and impacts tau clearance; and taucitR is elevated in AD and in animal models of tauopathy. Our central hypothesis argues that increased PAD4-induced tau citR prevents higher-order fibrillization which decreases tangle formation alters tau metabolismimpacts structure/ function and reduces seeding activity. Assumptions of this model will be tested in vivo and invitro by neuronal PADi4 overexpression and conditional knockout mice multiple biochemical techniqueselectrophysiologic and behavioral approaches. We will establish how neuronal PADi4 expression impacts tauneuropathologic changes. Aim 1 will advance our understanding for PADi4 gain/ loss of function to establish thefoundation for citR tau biology and the impact on behavior in different models of tauopathy. We will establishhow citR regulates tau biochemistry and biology in cellular models. Aim 2 will mechanistically determine howPAD4-induced citR tau alters tau clearance aggregation seeding and microtubule binding. We will establish thespatio-temporal signature of citR tau in common human tauopathies. Aim 3 will provide the qualitative frameworkand seeding activity of citR tau in common human tauopathies. The proposed work provides the necessaryfoundation in not only better characterizing the role of citR in tauopathies but also further establishing the firstmechanistic cause for loss and gain of function of PAD4 during tau pathogenesis. Overall our applicationdescribes a new tau PTM and provide a therapeutic strategy for a new pathway in tau biology and in AD.

project_terms:
Affect;Age;Aging;Alzheimer's Disease;Amino Acid Substitution;Animal Model;Animals;Area;Arginine;Arginine deiminase;Behavior;Behavioral;Binding;Biochemical;Biochemistry;Biology;Biosensor;Cell model;Cells;Charge;Client;Clinical;Cognition;Disease;Electrophysiology (science);Epitopes;Fostering;Foundations;Genes;Goals;Human;Impaired cognition;In Vitro;Knock-out;Knockout Mice;Knowledge;Lead;Long-Term Potentiation;Metabolism;Microdialysis;Microtubule Polymerization;Microtubules;Modeling;Molecular Conformation;Molecular Target;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurons;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phenotype;Phosphorylation;Play;Post-Translational Protein Processing;Proteins;Research;Risk;Role;Site;Structure;Syndrome;Tauopathies;Techniques;Testing;Therapeutic;Tissues;Tubulin;Work;age related;cell type;conditional knockout;conformer;dimer;extracellular;gain of function;improved;in vivo;in vivo evaluation;loss of function;monomer;nervous system disorder;neurofibrillary tangle formation;neuropathology;normal aging;novel;overexpression;polymerization;prevent;protein structure function;spatiotemporal;tau Proteins;tau aggregation;tau function;tau phosphorylation

public_health_relevance:
Tauopathies consist of a group of neurodegenerative diseases including Alzheimers disease(AD) and currently no therapeutic treatments exist for tauopathies. Post-translationalmodifications (PTMs) of tau are thought to play important mechanistic roles and could serve as atarget strategy. This study will test how the citrullination pathway of tau impacts tau biology andneuropathology in vitro and in vivo which may provide a new foundation for citrullination duringtauopathies and AD.


application_id: 10231303
project_number: 1R56AG069685-01
project_title: The Biological Mechanisms of Metformin Effects on Aging-Associated Inflammation
administering_ic: NIA
award_notice_date: 2020-09-15
opportunity_number: RFA-AG-20-044
application_type: 1
activity_code: R56
ic: AG
serial_number: 069685
program_official: GUO, MAX
project_start_date: 2020-09-15
project_end_date: 2022-08-31
study_section: ZAG1-ZIJ-U(A1)
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Inflammation rises in aging to promote age-associated diseases including type 2 diabetes cardiovasculardisease and cognitive decline and is thus recognized as a significant cause of death across the globe.Metformin broadly alleviates age-associated inflammation or inflammaging. The proposed project will identifymechanisms of metformin action on age-associated changes in CD4+ T cell function. Focus on this cell type isjustified by data herein that used bioinformatics to uncover a Th17 cytokine profile preferentially produced byCD4+ T cells from sexagenarians. This inflammaging profile is strikingly similar to the profile that characterizesa major challenge to healthspan type 2 diabetes. Our new data show that physiologically achievable amountsof metformin ameliorate the Th17 inflammaging profile by improving mitochondrial bioenergetics and/orautophagy in CD4+ T cells from older subjects. Metformin concurrently increased non-mitochondrial glycolysisand thus lactate production but had none of these effects on cells from younger subjects. Data hereinchallenge dogmas that glycolysis fuels inflammation and raise the possibility that metformin can target eitherone of the two required inflammatory pathways to lower age-related inflammation. We will test the centralhypothesis that metformin ameliorates a Th17 inflammaging profile through targeting one of two criticalmechanisms non-mitochondrial autophagy or excessive mitochondrial OXPHOS to increases lactate andblock age-related Th17 cytokine production.We will analyze CD4+ T cells from overweight/obese subjects 60-85 yrs of age with cytokine profiles as ourprimary outcome. Some studies will use cells from younger adults to test conclusion from aged cells. We willinhibit/activate each step of the hypothesized pathway in cells stimulated in the presence/absence ofmetformin and measure effects on downstream elements with rigorous statistical and bioinformatic tests toquery similarities/differences in cytokine profiles. This approach will establish cause/effect relationshipsamongst metformin and mechanisms that drive age-related inflammation. Finally comparison of mechanisticchanges in T cells from older subjects exposed to metformin in vitro and in vivo the latter from people whotake metformin as part of their clinical care will establish clinical relevance of our in vitro mechanistic work tomeet our main objective: to pinpoint mechanisms by which metformin lowers inflammaging en route toimproving healthspan.

project_terms:
Age;Aging;Alzheimer's Disease;Anti-Inflammatory Agents;Antioxidants;Autophagocytosis;Bioenergetics;Bioinformatics;Biological;CD4 Positive T Lymphocytes;Cardiovascular Diseases;Cause of Death;Cell Aging;Cell physiology;Cells;Clinical;Clinical Trials;Coupled;Cytokine Activation;Data;Defect;Diabetes Mellitus;Disease;Elements;Endothelial Cells;Equilibrium;Exposure to;Glycolysis;Health;Human;Immune System Diseases;Impaired cognition;Impairment;In Vitro;Inflammaging;Inflammation;Inflammatory;Interleukin-6;Lactate Dehydrogenase;Length;Life;Link;Longevity;Mathematics;Measures;Mediator of activation protein;Metabolic;Metformin;Methods;Mitochondria;Modeling;Molecular;Molecular Analysis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Overweight;Oxidation-Reduction;Pathogenicity;Pathway interactions;Pharmaceutical Preparations;Physiological;Positioning Attribute;Production;Research;Risk;Role;Route;STAT3 gene;Source;T-Lymphocyte;Testing;Work;age related;base;cell age;cell type;clinical care;clinical practice;clinically relevant;combinatorial;comorbidity;cytokine;gain of function;healthspan;improved;in vivo;insight;novel;primary outcome;trait;transcription factor;young adult

public_health_relevance:
Numerous studies support the premise that inflammation as indicated by circulating pro-inflammatory cytokines rises in aging and triggers age-related health declines. Drugs with anti-inflammatory actions such as metformin are being investigated as means to promote the lengthof one's life spent in good health. To better understand the anti-inflammatory actions ofmetformin we will define molecular mechanisms underlying metformin's impact on inflammatorycells from older subjects and compare those outcomes to cells from people who take metforminas part of their clinical care.


application_id: 10231269
project_number: 5R01DA046526-03
project_title: Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
administering_ic: NIDA
award_notice_date: 2021-08-24
opportunity_number: PA-18-060
application_type: 5
activity_code: R01
ic: DA
serial_number: 046526
program_official: NAIR, SUNILA GOPI
project_start_date: 2020-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Acetylcysteine;Alkaloids;Anti-Inflammatory Agents;Antioxidants;Astrocytes;Attenuated;Autoimmune Diseases;Award;Binding;Blood - brain barrier anatomy;Brain;Brain region;Cells;Chemosensitization;Chronic;Cigar;Cigarette;Clinical;Cocaine;Complex;Cues;Data;Development;Electronic cigarette;Electrophysiology (science);FDA approved;Gene Transfer;Glean;Glutamate Receptor;Glutamate Transporter;Glutamates;Health;Immunohistochemistry;Individual;Inflammatory;Intervention;Investigation;Knowledge;Label;Learning;Measures;Mediating;Membrane;Memory;Microglia;Monoclonal Antibodies;Morphology;N-Methylaspartate;NF-kappa B;Neurobiology;Neurons;Nicotine;Nicotine Dependence;Nicotine Withdrawal;Nucleus Accumbens;Outcome;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Phosphotransferases;Pre-Clinical Model;Process;Public Health;Relapse;Research;Rewards;Rheumatoid Arthritis;Risk Factors;Role;Self Administration;Signal Transduction;Smoker;Smoking;Smoking Behavior;Structure;Synapses;Synaptic plasticity;TNF gene;Techniques;Testing;Therapeutic;Time;Tobacco;Tobacco use;Viral;Visualization;Western Blotting;Withdrawal;addiction;base;cell motility;craving;cytokine;designer receptors exclusively activated by designer drugs;drug abstinence;drug reward;electronic liquid;glutamatergic signaling;innovation;insight;migration;neurobiological mechanism;neuroinflammation;nicotine abuse;nicotine exposure;nicotine seeking behavior;nicotine use;novel;novel strategies;novel therapeutics;prevent;receptor;response;restoration;selective expression;small molecule;smoking abstinence;smoking addiction;tool;vaping;vapor


application_id: 10231091
project_number: 5U01DA051079-02
project_title: Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2021-05-13
opportunity_number: PAR-18-219
application_type: 5
activity_code: U01
ic: DA
serial_number: 051079
program_official: KLINE, RICHARD
project_start_date: 2020-08-15
project_end_date: 2023-04-30
study_section: ZDA1-IXN-O(11)S
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cocaine abuse is a major public health problem that directly or indirectly affects most communities andfamilies. There is still no FDA-approved medication specific for treatment of cocaine dependence or overdose.Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocainemedication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites viathe most favorable cocaine-metabolizing pathwaycocaine hydrolysis catalyzed by humanbutyrylcholinesterase (BChE) in plasmais recognized as the most efficient treatment strategy for cocaineoverdose and dependence. Since the catalytic efficiency of wild-type BChE against the naturally occurring (-)-cocaine is low we have designed and discovered a set of BChE mutants known as cocaine hydrolases(CocHs) with at least 1000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE.Preclinical and clinical data for the first one of our previously discovered CocHs has demonstrated the promiseof enzyme therapy approach to the treatment of cocaine dependence. Our more recently designed anddiscovered novel CocH entity denoted as CocH5-Fc(M6) which has not only further improved catalyticefficiency against cocaine but also a considerably prolonged biological half-life. It has been demonstrated thata single dose of CocH5-Fc(M6) can be used to completely block cocaine-induced physiological behavioraland reinforcing effects for a long period of time in animal models. In addition a stable CHO cell line capable ofefficiently expressing CocH5-Fc(M6) and the corresponding master cell bank (MCB) have been developedalong with establishment of the robust upstream and downstream protein production processes ready forlarge-scale CocH5-Fc(M6) protein production. Built on the encouraging progress of our rational designdiscovery and development of the highly efficient long-acting CocH entity CocH5-Fc(M6) the proposed newproject is focused on further development of CocH5-Fc(M6) as a novel therapeutic candidate for cocainedependence treatment including large-scale production of the CocH5-Fc(M6) protein material using thedeveloped MCB and established robust upstream and downstream protein production processesinvestigational new drug (IND)-enabling studies and first-in-human (FIH) clinical trials. The obtained clinicaldata about the safety pharmacokinetics and ex vivo pharmacodynamics of CocH5-Fc(M6) in humans willenable us to rationally design the most appropriate dosage regimen for future further clinical trials to determinethe clinical efficacy of CocH5-Fc(M6) in cocaine-dependent patients. Thus this investigation will move apromising candidate of the highly desired enzyme therapy closer toward FDA approval for cocainedependence treatment.

project_terms:
Affect;Animal Model;Antibodies;Behavioral;Binding;Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cell Line;Chinese Hamster Ovary Cell;Clinical Data;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependence;Communities;Development;Dose;Double-Blind Method;Drug Kinetics;Enzymes;FDA approved;Family;Formulation;Future;Half-Life;Human;Hydrolase;Hydrolysis;Immunoglobulins;Infusion procedures;Intake;Investigation;Investigational Drugs;Legal patent;Medical;Metabolic;Metabolism;Monoclonal Antibodies;Neuraxis;Neurons;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Phase II/III Trial;Physiological;Placebos;Plasma;Process;Production;Proteins;Public Health;Randomized;Rattus;Regimen;Safety;Schedule;Self Administration;Serum Albumin;Time;Vaccines;Work;base;cell bank;clinical efficacy;cocaine overdose;design;dosage;drug of abuse;efficacy testing;enzyme therapy;first-in-human;improved;in vivo;large scale production;mutant;novel;novel therapeutics;placebo controlled study;placebo group;pre-clinical;preclinical safety;safety testing;small molecule;social;therapeutic candidate;treatment group;treatment strategy

public_health_relevance:
The outcomes of this investigation will enable us to design the most appropriate dosage regimen for futurefurther clinical trials to determine the clinical efficacy of the long-acting cocaine hydrolase in cocaine-dependent patients.


application_id: 10229513
project_number: 5R01HL142973-04
administering_ic: NHLBI
award_notice_date: 2021-07-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 142973
program_official: VARAGIC, JASMINA
project_start_date: 2018-08-20
project_end_date: 2023-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-08-01
project_title:
A novel mechanism by which smooth muscle BMAL1 regulates IL-6 and sexual dimorphism of abdominal aortic aneurysm

project_abstract:
PROJECT SUMMARYAbdominal aortic aneurysm (AAA) is a vascular disease affecting millions of Americans that accounts for15000 deaths per year in the United States. Currently open or endovascular surgery is the only therapeuticoption for AAA as no drug has been approved for treatment of this devastating disease highlighting an urgentneed for new mechanistic understandings of AAA. We recently reported that administration of mineralocorticoidreceptor (MR) agonists Aldo or deoxycorticosterone acetate (DOCA) plus salt but not Aldo DOCA or saltalone to 10-month-old C57BL/6 male mice potently induces AAA and our preliminary data demonstrated thatadministration of angiotensin II (Ang II) plus salt but not Ang II alone to 10-month-old C57BL/6 male mice alsopotently induces AAA. While the mechanism remains elusive our preliminary data show that Aldo- or Ang II-salt-induced AAA occurs only or mostly in male but not in female or orchidectomized (orx) male mice. Toelucidate the mechanism that underlies sexual dimorphism of AAA we identified several genes that wereselectively upregulated by Aldo-salt in aorta in male but not in female or orx male mice. Among these genescircadian clock BMAL1 and inflammatory cytokine interleukin 6 (IL-6) are particularly promising as BMAL1 hasnot been previously implicated in AAA despite wide recognition that aortic dissection and aneurysmal ruptureare characterized by circadian variation and as IL-6 has been associated with human AAA by recent largegenome-wide association studies (GWAS). Our preliminary data show that selective deletion of BMAL1 fromsmooth muscle (SM) completely abolished DOCA-salt-induced AAA and IL-6 upregulation. In addition wefound that treatment of mice with a novel small molecule inhibitor targeting the IL-6 signaling significantlydiminished Aldo-salt-induced AAA. Based on these provocative preliminary data and the literature thattestosterone (T) promotes AAA whereas estrogen (E2) protects against AAA we hypothesize that T and E2critically regulate sexual dimorphism in Aldo- or Ang II-salt-induced AAA via SM-BMAL1 and IL-6signaling and further that targeting IL-6 signaling represents a novel therapeutic strategy againstAAA. Two specific aims test this central hypothesis: Aim1. To determine whether sex hormone is crucial forAldo- or Ang II-salt to activate BMAL1 in aorta and thereby result in sexual dimorphism in Aldo- or Ang II-salt-induced AAA. Aim2. To define the mechanism by which IL-6 is transcriptionally regulated by SM-BMAL1 and totarget IL-6 signaling as a novel therapeutic strategy against Aldo- or Ang II-salt-induced AAA. To achieve theseaims we will administer Aldo- or AngII-salt and/or T or E2 to 10-month-old normal or castrated C57BL/6 maleor female mice SM-BMAL1-KO IL-6R-KO and wild-type control mice to induce SM-BMAL1 and IL-6 signalingand AAA. The proposed studies will shed new mechanistic insight into a novel role of BMAL1 and IL-6signaling in sexual dimorphism of AAA. Moreover the results will provide preclinical evidence that targeting IL-6 signaling represents a novel therapeutic strategy against AAA.

project_terms:
ARNTL gene;Abdominal Aortic Aneurysm;Accounting;Acetates;Affect;Age;Agonist;Aldosterone;American;Angiotensin II;Animal Model;Aorta;Cardiovascular Diseases;Cessation of life;Country;Data;Deoxycorticosterone;Disease;Dissection;Estrogens;Female;Genes;Genetic Transcription;Goals;Gonadal Steroid Hormones;Heart failure;Human;Hypertension;Inflammatory;Interleukin 6 Receptor;Interleukin-6;Left Ventricular Hypertrophy;Link;Literature;Mediating;Mineralocorticoid Receptor;Mus;Myocardial Infarction;Operative Surgical Procedures;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Play;Prevalence;Reporting;Rheumatoid Arthritis;Role;Rupture;Serum;Sex Differences;Signal Transduction;Smooth Muscle;Sodium Chloride;Stroke;Testing;Testosterone;Therapeutic;Transcriptional Regulation;United States;Up-Regulation;Variant;Vascular Diseases;Woman;base;circadian;circadian pacemaker;cytokine;effective therapy;genome wide association study;insight;male;men;mortality;neutralizing antibody;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;pre-clinical;salt intake;sexual dimorphism;sham surgery;small molecule inhibitor;tocilizumab

public_health_relevance:
PROJECT NARRATIVEAbdominal aortic aneurysm (AAA) is a vascular disease with greater prevalence in men than in women overthe age of 60 and a high mortality rate (65% to 85%) related to aneurysmal rupture accounting for about 2% ofall deaths in Western countries. The goals of this application are to use new animal models that we recentlydeveloped to elucidate the mechanisms responsible for sex difference of AAA and identify new therapeutictargets to develop new drugs for treatment of AAA.


application_id: 10228656
project_number: 5R01HD080205-07
administering_ic: NICHD
award_notice_date: 2021-07-19
opportunity_number: PA-18-480
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(90)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-08-01
project_terms:
Address;Anodes;Atrial Natriuretic Factor;Attenuated;Autonomic Dysfunction;Autonomic Dysreflexia;Biological Markers;Bladder;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Caring;Catheterization;Cathodes;Cervical;Chest;Chills;Data;Electrodes;Event;Feedback;Frequencies;Goals;Guidelines;Headache;Heart Rate;Home;Home environment;Homeostasis;Hormones;Human;Hypertension;Hypotension;Individual;International;Intestines;Laboratories;Lesion;Location;Maintenance;Manometry;Measures;Monitor;Norepinephrine;Outcome;Participant;Persons;Physiological;Piloerection;Population;Quality of life;Questionnaires;Recovery;Rectum;Reflex action;Renin;Reporting;Research;Severities;Sex Functioning;Signal Transduction;Societies;Spinal Cord;Spinal cord injury;Symptoms;System;Tension Headache;Therapeutic;Time;Training;Urodynamics;Vasopressins;Visceral;abdominal pressure;base;blood pressure regulation;improved;indexing;mobile application;multidisciplinary;pressure;prevent;programs;psychologic;rectal;response;time interval;urinary;vasoconstriction;voltage


application_id: 10228577
project_number: 5F30DE028166-04
project_title: Regulation of ZEB1 by Porphyromonas gingivalis in gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2021-07-28
opportunity_number: PA-18-673
application_type: 5
activity_code: F30
ic: DE
serial_number: 028166
program_official: BROWN, ANISSA F
project_start_date: 2018-09-01
project_end_date: 2022-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14903180
contact_pi: FITZSIMONDS, ZACKARY R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryOral cancer is the 11th most frequently diagnosed cancer in the world and due to its late diagnosis it has anapproximately 50% survival rate after 5 years. Metastasis is meditated through Epithelial to MesenchymalTransition (EMT) which is the process by which epithelial cells lose their tight junctions and apical/basal polarityand shift to a more invasive mesenchymal phenotype giving the cancer cells systemic access through invasionof the bloodstream. EMT is mediated through several transcriptional factors however we will focus on ZEB1.Porphyromonas gingivalis is an oral obligate anaerobe that when present shifts the host/microbe relationshipfrom synergy to a more dysbiotic environment which contributes to periodontal disease. P. gingivalis has beenshown to invade gingival epithelial cells and once inside the cells can inhibit apoptosis ramp up the cell cycleand more recently by our lab has been shown to upregulate ZEB1. Although we are beginning to understand thepotential oncogenic role of P. gingivalis we do not currently know how ZEB1 is regulated by P. gingivalis ingingival epithelial cells. Our preliminary data suggests that this regulation is occurring through SMAD signalingregulation and through the long non-coding RNA ZEB1-AS1. SMAD signaling is a branch of the TGF-b signalingpathway which during embryonic development is responsible for producing mesenchymal cells from the initialepithelium. SMAD signaling occurs by phosphorylation of SMAD2/3 by the TGF-b receptor followed by theformation of a transcriptional regulatory trimer by SMAD2/3 and SMAD4 and finally nuclear localization andupregulation of ZEB1. Additionally ZEB1 can bind to SMAD2/3 and SMAD4 to form a ZEB1/SMAD trimer toregulate ZEB1 transcription. We have found that P. gingivalis upregulates the regulatory SMAD3 which suggestsP. gingivalis is able to intercept this pathway to upregulate ZEB1. We have also found that P. gingivalisupregulates ZEB1-AS1 which has been shown in hepatocarcinoma and esophageal squamous cell carcinomato directly upregulate ZEB1 and our preliminary data supports this as knocking down ZEB1-AS1 leads toabrogation of ZEB1 regulation by P. gingivalis in gingival epithelial cells. We will investigate mechanisms ofregulation by ZEB1-AS1 including direct promotion of gene expression in the nucleus through binding to P300and/or control of ZEB1 mRNA stability. EMT regulation is a complex process that involves integration of severalhost signaling pathways so we also suspect that ZEB1-AS1 will be integrated with SMAD signaling by potentiallyacting as a scaffold for SMAD3. Developing a better understanding of P. gingivalis mediated EMT will lay thefoundation for future studies to target these regulatory mechanisms for diagnosis and treatment and ultimatelyreduce the 50% chance of survival current patients have 5 years after diagnosis.

project_terms:
Amanitins;Anaerobic Bacteria;Apical;Apoptosis;Binding;Biopsy;Blood Circulation;Cancer Patient;Cell Cycle;Cell Cycle Progression;Cell Nucleus;Cells;Co-Immunoprecipitations;Complex;Data;Development;Diagnosis;E-Cadherin;E1A-associated p300 protein;Embryonic Development;Environment;Epidemiology;Epithelial;Epithelial Cells;Esophageal Squamous Cell Carcinoma;Family;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Germ Cells;Gingiva;Homeobox;Human;Immunofluorescence Immunologic;Immunohistochemistry;Immunoprecipitation;Intercept;Invaded;Knowledge;Laboratories;Lead;Literature;Luciferases;MADH2 gene;MADH3 gene;MADH4 gene;MADH6 gene;MADH7 gene;MMP9 gene;Malignant Neoplasms;Measures;Mediating;Mesenchymal;MicroRNAs;Migration Assay;Molecular;N-Cadherin;Neoplasm Metastasis;Nuclear;Oncogenic;Oral;Oral cavity;Pathway interactions;Patients;Periodontal Diseases;Periodontitis;Phenotype;Phosphorylation;Plasmids;Play;Porifera;Porphyromonas gingivalis;Primary carcinoma of the liver cells;Process;Prognosis;Property;Quantitative Reverse Transcriptase PCR;RNA;RNA Synthesis Inhibitors;Ramp;Regulation;Role;Sampling;Signal Pathway;Signal Transduction;Speed;Survival Rate;TGF Beta Signaling Pathway;Testing;Tight Junctions;Time;Tongue Neoplasms;Transcription Coactivator;Transforming Growth Factor beta Receptors;Translating;Untranslated RNA;Up-Regulation;Western Blotting;Zinc Fingers;arm;cancer cell;cancer diagnosis;differential expression;dysbiosis;epithelial to mesenchymal transition;expression vector;genetic corepressor;host-microbe interactions;human tissue;knock-down;mRNA Expression;mRNA Stability;malignant mouth neoplasm;mouth squamous cell carcinoma;new therapeutic target;novel;novel diagnostics;novel therapeutics;overexpression;prevent;promoter;recruit;response;scaffold;synergism;transcription factor;tumor

public_health_relevance:
Project NarrativeOral Cancer is the eleventh most frequently diagnosed cancer in the world and has approximately a 50% survivalrate 5 years post diagnosis. In this project we will study the intricate molecular interplay between Porphyromonasgingivalis and gingival epithelial cells and how this can lead to an environment conducive to cancer. This projecthas the potential to identify novel contributors to oral cancer and could potentially lead to novel therapeutics inthe future.


application_id: 10227741
project_number: 5R01CA208343-05
project_title: Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2021-07-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 208343
program_official: TIMMER, WILLIAM C
project_start_date: 2017-08-01
project_end_date: 2023-07-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GAO, TIANYAN
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Altered cellular metabolism has been widely recognized as an emerging hallmark of cancer. Althoughrecent advances in cancer metabolism research have begun to elucidate how metabolic changes supportcancer cell growth and survival alterations in fatty acid (FA) metabolism in cancer cells have received lessattention. Increasing evidence has suggested that increased FA biosynthesis is needed not only toaccommodate high rates of proliferation by providing building blocks for membrane synthesis but also toenhance the ability of cancer cells to defend against oxidative stress- or chemotherapy-induced cell death bychanging membrane lipid composition. Studies from our laboratories and others have demonstrated that FAsynthase (FASN) a key enzyme of de novo lipid biosynthesis is significantly upregulated in colorectal cancer(CRC). Our in vivo studies demonstrate that RNAi-mediated inhibition of FASN markedly reduces lung andhepatic CRC metastases and inhibits tumor angiogenesis. Collectively our studies indicate FASN may serveas a potential target for novel therapeutic agents. Recently several orally-available reversible potent andselective FASN small molecule inhibitors have been developed by our collaborator 3-V Biosciences. Theseagents have excellent pharmaceutical profiles and achieve antitumor effects at tolerated doses in a broadrange of tumors including non-small cell lung cancer ovarian and triple negative breast cancers. Thetranslational goal of our project is to define the metabolic adaptations that occur in colon cancer and toconduct a clinical trial to evaluate the effect of FASN inhibitor TVB-2640 on modulating cellular metabolismand proliferation in colon cancer patients. The central hypothesis for our proposal is that upregulation ofFASN expression and activity occurs in a subset of colon cancer patients; therefore these individuals wouldbenefit from a therapeutic approach that includes targeted inhibition of de novo lipogenesis. The followingSpecific Aims are proposed: 1) to determine the effect of altered FASN expression on metabolic reprogramingin colon cancer; 2) to delineate the anti-proliferative effect of FASN inhibition using patient-derived xenograft(PDX) models of colon cancer; and 3) to perform a pilot clinical trial in collaboration with 3-V Biosciences toassess pharmacodynamic effects on metabolic endpoints following short-term treatment with a novel FASNinhibitor (TVB-2640) prior to colon resection. Our highly collaborative group has the requisite expertiseinnovative model systems state-of-the-art technology and novel inhibitors to make rapid progress that willsignificantly advance our understanding of the FASN-mediated metabolic alterations of colon cancers andpotentially provide novel treatment strategies based on a more focused and personalized approach.

project_terms:
Acute;Address;Apoptosis;Attention;Behavior;Benign;Biological;Biological Models;Biological Sciences;Cancer Cell Growth;Cancer Etiology;Carnitine;Cell Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Colorectal Cancer;DNA Sequence Alteration;Development;Dose;Enzymes;Epithelial Cells;Etiology;Excision;Fatty Acids;Fatty-acid synthase;Future;Glucose;Glycolysis;Goals;Growth;Hepatic;Individual;Laboratories;Lead;Lipids;Lung;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Membrane Lipids;Metabolic;Metabolism;Mitochondria;Mucous Membrane;Non-Small-Cell Lung Carcinoma;Oncogenic;Oral;Ovarian;Oxidative Stress;Palmitates;Pharmacodynamics;Pharmacologic Substance;Phospholipids;Production;RNA Interference;Research;Resected;Respiration;Signal Pathway;Slice;Techniques;Technology;Therapeutic;Therapeutic Agents;Tissues;Triglycerides;Tumor Angiogenesis;United States;Up-Regulation;Warburg Effect;antitumor effect;base;beta catenin;cancer cell;cell growth;cell transformation;chemotherapy;colon cancer patients;colon cancer treatment;colorectal cancer metastasis;colorectal cancer progression;experimental study;extracellular;fatty acid biosynthesis;fatty acid metabolism;in vivo;inhibitor/antagonist;innovation;lipid biosynthesis;lipid metabolism;membrane synthesis;metabolomics;multidisciplinary;neoplastic;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;patient subsets;personalized approach;randomized placebo-controlled clinical trial;response;secondary endpoint;small molecule inhibitor;stable isotope;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor metabolism;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEColorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Alteredcellular metabolism is required to drive tumorigenesis and progression. Our study will define the metabolicadaptations associated with increased fatty acid synthase (FASN) expression in colon cancer patients anddelineate the subset of patients who may benefit from treatment with FASN inhibitors.


application_id: 10227663
project_number: 5F31NS116912-02
project_title: Understanding the immune response after mild TBI: Do endothelial cells play a major role?
administering_ic: NINDS
award_notice_date: 2021-08-12
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: NS
serial_number: 116912
program_official: AWWAD, HIBAH OMAR
project_start_date: 2020-09-01
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 15837218
contact_pi: BODNAR, COLLEEN
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT:The vast majority (over 90%) of traumatic brain injuries (TBI) are classified as mild TBI (mTBI). While mostindividuals recover from mTBI quickly a significant minority (10-15%) of patients with mTBI experiencepersistent symptoms  there are no FDA approved treatments for these individuals. Chronic neuroinflammationand vascular disruption following TBI create an unfavorable environment for recovery. More broadlyneuroinflammation and vascular dysfunction are significant contributors to other CNS diseases as wellincluding Alzheimers disease. My preliminary results demonstrate that interleukin-1 (IL-1) signaling throughinterleukin-1 receptor 1 (IL-1R1) may be as a link between chronic neuroinflammation and vascular pathologyand serve as a therapeutic avenue. IL-1 a major pro-inflammatory cytokine is upregulated following all TBIseverities. IL-1 release has been linked with downstream alterations of the vasculature including changes tothe neurovascular unit blood flow alteration angiogenesis and increased release of cytokines chemokinesand growth factors. We have found that brain endothelial cells express a high number of IL-1R1 receptors.Further we have demonstrated that mice lacking IL-1R1 show reduced neuroinflammation followingexperimental mTBI. We hypothesize that following mTBI brain endothelial cells specifically through IL-1R1 act as a mediator of the neuroimmune and vascular responses. To test this hypothesis we will use aclosed head injury model (CHI) to model a mTBI in mice. Further we will manipulate IL-1R1 using an inducibleendothelial cell-specific IL-1R1 knockout (eKO) a global knockout in which IL-1R1 has been restored only inthe endothelial cells (eRestore) and an IL-1R1 reporter mouse in which the protein and mRNA are labeled. Inaim 1 we will determine the cellular and temporal expression changes of IL-1R1 in the brain following CHIusing the reporter mice. Through this aim I will be able to determine how TBI alters IL-1R1 across time as wellas IL-1R1 association with arteries veins and capillaries while also honing my skills in histology techniques.In aim 2 we will delineate endothelial IL-1R1-dependent neuroinflammatory responses following CHI inwildtype eKO and eRestore mice. Through this aim I will get experience in animal surgeries as well as RNAisolation and Nanostring gene expression analysis. Finally in aim 3 we will investigate the involvement ofendothelial IL-1R1 in vascular structure and blood flow changes after TBI. To do this we will use vesselpainting and speckle contrast diffusion correlated tomography (scDCT). If we find support for our hypothesiswe will provide the groundwork for the development of IL-1 therapeutics for the treatment of mTBI as well asdescribe a physiological response of the CNS that can be applied to other diseases. Overall the questionoutlined in this proposal not only moves the field forward but also provides significant scientific training whichwill position me as a strong candidate for post-doctoral work and a future career as an independent scientist.

project_terms:
3-Dimensional;Acute;Address;Affect;Alzheimer's Disease;Animals;Antibodies;Arteries;Astrocytes;Behavior;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Blood flow;Brain;Brain Diseases;Brain Injuries;Cells;Central Nervous System Diseases;Cerebrovascular Circulation;Chronic;Closed head injuries;Cognitive;Confocal Microscopy;Development;Diffusion;Disease;Eko;Endothelial Cells;Endothelium;Environment;FDA approved;Fluorescence-Activated Cell Sorting;Fluorescent Dyes;Future;Gene Expression Profiling;Genes;Growth Factor;Hemagglutinin;Histology;Hour;Human;Image;Immune;Immune response;Immunohistochemistry;Individual;Inflammation;Inflammatory;Inflammatory Response;Influenza Hemagglutinin;Injury;Interleukin-1;Interleukin-1 Receptors;Knock-out;Label;Link;Location;Mediating;Mediator of activation protein;Messenger RNA;Minority;Modeling;Mus;Neurodegenerative Disorders;Neuroimmune;Operative Surgical Procedures;Oranges;Pathology;Pathway interactions;Patients;Pattern;Pericytes;Physiological;Play;Positioning Attribute;Postdoctoral Fellow;Proteins;RNA;Recovery;Reporter;Role;Scientist;Severities;Signal Transduction;Structure;Techniques;Testing;Therapeutic;Time;Training;Traumatic Brain Injury;United States;Vascular Diseases;Veins;Work;angiogenesis;brain endothelial cell;career;cell cortex;chemokine;cytokine;density;experience;functional outcomes;genetic manipulation;improved;lipophilicity;mild traumatic brain injury;nano-string;neuroinflammation;neurovascular unit;persistent symptom;receptor;reconstruction;red fluorescent protein;response;skills;tomography

public_health_relevance:
Project NarrativeChronic neuroinflammation and vascular pathologies are seen in traumatic brain injury Alzheimers and othercentral nervous system diseases  endothelial interleukin-1 receptor 1 (IL-1R1) may serve as the link betweenthese two pathologies. Our studies will provide support that endothelial IL-1R1 signaling can be a targetablepathway in brain injury as well as other neurodegenerative diseases that affect millions of individuals in theUnited States and worldwide.


application_id: 10227662
project_number: 5F30EY031545-02
project_title: Ocular complications of CHARGE Syndrome: The role of Sox11
administering_ic: NEI
award_notice_date: 2021-08-18
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: EY
serial_number: 031545
program_official: AGARWAL, NEERAJ
project_start_date: 2020-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-F03A-N(20)L]
contact_pi_person_id: 15716225
contact_pi: KRUEGER, LAURA
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Disruptions in eye development are associated with structural birth defects such as microphthalmiaanophthalmia and coloboma (collectively referred to as MAC) and are a significant cause of pediatricblindness. Ocular abnormalities often occur alongside those of brain and craniofacial defects highlighting thesignificant signaling interactions between the developing structures of the head; indeed MAC is a commonfeature of systemic congenital malformation syndromes. One example is CHARGE syndrome a genetic neuralcristopathy characterized by coloboma heart defects choanal atresia growth retardation genitalabnormalities and ear abnormalities. Mutations in chromodomain helicase binding protein 7 (CHD7) anddefects in neural crest cell development and migration have been implicated in the pathogenesis of CHARGEsyndrome however the mechanisms underlying the ocular birth defects observed in CHARGE patients havenot been identified. Our laboratory studies the development of the vertebrate visual system using zebrafish (Danio rerio).Previous work from our lab has shown that knockdown of Sox11 a member of the SoxC family of transcriptionfactors in zebrafish results in microphthalmia coloboma brain trunk and heart defects all phenotypesobserved in CHARGE syndrome. Furthermore we found that Sox11 is required for the expression of Bonemorphogenic proteins (BMPs) during ocular development. In humans a duplication of Sox11 has beenidentified in a patient clinically diagnosed with CHARGE syndrome and CHD7 has been shown to directlyinteract with Sox11 and Sox4 in neural stem cells. Based on these data my central hypothesis is that the lossof Sox 11 expression leads to disruptions in neural crest cell dynamics as well as alterations in BMP signalingduring development. This hypothesis will be tested in the following aims 1) Determine the role that Sox11 andChd7 play in the specification proliferation survival and migration of cranial neural crest cells and 2)Determine whether Sox11 and Chd7 deficiency alters cranial BMP signaling. This proposal will employinnovative and cutting edge live imaging techniques as well as advanced biochemical and molecular biologyapproaches and will leverage the power of the zebrafish model to tackle an important problem in ocularpediatric genetics. Successful completion of this project will define the role of Sox11 in the pathogenesis of the oculardefects such as those observed in CHARGE syndrome and make progress towards improving theidentification management and treatment of congenital eye malformations. Additionally this predoctoralproposal allows the candidate to develop unique technical critical thinking and effective communication skillscrucial to a physician-scientist specializing in ophthalmic pediatric genetics.!

project_terms:
Anophthalmos;Binding Proteins;Biochemical;Biological Models;Blindness;Brain;CHARGE syndrome;CHD7 gene;Cephalic;Childhood;Choanal Atresia;Chromatin;Chromosomal Duplication;Code;Coloboma;Communication;Communication Research;Confocal Microscopy;Congenital Abnormality;Craniofacial Abnormalities;Critical Thinking;DNA Binding Domain;Data;Defect;Development;Disease;Ear;Eye;Eye Development;Eye diseases;Family;Fetal Development;Fluorescence-Activated Cell Sorting;Future;Genes;Genetic;Genetic Research;Genital;Genitalia;Goals;Growth;Head;Heart Abnormalities;Human;Image;Imaging Techniques;Immunoprecipitation;Inherited;Label;Laboratories;Laboratory Study;Light;Microphthalmos;Microscopy;Modeling;Molecular Biology;Morphogenesis;Mutation;Names;Neural Crest Cell;Pathogenesis;Pathway interactions;Patients;Phenotype;Physicians;Play;Process;Proteins;Regulation;Reporter;Research;Research Ethics;Role;SOX11 gene;SOX4 gene;Scientist;Signal Pathway;Signal Transduction;Signaling Protein;Structural Congenital Anomalies;Structure;Syndrome;Testing;Training;Transcription Coactivator;Transgenic Organisms;Visual impairment;Visual system structure;Work;Zebrafish;base;bone morphogenic protein;clinical Diagnosis;clinical phenotype;developmental genetics;eye formation;helicase;improved;innovation;knock-down;malformation;member;migration;mutant;nerve stem cell;novel therapeutics;pre-doctoral;preservation;relating to nervous system;sex;sight restoration;skills;sry Genes;transcription factor;vision development

public_health_relevance:
Microphthalmia anophthalmia and coloboma (collectively referred to as MAC) are congenital ocular disordersthat are a significant cause of visual impairment. The proposed research will define the role of protein codinggene Sox11 in development of the eye and will determine if defects in Sox11 cause inherited eye diseases.Findings from this project will further our understanding of eye formation during fetal development and provideavenues for future treatments of inherited eye diseases.!


application_id: 10227221
project_number: 5R21AT010847-02
project_title: Mechanisms underlying local and systemic effects of massage
administering_ic: NCCIH
award_notice_date: 2021-07-22
opportunity_number: PA-18-322
application_type: 5
activity_code: R21
ic: AT
serial_number: 010847
program_official: TUTTLE, ALEXANDER H
project_start_date: 2020-08-01
project_end_date: 2023-07-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYThe loss of skeletal muscle mass is a common symptom associated with diseases such as cancer AIDS diabetes congestive heart failure and with aging. Muscle atrophy is associated with poor disease prognosis and decreased quality of life and therefore maintaining muscle size and reducing the loss of muscle during disuse atrophy is of vital significance. Mechanical stimulation of muscle such as during resistance exercise induces protein synthesis needed to increase muscle protein content and muscle size. We showed that mechanical stimulation applied to skeletal muscle in the form of massage is an effective mechanotherapy in rats since it leads to a shift in protein turnover favoring anabolism and enhanced regrowth after disuse-induced atrophy. Whether the same positive effect of massage occurs in humans is currently unknown but would be extremely beneficial for skeletal muscle and overall health in case where resistance exercise is contraindicated or not feasible. In addition to the direct anabolic effects on the massaged rat muscle we showed an equally beneficial response on the homologous muscle in the contralateral non-massaged limb of rats and humans. This novel finding indicated the existence of indirect mechanisms that could have profound systemic effects beyond the massaged muscle. Extracellular vesicles (EVs) are lipid membrane-bound vesicles released from cells with the ability to modulate function of cells from which they are released as well as in cells with which they fuse. As such EVs are likely mediators of the well-documented but poorly-understood effects of massage in humans on the brain and other organs such as relief of pain anxiety or depression or changes in immunity. Therefore the goal of this proposal is to determine anabolic effects of massage in human muscle and to identify whether EVs released with massage are candidates for beneficial effects of this mechanotherapy on muscle as well as other organs. The contribution of neuronal activity will also be investigated. In Aim 1 we will address the following hypothesis: Massage acts as a mechanotherapy by shifting protein biogenesis towards anabolism. Using a novel massage device we will apply mechanical load to muscle undergoing atrophy through unilateral lower limb suspension and mechanisms underlying muscle size regulation determined. Protein synthesis will be the primary outcome. In the exploratory Aim 2 we will test the hypothesis that massage induces cross-over effects through changes in EVs or neuronal activity. We will measure EVs and their miRNA cargo in the serum and markers of EV biogenesis in muscle of human subjects from Aim 1. Muscle activation in the contralateral limb will also be measured. Results from this study will indicate not only how mechanotherapy such as massage can attenuate atrophy and enhance anabolic processes during disuse but also determine whether EVs are a candidate mechanism for the overall health benefits of massage. This application directly addresses the goals set out in the following program announcement from the National Center for Complementary and Integrative Health: PA-18-322 Health: Fundamental Science Research on Mind and Body Approaches (R21).

project_terms:
Acquired Immunodeficiency Syndrome;Address;Aging;Anabolism;Anxiety;Area;Atrophic;Attenuated;Biogenesis;Biopsy;Brain;Cell Count;Cell physiology;Cells;Clinical;Communication;Complementary Health;Congestive Heart Failure;Contralateral;DNA;DNA biosynthesis;Data;Devices;Diabetes Mellitus;Disease;Distant;Disuse Atrophy;Female;Funding Opportunities;Future;Goals;Grant;Health;Health Benefit;Human;Immunity;Integrative Medicine;Intensive Care Units;Intervention;Limb structure;Lipids;Lower Extremity;Maintenance;Malignant Neoplasms;Massage;Measurement;Measures;Mechanical Stimulation;Mechanics;Mediator of activation protein;Membrane Lipids;Mental Depression;MicroRNAs;Mind-Body Intervention;Muscle;Muscle Fibers;Muscle Proteins;Muscular Atrophy;NIH Program Announcements;Neurons;Organ;Orthopedic Surgery;Outcome;Participant;Pathway interactions;Patients;Population;Process;Prognosis;Protein Biosynthesis;Proteins;Quality of life;RNA;Rattus;Regulation;Research;Resistance;Ribosomes;Science;Sedation procedure;Serum;Serum Markers;Site;Skeletal Muscle;Suspensions;Testing;Tissues;Trauma;associated symptom;attenuation;clinically significant;common symptom;extracellular vesicles;human subject;innovation;male;mechanical load;mechanotransduction;muscle form;novel;pain relief;primary outcome;protein degradation;release factor;resistance exercise;response;satellite cell;secondary outcome;skeletal muscle wasting;standard care;symptom management;vesicular release;young adult

public_health_relevance:
NARRATIVEMaintenance of muscle mass is clinically significant not only because muscles are required for mobilizationand serve as a reservoir for protein but also because loss of muscle is associated with poor health outcomes.We propose that the mechanical activity of massage can produce beneficial effects in humans to maintainmuscle size and protein synthesis during atrophy. Data obtained from this study will form the basis for futuretrials with clinical populations in which muscle atrophy is prevalent and cannot be treated with resistanceexercise such as in patients under sedation in intensive care units or after orthopedic surgery or trauma inwhich non-weight bearing is prescribed.


application_id: 10227171
project_number: 5R01EY021769-09
project_title: Vertebrate photoreceptor development and regeneration
administering_ic: NEI
award_notice_date: 2021-07-30
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2023-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYInherited retinal dystrophies such as retinitis pigmentosa (RP) are a leading cause of blindness forwhich there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby precursor cells are transplanted into the diseased eye toreplace the lost photoreceptors. While this is an exciting possibility several challenges to theimplementation of transplantation therapies must be overcome including the inefficient integration ofphotoreceptor precursors into the recipient retina and the difficulty of obtaining sufficient numbers ofphotoreceptor precursors for clinical application. To improve protocols for the in vitro culture of suchcells we must have a better understanding of the transcriptional networks that promote specificationof photoreceptor precursors. One of the long-term goals of our laboratory is to contribute to theseefforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish isespecially useful for studying photoreceptor biology because its retina contains numerous conesubtypes in addition to rods. Furthermore unlike mammals the zebrafish retina is able to regenerateneurons in response to experimental damage. The experiments described in this proposal will definethe role of three transcription factors -- Sox Sox11 and Her9 -- during retinal neurogenesis throughthe application of gene targeting and molecular genetic approaches. Our specific aims are as follows:Specific Aim I: Determine the role of Sox4 and Sox11 in photoreceptor differentiation. Using newlygenerated loss-of-function mutants in this aim we will 1) determine whether there is a dosage effectof Sox4/11 activity on rod photoreceptor number; 2) use state-of-the-art time-lapse imaging todetermine when and where Sox4 expression is required to achieve proper rod photoreceptordevelopment; 3) determine precisely how Sox4/11 regulate Hh and Bmp signaling; and 4) identify themolecular targets of Sox4/11. Specific Aim II: Determine the cause and extent of photoreceptordefects in the zebrafish her9 mutant. In this aim we will 1) determine the mechanism forphotoreceptor defects in her9 mutants; 2) determine whether loss of Her9 impairs vision; 3) identifythe upstream signaling pathway(s) that regulate her9 expression in the retina; and 4) determinewhether Her9-mediated VEGF expression in the avascular zebrafish retina regulates retinalprogenitor cell proliferation and differentiation. Completion of our proposal will bridge important gapsin our understanding of the molecular mechanisms of vertebrate photoreceptor differentiation andreveal underlying principles relevant to the development of approaches for the treatment of humanretinal degenerative disease.

project_terms:
Adoption;Animal Model;Biochemical;Biology;Blindness;Cell Differentiation process;Cell Transplantation;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Cone;Data;Defect;Development;Developmental Biology;Disease;Embryo;Event;Evolution;Eye diseases;Family;Gene Targeting;Genetic;Genetic Diseases;Genetic Transcription;Goals;Health;Homologous Gene;Human;Image;In Vitro;Inherited;Injury;Laboratories;Mammals;Mediating;Microphthalmos;Modeling;Molecular;Molecular Genetics;Molecular Target;Morphogenesis;Morphology;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Optics;Pathway interactions;Photoreceptors;Protocols documentation;Regulator Genes;Retina;Retinal Cone;Retinal Degeneration;Retinal Dystrophy;Retinitis Pigmentosa;Rod;Role;SOX11 gene;SOX4 gene;Signal Pathway;Signal Transduction;Suggestion;System;Therapeutic;Time;Transcription Repressor;Transgenic Organisms;Transplantation;Vascular Endothelial Growth Factors;Vertebrate Photoreceptors;Visual;Visual impairment;Visual system structure;Work;Zebrafish;base;cellular imaging;clinical application;dosage;experimental study;gene therapy;genetic approach;genome editing;imaging modality;improved;in vivo;loss of function;member;mouse genome;mutant;neurogenesis;notch protein;novel;optic cup;photoreceptor degeneration;precursor cell;response;retinal neuron;retinal progenitor cell;retinal rods;stem cell differentiation;stem cell proliferation;therapy development;transcription factor;transplantation therapy

public_health_relevance:
PROJECT NARRATIVE/RELEVANCE TO HUMAN HEALTHThe development of therapies to treat visual impairment resulting from photoreceptordegeneration will directly benefit from studies of animal models such as the zebrafish whichdevelops ex utero remains optically transparent throughout development and which displaysthe capacity for injury-induced neural regeneration. The goal of our proposal is to define the roleof the transcription factors Sox4 Sox11 and Her9 in the development of photoreceptor cellsand to identify the pathways that regulate their expression and what they in turn regulate. Thisinformation will facilitate efforts to understand photoreceptor developmental biology and to guidephotoreceptor differentiation from stem cells in vitro and in vivo for therapeutic purposes.


application_id: 10226362
project_number: 5R01DK048498-26
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2021-06-18
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2024-06-30
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The mammalian intestinal mucosa undergoes a process of continual renewal characterized by activeproliferation of stem cells localized near the base of the crypts; progression of these cells up the crypt-villusaxis with cessation of proliferation; and subsequent differentiation into one of the four primary cell types (i.e.enterocytes goblet cells Paneth cells and enteroendocrine cells). An imbalance in this highly-regimented andorderly process within the crypts is associated with a number of common intestinal pathologies (e.g. colorectalcancer and inflammatory bowel disease [IBD]). Delineating the molecular factors regulating intestinalproliferation and differentiation is crucial to our understanding of not only normal gut development andadaptation but also aberrant gut growth. With the support of this grant we have shown the importance of thePI3K/Akt/mTOR and Wnt/-catenin pathways in the regulation of intestinal cell proliferation and differentiation.In addition we showed that enhanced ketogenesis by mTORC1 inhibition contributes to the regulation ofintestinal cell differentiation and that tuberous sclerosis complex 2/mTORC1 signaling contributes to themaintenance of intestinal epithelial homeostasis. Moreover we found that activation of Wnt/-catenin signalingsuppresses the expression of the ketogenic enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) whichinhibits glycolysis in intestinal cells. Recently we have shown that deficiency of SIRT2 a member of the sirtuinfamily of proteins results in the activation of Akt/mTORC1 and Wnt/-catenin increased intestinal cellproliferation and stemness and increased expression of glycolytic hexokinases (HK) 1 and 2. Using single cellsequencing we found that HK1 and HK2 were differentially expressed in various types of intestinal cells;knockdown of HK2 but not HK1 increased Paneth and goblet cell differentiation. Based on our recentlypublished and preliminary findings we have further refined our central hypothesis to state that the glycolyticenzyme HK2 acting downstream of SIRT2 significantly contributes to the maintenance of normal intestinalhomeostasis. To examine our central hypothesis we have planned experiments with the following SpecificAims: 1) to further delineate the cellular mechanisms for SIRT2-mediated alterations of glycolysis andoxidative phosphorylation in intestinal cells; 2) to better define the role of HK2 in mediating the effects of SIRT2in the intestine; and 3) to determine the impact of alterations of SIRT2/HK2 on intestinal homeostasis in vivo.The studies in the current proposal represent direct and novel extensions of our previous findings and aredesigned to define in a systematic fashion the molecular mechanisms and signaling events regulating theprocesses of intestinal proliferation differentiation and adaptation utilizing a number of innovative techniquesincluding murine and human intestinal organoids novel transgenic models single-cell sequencing and stableisotope resolved metabolomics (SIRM).

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Biochemical;Cell Differentiation process;Cell Proliferation;Cell model;Cells;Colorectal Cancer;Data;Development;Differentiation and Growth;Enterocytes;Enteroendocrine Cell;Enzymes;Equilibrium;Event;FRAP1 gene;Glycolysis;Goblet Cells;Grant;Growth;Hexokinase 2;Homeostasis;Human;In Vitro;Inflammation;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Knock-out;Knockout Mice;Lead;Maintenance;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Mus;Organoids;Oxidative Phosphorylation;Paneth Cells;Pathology;Pathway interactions;Patients;Play;Process;Protein Family;Proteins;Publishing;Regulation;Role;SIRT1 gene;Seminal;Signal Pathway;Signal Transduction;Sir2-like Deacetylases;Sirtuins;System;Techniques;Testing;Transgenic Model;Tuberous sclerosis protein complex;Villus;base;beta catenin;cell type;clinically relevant;design;differential expression;experimental study;hexokinase;in vivo;innovation;insight;intestinal epithelium;intestinal homeostasis;ketogenesis;ketogentic;knock-down;member;metabolomics;mouse model;novel;novel therapeutic intervention;single cell sequencing;stable isotope;stem cell function;stem cell proliferation;stemness

public_health_relevance:
NarrativeThe intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to thistightly-controlled and highly-regimented process remain to be completely elucidated. Our recent findings haveidentified the glycolytic enzyme hexokinase 2 (HK2) acting downstream of SIRT2 as a critical factor in themaintenance of normal gut growth and differentiation. Delineating the cellular factors regulating these normalprocesses is crucial to our understanding of normal gut development and maturation and also various intestinalpathologies (e.g. inflammation) that can arise from deregulation of these pathways.


application_id: 10225435
project_number: 5R01NS107548-04
administering_ic: NINDS
award_notice_date: 2021-07-16
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 107548
program_official: FOUNTAIN, JANE W
project_start_date: 2018-08-15
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-08-01
project_title:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics

project_abstract:
Failure of anticancer drug treatment is largely due to overexpression of the P-gp/BCRP drug efflux system atthe blood-brain barrier. New evidence suggests that glioblastoma multiforme (GBM) induces P-gp/BCRP over-expression in capillaries of the brain hemisphere that is contralateral to the tumor. Thus after surgical removalof the primary tumor remnant tumor cells that are scattered throughout the brain remain shielded from anti-cancer drugs. This poses a significant clinical problem and represents an unmet critical need to develop strat-egies to overcome P-gp/BCRP. The absence of such strategies will likely prevent improvements in GBM ther-apy. The long-term goal of the investigator is to identify molecular mechanisms that control blood-brain barrierfunction and can be targeted to improve brain uptake of anticancer drugs. The overall objective of this applica-tion is to develop an effective therapeutic strategy to overcome P-gp/BCRP-mediated anticancer drug effluxand prolong survival in mice with GBM. Based on preliminary data the central hypothesis is that GBM inducesP-gp/BCRP overexpression and that inhibiting PI3K/Akt will decrease P-gp/BCRP overexpression which willincrease brain uptake of anticancer drugs thereby reducing tumor size and prolonging GBM mouse survival.The rationale for this research is that its successful completion is expected to provide a solid evidence-basedscientific framework for translating our strategy into the clinic. Based on strong preliminary data this hypothesiswill be tested by pursuing three specific aims: 1) Determine the mechanism(s) by which GBM inducesP-gp/BCRP overexpression; 2) Identify pathways that regulate P-gp/BCRP at the human blood-brain barrier;and 3) Develop a therapeutic strategy to increase anticancer drug brain uptake in GBM mice. Under the firstaim mechanistic steps involved in GBM-induced overexpression of P-gp/BCRP will be assessed in brain capil-laries of the hemisphere contralateral to the primary tumor. The impact of blocking these steps on brain uptakeof anticancer drugs in GBM-bearing mice will be determined. Under the second aim P-gp/BCRP regulation bythe PTEN/PI3K/Akt/mTOR pathway will be determined in brain capillaries from normal individuals and fromGBM patients. Under the third aim the therapeutic benefit of combining PI3K/Akt inhibitors with anticancerdrugs to reduce P-gp/BCRP levels with the goal of improving brain uptake of anticancer drugs and prolongingsurvival will be assessed in three different GBM models. The proposed research is innovative in the appli-cant's opinion because it represents a new and substantive departure from the status quo by shifting the focusto GBM-induced overexpression of blood-brain barrier P-gp/BCRP in the contralateral hemisphere and by uti-lizing a molecular switch-based approach to overcome P-gp/BCRP-mediated drug efflux to target remnant tu-mor cells distant from the primary tumor. The proposed research is significant because it is expected that thenew knowledge may have broad translational importance in the treatment of patients with GBM and potentiallyother brain tumors as well.

project_terms:
ABCB1 gene;ABCG2 gene;AKT inhibition;Antineoplastic Agents;Blood - brain barrier anatomy;Blood capillaries;Brain;Brain Neoplasms;Cells;Cerebral hemisphere;Clinic;Clinical;Contralateral;Data;Development;Distant;Drug Efflux;Excision;FRAP1 gene;Failure;Glioblastoma;Goals;Human;Individual;Ipsilateral;Knowledge;Lateral;Lead;Mediating;Mission;Modeling;Molecular;Mus;National Institute of Neurological Disorders and Stroke;Natural regeneration;Outcome;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Primary Neoplasm;Public Health;Regulation;Research;Research Personnel;Signal Transduction;Solid;System;TNF gene;TNFRSF1A gene;Testing;Therapeutic;Translating;Treatment outcome;United States National Institutes of Health;Work;base;blood-brain barrier function;cerebral capillary;effective therapy;evidence base;expectation;improved;in vivo;inhibitor/antagonist;innovation;lapatinib;neoplastic cell;nervous system disorder;novel;novel strategies;overexpression;prevent;therapeutically effective;treatment strategy;tumor;uptake

public_health_relevance:
The proposed research is relevant to public health because it is expected to provide a novel treatment strategyto overcome blood-brain barrier drug efflux for improved delivery of therapeutics into the brain specificallyanticancer drugs. Thus the proposed research is relevant to the mission of the NIH/NINDS that pertains todeveloping fundamental knowledge that will help reduce the burden of neurological disease.


application_id: 10225389
project_number: 5R01ES027778-05
project_title: Mechanism for arsenic induced carcinogenesis
administering_ic: NIEHS
award_notice_date: 2021-07-20
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 027778
program_official: TYSON, FREDERICK L
project_start_date: 2017-08-01
project_end_date: 2024-01-22
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractChromosomal instability (CIN) contributes to carcinogenesis by promoting aneuploidy. Arsenic is well known toinduce aneuploidy however the molecular mechanism by which arsenic induces aneuploidy-mediatedcarcinogenesis is yet to be delineated. We have identified a miRNA (hsa-miR-186) that is overexpressed inarsenic-induced squamous cell carcinoma and that induces CIN when overexpressed in human keratinocytes.This miRNA is encoded within intron 9 of the ZRANB2 gene and is co-transcribed as part of the ZRANB2transcript. Such embedded microRNAs are processed out of the intronic RNA by the microRNA maturationmachinery. ZRANB2 encodes an alternative splicing factor containing two zinc fingers each with four-cysteinescoordinating the zinc. These types of zinc fingers are targets for arsenite displacement of zinc. We hypothesizethat chronic arsenic exposure disrupts ZRANB2 function by displacing zinc from the zinc fingers; cellularhomeostatic mechanisms induce ZRANB2 transcription; coincident increased hsa-miR-186 leads to CINcontributing to arsenic-induced carcinogenesis. This project will determine the role of hsa-miR-186 in arsenicinduced CIN in human keratinocytes and how ZRANB2 structure and function are modulated by arsenicexposure. The following specific aims will be pursued to test this hypothesis: 1. Determine role of hsa-miR-186in carcinogenic transformation of immortalized keratinocytes (HaCaT cells).; 2. Determine mechanism ofarsenite disruption of ZRANB2 structure and function; 3. Determine potential of hsa-miR-186 over-expressionto induce chromosomal instability and potential of arsenite to inhibit ZRANB2 directed splicing in primarykeratinocytes. Successful completion of these aims will demonstrate a novel mechanism for epigeneticresponse to the environmental stress of arsenic exposure and demonstrate that this response causeschromosomal instability (CIN) linked to arsenic-induced skin carcinogenesis. This mechanism likely plays arole in arsenic-induced carcinogenesis in other organs as well. Thus hsa-miR-186 could be a biomarker forarsenic induced internal cancers in arsenic exposed patients. Demonstration of arsenite-exposure disturbanceof mRNA splicing patterns will open a new area of research into mechanisms of arsenic induced disease.

project_terms:
Acute;Alternative Splicing;Aneuploidy;Area;Arsenic;Arsenites;Binding;Biochemical;Biological Assay;Biological Markers;Biophysics;CRISPR/Cas technology;Cell Culture Techniques;Cells;Chromosomal Instability;Chromosome abnormality;Chronic;Circular Dichroism;Cysteine;Data;Disease;Dose;Electrophoretic Mobility Shift Assay;Epigenetic Process;Fingers;Generations;Genes;Genetic Transcription;Health;Human;Incubated;Introns;Knock-out;Lentivirus;Link;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Messenger RNA;MicroRNAs;Mitosis;Molecular;Monitor;Organ;Outcome;Patients;Pattern;Play;Process;RNA;RNA Splicing;Recombinants;Research;Role;Sampling;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;Stochastic Processes;Stress;Structure;Testing;Time;Transcript;Zinc;Zinc Fingers;arsenic-induced carcinogenesis;carcinogenesis;carcinogenicity;drinking water;experimental study;in vitro Model;in vivo Model;keratinocyte;novel;overexpression;response;tool;transcriptome sequencing;vector control

public_health_relevance:
NarrativeArsenic exposure via drinking water is a world-wide health problem. Skin is the major target organ of arsenicand skin cancer is a common outcome of chronic arsenic exposure. This application proposes to investigate anovel mechanism of arsenic-induced skin cancer.


application_id: 10225371
project_number: 5P30GM127211-04
project_title: Core B - Analytical Core
administering_ic: NIGMS
award_notice_date: 2021-07-29
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: ZGM1-RCB-3
subproject_number: 5340
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Phase III Analytical Core will support research into mechanisms linking obesity lipid metabolism andhuman disease risk through continued use of facility core instrumentation and resources to develop andsupport a suite of analytical services tailored for studies of the relationship between diet obesity and diseasemechanisms using preclinical models and clinical approaches. In addition expansion of services in lipidomicsand stable isotope tracer studies will augment capabilities for small animal metabolic phenotyping. This corehas developed extensive instrumentation that enables quantitation of a broad range of small moleculesuntargeted profiling of lipids in complex mixtures targeted quantification of biomarkers linking obesity todisease and methods for studies of glucose and fatty acid metabolism. Each of these analytical capabilitiesare of direct relevance to studies focused on diet nutrition and obesity in disease development. This core hascontributed data for more than 110 peer reviewed publications since 2008 in high impact journals providedservices for more than 60 investigators and contributed to new grant awards in environmental sciences. Thecore is well equipped and with expanded services is anticipated to develop self-sustaining capacity in PhaseIII of the COCVD.

project_terms:
Adipose tissue;Analytical Chemistry;Animals;Area;Award;Biological Assay;Biological Markers;Blood;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Collaborations;Complex Mixtures;Core Facility;Coupled;Data;Development;Diet;Diet and Nutrition;Dietary Carbohydrates;Dietary Fats;Disease;Ecology;Ensure;Fees;Funding;Glucose;Goals;Grant;High Pressure Liquid Chromatography;Human;Incidence;Individual;Institution;Journals;Kentucky;Laboratories;Link;Lipids;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Measures;Medicine;Methods;National Institute of Environmental Health Sciences;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Obesity associated disease;Peer Review;Phase;Phospholipids;Pre-Clinical Model;Publications;Reporting;Research;Research Personnel;Research Support;Resolution;Resources;Risk Factors;Rural;Services;Structure;Testing;Time;Tissues;Tracer;Training and Education;Triglycerides;United States National Institutes of Health;Urine;analytical method;base;biomarker development;cardiovascular risk factor;cohort;college;computational platform;disorder risk;energy balance;fatty acid metabolism;human disease;human subject;instrumentation;interest;lipid metabolism;lipidomics;metabolic abnormality assessment;metabolic phenotype;obesity development;operation;programs;small molecule;stable isotope;western diet


application_id: 10224876
project_number: 5R01DA016718-14
project_title: Licit and Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2021-08-11
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: WANG, JIA BEI
project_start_date: 2004-07-10
project_end_date: 2024-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Opioid misuse including prescription opioids heroin and fentanyl is epidemic in the United States andis associated with high morbidity and mortality. The current National Survey on Drug Use and Health estimatesthat at least 2.6 million people met criteria for an opioid use disorder (including prescription opioids and heroin).Opioid-related overdose deaths continue to climb with nearly 30000 deaths reported in 2014. Toxicologicalevidence from post-mortem studies reveals that polypharmacy is a very common finding in opioid-relateddeaths and it is especially common to find co-occurring substances with sedative properties. Despite thewidespread acknowledgment that non-opioid sedatives may enhance the risk of death from an opioidoverdose few controlled data exist on the pharmacodynamic effects of opioids in combination with theseagents and their co-prescription by providers is common. These studies aim to fill this critical knowledge gapby assessing agents with sedative properties that commonly are 1) prescribed with opioids (i.e.benzodiazepines gabapentin) 2) abused in combination with opioids and 3) found in combination at autopsy(benzodiazepines alcohol and gabapentin). Three inpatient human laboratory studies will be conducted thatemploy rigorous controlled experimental procedures to characterize the pharmacological interaction betweenoxycodone when taken in combination with either alprazolam (Experiment 1) alcohol (Experiment 2) orgabapentin (Experiment 3). Individuals with appropriate recreational drug use histories who are otherwisehealthy will be enrolled. An initial dose finding phase will precede each study to ensure subject safety andscientific rigor before proceeding to a robust randomized controlled design. The three studies will employrandomized placebo-controlled within-subject double-blind crossover designs and will be conducted in acontrolled hospital setting where appropriate medical supervision is available. Key safety outcomes includingexpired CO2 and other respiratory function indices pharmacodynamic measures related to abuse potentialand cognitive/psychomotor performance will be thoroughly examined over a range of doses for all drugs alone.Pharmacokinetic data (Exp. 1) will also be collected to assess the potential pharmacokinetic interaction as anunderlying mechanism of action and experimental analgesia/algesia data will be collected in Exp. 3 asgabapentin is commonly co-prescribed for pain relief with opioids. The analytic approach will include traditionalstatistics and modified isobolographic analyses to further elucidate the nature of the pharmacodynamicinteractions. The findings from these studies may directly inform prescribing practices and inform clinicalguidelines for physicians and other providers regulatory decision-making and may provide new information fortargeted interventions to reduce the harms of polysubstance prescribing and misuse.

project_terms:
Absence of pain sensation;Alcohols;Alprazolam;Autopsy;Benzodiazepines;Carbon Dioxide;Cessation of life;Characteristics;Clinical;Cognitive;Comparative Study;Crossover Design;Data;Decision Making;Dose;Double-Blind Method;Drug Controls;Drug Interactions;Drug Kinetics;Drug usage;Enrollment;Ensure;Epidemic;Fentanyl;Guidelines;Health;Heroin;Hospitals;Human;Individual;Inpatients;Intervention;Knowledge;Laboratories;Laboratory Study;Measures;Medical;Metabolic Pathway;Morbidity - disease rate;Nature;Opioid;Opioid agonist;Outcome;Overdose;Oxycodone;Pain Disorder;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Physicians;Physiological;Placebos;Polypharmacy;Procedures;Property;Provider;Psychomotor Performance;Randomized;Recording of previous events;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Safety;Sedation procedure;Supervision;Surgeon;Surveys;Testing;Time;Toxicology;United States;Work;benzodiazepine abuse;cognitive performance;experience;experimental study;gabapentin;illicit drug use;illicit opioid;indexing;mortality;mortality risk;non-opioid analgesic;off-label use;opioid abuse;opioid misuse;opioid mortality;opioid overdose;opioid use disorder;overdose death;pain model;pain relief;participant safety;prescription opioid;randomized controlled design;recreational drug use;safety outcomes;sedative;statistics;targeted agent;volunteer

public_health_relevance:
PROJECT NARRATIVEOpioid fatal and non-fatal overdoses have reached epidemic levels in the United States and many are theresult of combined use or misuse of opioids with other sedative-like substances. This research will provideimportant information on the relative safety and abuse-related risks of combining oxycodone with threedifferent classes of sedatives: benzodiazepines alcohol and gabapentinoids. The results of these studies mayinform medical prescribing practices and regulatory drug control.


application_id: 10224543
project_number: 7R01AG054559-04
project_title: Emerging Roles of Higher-order Polyamines During Tauopathies
administering_ic: NIA
award_notice_date: 2020-09-01
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: AG
serial_number: 054559
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-T(56)R]
contact_pi_person_id: 9300523
contact_pi: LEE, DANIEL CARL
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Collectively tauopathies including Alzheimers disease (AD) impact close to 6 million Americans and cost over$200 billion in medical care. They devastate families and cause victims to lose their memory their dignity andfinally their identity. Currently no disease modify agents exist for treating tauopathies and AD andspontaneous recovery is unknown; a diagnosis of tauopathy is a death sentence. Strategies proposed toreduce tau burden include increasing clearance decreasing phosphorylation or nitration reducing aggregationand diminishing inflammation among others. Arginine metabolism is poised at a critical branch-point andserves as a precursor for nitric oxide generation from nitric oxide synthases or polyamine production fromarginase (Arg1). Our data indicates that Arg1 overexpression in a mouse model of tauopathy reduces multipleaspects of the tau phenotype; phospho-tau deposition Gallyas staining hippocampal atrophy high molecularweight tau multimers tau nitration cytokine markers of inflammation inhibitors of autophagy and proteinkinase activation. Many of these effects can also be demonstrated in cell culture. We also show that higher-order polyamines directly block tau aggregation and promote microtubule assembly in solution at physiologicalconcentrations but acetylated polyamines fail to mimic this affect. Several distinct effects of this manipulationcould mediate these remarkable benefits of Arg1 over expression and polyamine metabolism. The goal of thisapplication is to better understand how polyamines contribute to the benefits of reducing the tau phenotypeand identify other potential targets for treating tauopathies and possibly AD. Utilizing gene therapy mousemodels of tauopathy and knockout models we will test four aims. 1) Determine if Increased PolyaminesDiminish Tau Pathology. 2) Determine if Reduced Polyamines Enhance Tau Pathology. 3) Test ifPharmacological Nutritional Modulation of Polyamines Regulates Tau Pathology and 4) Test if the Deletion ofSSAT Reduces Tau Pathology. Success in these aims will increase our knowledge regarding the role ofpolyamines metabolism in regulating the tau phenotype. Our goal is to identify additional therapeutic targetsthat could be regulated by pharmacological agents to arrest or slow the progression of the tau deposition inhumans with neurodegenerative disease.

project_terms:
Acetylation;Affect;Age;Alzheimer's Disease;American;Anabolism;Animal Model;Arginine;Autophagocytosis;Axon;Back;Behavioral;Caring;Catabolism;Cell Culture Techniques;Cells;Cessation of life;Cognition;DL-alpha-Difluoromethylornithine;Data;Dependovirus;Deposition;Diagnosis;Diet;Dietary Administration;Disease;Drug Targeting;Enzymes;Family;Functional disorder;Generations;Goals;Human;Inflammation;Knock-out;Knockout Mice;Knowledge;Learning;Length;Measures;Mediating;Medical;Memory;Metabolism;Microtubules;Modeling;Molecular Weight;Mus;Neurodegenerative Disorders;Neurons;Nitrates;Nitric Oxide;Nitric Oxide Synthase;Nutritional;Ornithine;Ornithine Decarboxylase;Ornithine Decarboxylase Inhibitor;Pathology;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Physiological;Polyamine Catabolism;Polyamines;Production;Protein Kinase;Proteins;Recovery;Regulation;Reporting;Role;Spermidine;Spermidine Synthase;Spermine;Spermine Synthase;Stains;Supplementation;System;Tauopathies;Testing;Therapeutic;Transferase;Transgenic Mice;age related;arginase;behavioral outcome;biological adaptation to stress;chronic traumatic encephalopathy;cost;cytokine;gene therapy;hippocampal atrophy;inflammatory marker;inhibitor/antagonist;mouse model;nitration;novel;ornithine decarboxylase antizyme;overexpression;response;success;tau Proteins;tau aggregation;tau-1;therapeutic target;transcription factor

public_health_relevance:
Tauopathies consist of a group of neurodegenerative diseases including Alzheimers disease and currently notherapeutic treatments exist for tauopathies. This study will test various aspects of how polyamines impacts tauand how tau disrupts the polyamine system. We aim to identify novel targets along the polyamine pathway andlearn how dysregulation of this pathway promotes tau neuropathology.


application_id: 10224172
project_number: 5R01DK112136-05
project_title: Community to Clinic Navigation to Improve Diabetes Outcomes
administering_ic: NIDDK
award_notice_date: 2021-07-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 112136
program_official: RAJAPAKSE, NISHADI
project_start_date: 2017-08-01
project_end_date: 2024-07-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTReducing adverse outcomes from Type 2 Diabetes Mellitus (T2DM) requires optimal self-management andappropriate clinical care.1 Combining an evidence-based intervention to improve diabetes self-managementwith individually-tailored patient navigation to improve appropriate clinical care holds great promise. Only oneknown randomized controlled trial has been tested that combines these two most essential components ofdiabetes control. That trial resulted in improvements to glycemic control blood pressure and diabetes self-management but was implemented in a clinical setting.2 We aim to enhance this work by recruiting from andlocating most research activities in community-based settings to insure involvement of the most vulnerablehardest to reach populations who may not be receiving regular health care and by leveraging CommunityHealth Workers and Patient Navigators who are essential and sustainable outreach workers in health careprofessional shortage areas.We propose testing a refined intervention Community to Clinic Navigation (CCN) shown to be promisingfeasible and acceptable in our pilot study. Given that Appalachian and rural residents maintaindisproportionately high rates of T2DM and suffer tremendous burdens from diabetic complications3 this settingprovides a perfect opportunity to test the intervention with a hard to reach population while addressing healthinequities. We will administer a 3 arm group randomized design including (1) Diabetes Self-managementProgram DSMP only; (2) tailored Patient Navigation PN only; and (3) the combined DSMP + PN: Communityto Clinic Navigation program CCN. Outcomes include biometrics (HbA1c BMI blood pressure lipids waistcircumference); diabetes self-management and clinic attendance as mediators of the primary outcomes; costeffectiveness and participant satisfaction. Persons with diabetes will be recruited through churches and othercommunity venues. Our project leverages sustainable assets available in most health disparity communities--faith organizations community centers federally qualified health clinics strong social ties and talented locallay people who can be trained to educate and navigate those diagnosed with T2DM. Our sustainedinvolvement in Appalachian Kentucky positions our team to appropriately and efficiently test this promisingprogram with strong potential for future dissemination to other traditionally underserved environments.

project_terms:
Address;Affect;American;Appalachian Region;Biometry;Blood Pressure;Body mass index;Church;Clinic;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Data;Diabetes Mellitus;Diagnosis;Dissemination and Implementation;Education;Environment;Epidemic;Evidence based intervention;Focus Groups;Future;Glycosylated hemoglobin A;Goals;Health;Health care facility;Healthcare;Individual;Influentials;Intervention;Interview;Kentucky;Lipids;Low income;Mediator of activation protein;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Positioning Attribute;Prediabetes syndrome;Protocols documentation;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Activity;Rural;Rural Population;Self Management;Social support;Talents;Testing;Training;Vulnerable Populations;Work;adverse outcome;arm;base;behavioral outcome;clinical care;community center;community setting;cost effectiveness;design;diabetes control;diabetes self-management;evidence base;glycemic control;health care quality;health care service organization;health disparity;health disparity populations;health inequalities;health professional shortage areas;improved;improved outcome;innovation;low socioeconomic status;meetings;member;outreach;primary outcome;programs;randomized trial;recruit;relative cost;rural dwellers;satisfaction;self-management program;social;theories;underserved community;waist circumference

public_health_relevance:
PROJECT NARRATIVESince diabetes has reached epidemic proportions in the US especially among low income and rural residentswe aim to test a refine and promising program called Community to Clinic Navigation (CCN) that combinesdiabetes self-management education with tailored patient navigation to improve clinical care. To ourknowledge no one has ever combined these two approaches which is surprising because these are the mostimportant ways to manage and control diabetes. If this theory-based culturally appropriate intervention showsimprovement in physical and behavioral outcomes then CCN can easily be applied to other communities withhealth disparities.1


application_id: 10224151
project_number: 5K12DA035150-10
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Researchers
administering_ic: NIDA
award_notice_date: 2021-08-06
opportunity_number: RFA-OD-16-013
application_type: 5
activity_code: K12
ic: DA
serial_number: 035150
program_official: BABECKI, BETH
project_start_date: 2012-08-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1-PSE-W(50)R]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The BIRCWH Program at the University of Kentucky (UK) is built around three pillars:interdisciplinary research mentoring and career development. We will continue to provide theformal framework through which experienced faculty members who share common interests inwomen's health will offer mentoring to provide in-depth research experiences and didactictraining to junior faculty members. Our goal is to provide UK BIRCWH scholars withopportunities for an interdisciplinary mentored career development experience to facilitatetheir transition to become independent extramurally funded investigators in women's healthresearch. We choose to focus our scholarship efforts on those health challenges prevalent toAppalachian Kentucky. Because the Appalachian region is disproportionately affected by drugabuse violence and poor health we will actively engage women living in Appalachian Kentuckyin our research agenda with research flowing bidirectionally between communities andresearchers. This approach will continue to provide our BIRCWH scholars with state-of-the-artmultidisciplinary training leading to their development as faculty with independent NIH andextramural funding. The focused areas targeted towards improving women's health in thisapplication include: 1) substance abuse 2) violence against women and 3) changes across awoman's lifespan. Through this BIRCWH program strengthening the capacity for women'shealth research will be accomplished by the following Aims: 1) to provide the environmentmentorship and facilities to enhance the ability of BIRCWH scholars to compete for NIHresearch grants in diverse areas of women's health research 2) to deepen our understanding ofthe unique role of gender in the manifestation of health and disease 3) to develop andimplement new communication and social networking technologies to address women's health4) to personalize prevention diagnostics and therapeutics to address health disparities amongwomen such as substance abuse and violence 5) to stimulate new collaborations in focusedinterdisciplinary and interactive research areas that are essential for improving women'shealth; and 6) to use a thematic multidisciplinary focus as a platform for enhancingtranslational research between basic clinical and public health scientists. The foundation of theBIRCWH program will continue to be practical research experiences within interdisciplinaryteams guided by experienced mentors. As evident by the success of our former BIRCWHscholars we are well positioned to continue the tradition of excellence in mentoring our scholarsto become independent researchers in women's health.

project_terms:
Address;Affect;Appalachian Region;Area;Clinical;Collaborations;Communication;Communities;Development;Diagnostic;Disease;Drug abuse;Environment;Extramural Activities;Faculty;Foundations;Funding;Gender;Goals;Health;Interdisciplinary Study;Kentucky;Longevity;Mentors;Mentorship;Positioning Attribute;Public Health;Research;Research Personnel;Research Project Grants;Role;Scholarship;Scientist;Social Network;Substance abuse problem;Technology;Therapeutic;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;Violence;Woman;Women's Health;career development;experience;health disparity;improved;individualized prevention;interest;member;multidisciplinary;next generation;programs;success;violence against women

public_health_relevance:
Emphasizing sex and gender differences in effective health care research and treatment iscritical. We must train the next generation of scientists to recognize these differences. Thisproposal will provide a platform to mentor and train promising young scientists in focused areasof women's health research to address the unique needs of sex and gender differences especiallyfor those who are underserved such as the Appalachian region of Kentucky


application_id: 10223919
project_number: 5P01HL078825-15
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2021-07-30
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2004-12-01
project_end_date: 2023-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP(JH)]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Clinical translation of cell therapy has been hindered by i) lack of understanding of basic mechanisms and ii)borderline or inconsistent results in clinical trials. The overarching objective of this renewal application is todirectly address these two problems; specifically to advance our understanding of the mechanism of action ofcell therapy and to develop strategies that optimize its therapeutic efficacy. We will focus on cardiacmesenchymal cells (CMCs) a promising new population of heart-derived cells that we have recentlydiscovered and that appears to be particularly suitable for clinical translation. Four closely inter-related andinter-dependent Projects will address different facets of this theme. Project 1 (Bolli) will carefully evaluate theuse of repeated treatments to maximize therapeutic benefit including translational studies in a preclinicalporcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase thebeneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. Project 2(Wysoczynski) will elucidate the role of immune cells in mediating the beneficial effects of cell therapy and testthe hypothesis that CMCs and EVs facilitate recruitment of monocytes and activation of reparativemacrophages which are endogenous mediators of repair. Project 3 (Jones) will illuminate the role of thestromal compartment (including fibroblast activation and hyaluronan metabolism) in the reparative actions ofCMCs and EVs and identify and correct defects in CMCs rendered incompetent by heart failure (HF). Theoverarching hypothesis is that CMCs attenuate remodeling by favorably enhancing hyaluronan metabolismwhich is defective in HF. Project 4 (Bhatnagar) will determine how diabetes affects CMC-mediated myocardialrepair and how CMC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetescompromises the therapeutic efficacy of CMCs by increasing glycolysis which alters paracrine mechanismsand that Sirt1 improves CMC repair capacity by decreasing glycolysis. Thus all four Projects focus cohesivelyon CMCs. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgerycell transplantation CMC culture and phenotyping pathology flow cytometry and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long historyof collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. Throughout thefour Projects the effects of CMCs will be systematically compared with those of EVs. These will be the firststudies to systematically examine the effects of repeated doses and the role of immune and stromal cellsglycolysis and Sirt1 in the salubrious effects of cell therapy; thus the results will be entirely new. The pigstudies (3 Projects) will lay the groundwork for translational investigations of CMC therapy in patients with HF.This PPG may generate disruptive new knowledge including two new therapeutic paradigms (repeatedtreatments and use of cell-free EV products) either of which in itself would revolutionize cell therapy.

project_terms:
Address;Affect;Animal Model;Animals;Attenuated;Autologous;Cardiac;Catabolism;Cell Culture Techniques;Cell Separation;Cell Therapy;Cell Transplantation;Cells;Chronic;Clinical Trials;Collaborations;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Dose;Engraftment;Event;Fibroblasts;Flow Cytometry;Funding;Glycolysis;Goals;Heart;Heart failure;Hyaluronan;Immune;Immune response;Infarction;Inflammation;Intervention;Investigation;Knowledge;Left Ventricular Remodeling;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolism;Mitochondria;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Paracrine Communication;Pathology;Patients;Phenotype;Population;Property;Recording of previous events;Regulation;Research Design;Research Personnel;Role;SIRT1 gene;Stromal Cells;Study models;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Translations;Treatment Efficacy;Treatment Protocols;cardiac repair;cell type;clinical application;clinical translation;cohesion;comorbidity;diabetic;effective therapy;extracellular vesicles;first-in-human;heart function;immunomodulatory therapies;improved;improved outcome;inflammatory modulation;insight;ischemic injury;macrophage;monocyte;non-diabetic;novel;novel therapeutics;paracrine;porcine model;pre-clinical;preclinical study;programs;recruit;repaired;reparative medicine;response;stem;therapeutically effective;tool;translational study;vesicular release;virtual

public_health_relevance:
The goal of this application is to study cardiac mesenchymal cells (CMCs) a promising newpopulation of heart-derived cells that we have recently discovered and that appears to beparticularly suitable for clinical application. The overall objective of this renewal application is toadvance our understanding of the mechanism of action of CMCs and to develop strategies thatoptimize their efficacy for treating heart failure caused by a heart attack (myocardial infarction).The results of these studies will lay the groundwork for first-in-human clinical trials of CMCs.


application_id: 10222787
project_number: 5R44NS084701-05
project_title: Catheter for Large Volume Intraparenchymal Brain Therapies
administering_ic: NINDS
award_notice_date: 2021-09-01
opportunity_number: PA-18-574
application_type: 5
activity_code: R44
ic: NS
serial_number: 084701
program_official: AUBRECHT, TARYN GRACE
project_start_date: 2014-09-30
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(10)B]
contact_pi_person_id: 12334483
contact_pi: ABRAMOV, VASILIY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 786659719
primary_uei: CBL5M5DKH3K7
duns_number: 786659719
uei: CBL5M5DKH3K7
fips: US
organization_id: 10021015
organization_name: CREOSALUS, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402046033
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project AbstractSignificance: Neurodegenerative and malignant diseases along with injury of the central nervous system(CNS) affect millions of Americans. These injuries and diseases are often devastating and difficult to treat andeffective drug delivery remains a significant challenge. Infusion of drugs into the brain parenchyma usingconvection-enhanced delivery (CED) allows direct treatment of lesions circumventing the blood brain barrier.In particular new treatments and diseases call for large regions of brain to be subjected to therapeutic doses.Multiple clinical trials have been conducted using CED to deliver large volumes of chemotherapy andimmunotoxins in patients with gliomas but actual drug delivery to the tumor has been poor for several reasonsincluding the unpredictable dispersion of the drug in the tissue. These adverse events result in reducedefficacy and increased toxicity. To overcome the limitations associated with conventional CED catheters inheterogeneous tissue the Applicants have developed a Porous Brain Infusion Catheter (PBIC) for improvedCNS drug delivery. Hypothesis: The Applicant proposes that Phase II research will create a multi-capabilityPBIC optimized for small to large volume distribution and short to long durations for multiple (small to large)neurological therapeutics. Phase I Results: Applicant has developed a PBIC that met Aim 1 designrequirements as demonstrated in Aim 3 design verification testing that has been passed. In Aim 2 in vivoporcine testing the PBIC demonstrated superior large volume distribution (p=.03) compared to a standard endport brain infusion catheter such that the PBIC is expected to be used in brain tumor human studies by aleading brain tumor center. Specific Aims: With the proposed Phase II PBIC research the Applicants expectto verify and validate an optimized PBIC design that provides broad CED performance capabilities to CNSincluding chronic delivery to enhance commercialization potential. Aim 1: The PBIC design will be optimizedfor small to large volume distribution for multiple therapeutics and short to long durations. The resulting PBICdesign verification and performance characterization testing in vitro and in vivo will be completed to allow forhuman use and product approvals. Aim 2: The PBIC design will be validated for human use with therapeuticsin non-clinical models including chronic delivery with the infusion of a chemotherapeutic in companion dogbrain tumor patients demonstrating the IND enabling capabilities of the PBIC for a broad range of therapeuticadministration protocols. These Aim 2 studies will reduce PBIC clinical risk and are expected to acceleratecustomer human study adoption.

project_terms:
Acute;Address;Adoption;Adverse event;Affect;American;Animals;Anti-Mullerian Hormone Receptor Type II;Award;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Brain region;Canis familiaris;Catheters;Central Nervous System Agents;Chronic;Clinical Research;Clinical Trials;Companions;Convection;Data;Disease;Dose;Drug Delivery Systems;Elements;Evaluation;Experimental Models;FDA approved;Family suidae;Glioma;Human;Immunotoxins;Implant;Implantable Pump;In Vitro;Infusion procedures;Injury;Investigation;Kentucky;Lesion;Letters;Malignant - descriptor;Mechanics;Medical center;Minnesota;Modeling;Nerve Degeneration;Neuraxis;Neurologic;Neurosciences;Patients;Performance;Pharmaceutical Preparations;Phase;Preparation;Primary Brain Neoplasms;Product Approvals;Protocols documentation;Research;Research Personnel;Small Business Innovation Research Grant;Sterility;Study Section;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Tracer;Treatment Efficacy;Universities;Virginia;biomaterial compatibility;brain parenchyma;central nervous system injury;chemotherapy;clinical efficacy;clinical risk;commercial application;commercialization;design;human study;improved;in vivo;interest;novel;safety study;standard of care;technological innovation;tumor

public_health_relevance:
Project NarrativeEffective drug delivery of large volumes of solutions containing therapeutic agents into the brain remains asignificant obstacle to achieving clinical efficacy of therapies for injuries neurodegenerative and malignantdiseases affecting the central nervous system (CNS). The Applicant has developed novel porous brain infusioncatheters which demonstrate more uniform and better distribution of infusates into CNS tissue as compared tostandard of care catheters. In this project bench and animal studies will be conducted including designverification testing to generate data for product and clinical study approvals.


application_id: 10222697
project_number: 5R01EY028188-05
project_title: Understanding signal processing in retinal bipolar cell pathways
administering_ic: NEI
award_notice_date: 2021-06-04
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 028188
program_official: WRIGHT, CHARLES BAKER
project_start_date: 2017-09-01
project_end_date: 2024-05-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 11294714
contact_pi: BORGHUIS, BART GERARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have developed a powerful mouse model to study information processing in parallel retinal bipolar cellpathways. Bipolar cells are essential for transmitting the photoreceptor output to the ganglion cells whichsignal visual information to a range of target areas in the brain. Bipolar cells divide into about a dozen typesand constitute the first level of information processing in the visual system. While several aspects of bipolarcell function have been addressed in retinal slice preparations of a variety of species information aboutthree fundamental aspects of bipolar cell signaling is still lacking. First is a concise quantitative descriptionof the spatio-temporal receptive field for any genetically identified bipolar cell type. Second is acomprehensive account of the neural mechanisms that govern the input-output transfer function of each BCtype based on light-evoked responses with intact circuitry (whole-mount retina preparation). Third is theimpact of light-adaptive mechanisms on bipolar cell visual function.We will leverage our recently developed live-cell imaging and whole-cell recording methods toaddress these issues. Specifically we will make targeted electrophysiological recordings in the whole-mount retina of transgenic mice with genetically identified bipolar cells; we will use two-photon fluorescenceimaging with genetically encoded fluorescent biosensors for calcium and glutamate in transgenic mice withloss-of function mutations in the OFF bipolar pathways; and we will use advanced visual stimulationmethods to elucidate mechanisms of light-adaptation at the bipolar cell level. These studies will providevaluable information about how bipolar cells encode visual information and how visual sensitivity ismaintained under varying stimulus conditions. Understanding information processing in identified retinalsignaling pathways is critical for the study and potential treatment of developmental and neurologicaldisorders and retinal disease.

project_terms:
Address;Aging;Amacrine Cells;Area;Axon;Biosensor;Brain;Calcium;Cell physiology;Cells;Electrophysiology (science);Equilibrium;Feedback;Glutamate Receptor;Glutamates;Glycine;Goals;Image;Individual;Kainic Acid Receptors;Kinetics;Knowledge;Light;Light Adaptations;Lighting;Maps;Measures;Methods;Molecular;Natural regeneration;Neurons;Optic Nerve;Output;Pathway interactions;Photic Stimulation;Photoreceptors;Preparation;Process;Property;Retina;Retinal Diseases;Retinal Ganglion Cells;Role;Route;Series;Shapes;Signal Pathway;Signal Transduction;Slice;Stimulus;Stratification;Structure;Synapses;Testing;Transgenic Mice;Vision;Visual;Visual system structure;Whole-Cell Recordings;base;cell type;developmental disease;experimental study;extrastriate visual cortex;fluorescence imaging;gamma-Aminobutyric Acid;ganglion cell;information processing;innovation;live cell imaging;loss of function mutation;luminance;mouse model;nervous system disorder;neural circuit;neuromechanism;parallel processing;postsynaptic;preservation;prevent;receptive field;receptor;response;retinal rods;signal processing;spatiotemporal;transmission process;two-photon;visual information;visual processing;voltage;voltage gated channel

public_health_relevance:
Vision critically depends on the transmission of visual information from the photoreceptors in the retina tocentral visual areas in the brain. Space limitations within the optic nerve in particular prevent individualphotoreceptor cells to contact central areas in the brain directly. Instead the photoreceptor output isintegrated and processed by neural circuits within the retina to generate a more compact representation ofthe visual image for transmission to the brain. The goal of this proposal is to further our understanding of acritical information-processing step within the retina that is performed by the retinal bipolar cells. In a seriesof innovative experiments we will measure and compare information processing properties across bipolar cells types identify the neural mechanisms that give rise to their unique visual encoding and study howstimulus conditions impact bipolar cell function. Understanding information processing in retinal bipolar cells is an essential prerequisite for understanding the neural circuit functions that need to be reestablishedthrough regenerating and restoring neuronal connections during retinal disease and aging an `audacious goal' established by the NEI.


application_id: 10222657
project_number: 5R01DK113625-05
project_title: Contributions of hepatic and intestinal pathways to cholesterol excretion
administering_ic: NIDDK
award_notice_date: 2021-07-21
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 113625
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2017-09-13
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-P(02)M]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
7. Project SummaryThe elimination of excess cholesterol from the body is essential in maintaining homeostasis andopposing the development of a number of metabolic diseases most notably atheroscleroticcardiovascular disease. Classically cholesterol elimination is thought to be accomplished by hepaticmetabolism of cholesterol to bile acids and the secretion of both bile acids and cholesterol in the bile.However under a number of conditions in which biliary secretion of cholesterol is compromised fecalexcretion is maintained indicating the presence of a non-biliary alternate pathway. Previouslypublished and preliminary studies demonstrate that the proximal small intestine is capable ofsecreting cholesterol and that the rate of intestinal cholesterol secretion increases when biliarycholesterol secretion is reduced. The hypothesis of this proposal is that transintestinal cholesterolelimination (TICE) is regulated by biliary cholesterol output by plasma lipoprotein donors and by anenterohepatic signaling axis involving bile acids. To date the contribution of the intestine tocholesterol excretion has largely been inferred by calculating differences in cholesterol concentrationsin bile among strains of mice or in response to pharmacological agents relative to the changes in fecalneutral sterols. We have developed a novel surgical procedure to simultaneously measure rates ofbiliary and intestinal cholesterol secretion in mice. This will allow us to address for the first time therelative rates of biliary and intestinal cholesterol secretion track the delivery of cholesterol fromplasma lipoproteins to both the hepatic and intestinal pathway and better understand how theintestine adapts to alterations in biliary cholesterol secretion. The aims are to: I) determine the impactof biliary cholesterol secretion on intestinal cholesterol secretion rates II) determine the lipoproteindonors to both the biliary and intestinal pathway under conditions of high and low biliary cholesterolsecretion and III) determine the impact of bile acid signaling in the intestine on hepatic and intestinalcholesterol secretion. The accomplishment of these aims will further our understanding of theintestine as a regulator of cholesterol homeostasis and identify novel regulators of intestinalcholesterol secretion that may be targeted to promote cholesterol excretion and the removal of excesscholesterol from the body.

project_terms:
Address;Antisense Oligonucleotides;Atherosclerosis;Bile Acids;Bile fluid;Biliary;Cells;Cholesterol;Cholesterol Ester Transfer Proteins;Cholesterol Homeostasis;Data;Development;Distal;Event;Excision;Excretory function;GPBAR1 gene;Gallbladder;Genetic Complementation Test;Hepatic;Hepatobiliary;High Density Lipoprotein Cholesterol;Homeostasis;Intestines;Investigation;LDL Cholesterol Lipoproteins;Lipids;Lipoproteins;Liver;Low-Density Lipoproteins;Measures;Metabolic Diseases;Metabolism;Methods;Micelles;Modeling;Mouse Strains;Mus;Operative Surgical Procedures;Organ;Output;Parabiosis;Pathway interactions;Peripheral;Pharmacology;Plasma;Play;Prevention;Process;Publishing;Regulation;Rodent;Role;Signal Transduction;Small Intestines;Sterols;Time;adeno-associated viral vector;gut-liver axis;liver metabolism;man;novel;receptor;response;reverse cholesterol transport;synergism;uptake

public_health_relevance:
Project NarrativeThe elimination of excess cholesterol from the body is critical to homeostasis and the prevention andtreatment of atherosclerotic disease. Cholesterol excretion is thought to be predominantly controlledby the liver; however recent developments indicate that the intestine can also play a role in under avariety of conditions. This proposal seeks to understand how the intestine maintains cholesterolhomeostasis in response to changing biliary cholesterol secretion rates and to identify factors thatregulate these responses.


application_id: 10221629
project_number: 5R01CA211137-04
project_title: Targeting Abl kinases in BRAF-driven melanomas
administering_ic: NCI
award_notice_date: 2021-07-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 211137
program_official: MERCER, NATALIA
project_start_date: 2018-08-13
project_end_date: 2023-07-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Despite the success of new targeted agents and immunotherapies metastatic melanoma remains an incurabledisease for many patients. Although BRAF inhibitors (BRAFi) show promise for reducing metastatic burdensome melanomas are intrinsically resistant and most responding patients eventually acquire resistance. Thesedata underline the importance of identifying new markers for treatment response and novel drug combinationsfor treating metastatic and BRAFi-resistant disease. We show that Abl/Arg non-receptor tyrosine kinases arehighly expressed in melanoma and are activated in a subset (40-60%). Moreover SFKs and BRAFV600E themost common genetic alteration in melanoma both contribute to Abl/Arg activation in melanoma cells. Onceactivated Abl/Arg promote proliferation survival a switch in EMT transcription factor expression invasion andmetastasis and bidirectionally regulate and potentiate BRAFV600E signaling. Moreover inhibitors of Abl/Arg anda parallel pathway which drives intrinsic BRAFi resistance (PI3K/Akt/PTEN) cooperate to prevent melanomaviability and tumor growth. Based on these findings we hypothesize that BRAFV600E/ERK and SFKscooperatively activate Abl/Arg which synergize with Akt to drive melanoma development progressionphenotypic switching and subsequent resistance. We propose a comprehensive hypothesis-drivenexperimental design that will establish Abl/Arg as novel and exploitable drug targets. Aim 1 will define themechanism by which Abl/Arg are activated in melanoma. To achieve our objective biochemical molecularbiological and cell biological approaches using melanocytes melanoma cell lines tissue microarrayspharmacological inhibitors/RNAi mass spectrometry and immunohistochemistry will be used to test theprediction that BRAFV600E/ERK-mediated phosphorylation prevents nuclear targeting of Abl and facilitatesactivation of Abl/Arg by SFKs. In Aim 2 2D/3D culture rescue experiments and xenograft approaches will beused to identify the mechanism by which Abl/Arg drive the EMT transcription factor switch potentiateBRAFV600E signaling and promote acquired BRAFi resistance. Finally in Aim 3 genetically engineered (GEM)and xenograft mouse models as well as loss- and gain-of-function approaches will be used to test theprediction that Abl/Arg cooperate with activated Akt in mutant PTEN melanomas to promote melanomagrowth/metastasis and BRAFi/MEKi resistance. Data obtained from this project not only will allow us to gainimportant insight into fundamental mechanisms by which Abl/Arg are activated in melanoma which likely isapplicable to other solid tumors but also may lead to clinical studies testing the efficacy of Akt inhibitors incombination with Abl/Arg inhibitors for treating mutant BRAF/PTEN melanomas which often are resistant tocurrent therapeutic approaches.

project_terms:
Automobile Driving;BRAF gene;Binding;Binding Sites;Biochemical;Biological;Cell Cycle Progression;Cell Line;Cells;Chronic;Clinical Research;Complex;Data;Development;Disease;Disease Resistance;Disease remission;Drug Targeting;Environment;Experimental Designs;FDA approved;Genetic Engineering;Goals;Growth;Immunohistochemistry;Immunotherapy;Incidence;Intrinsic drive;Knock-in;Lead;Link;Malignant Neoplasms;Masks;Mass Spectrum Analysis;Mediating;Melanoma Cell;Messenger RNA;Metastatic Melanoma;Molecular;Mucous Membrane;Mutation;Nature;Neoplasm Metastasis;Nuclear;Nuclear Localization Signal;Oncologist;Outcome;PTEN gene;Pathway interactions;Patients;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Physiological;Play;Positioning Attribute;Proteins;Proto-Oncogene Protein c-kit;RNA Interference;Refractory Disease;Repression;Research;Resistance;Resistance development;Role;Signal Transduction;Solid Neoplasm;Sun Exposure;TWIST1 gene;Testing;Therapeutic;Threonine;Time;Tissue Microarray;Work;Xenograft Model;Xenograft procedure;base;design;efficacy testing;experimental study;gain of function;genetic approach;in vivo;in vivo Model;inhibitor/antagonist;innovation;insight;leukemia;loss of function;melanocyte;melanoma;mouse model;mutant;novel;novel drug combination;novel marker;prevent;recruit;src-Family Kinases;success;targeted agent;therapy resistant;three dimensional cell culture;transcription factor;treatment response;tumor growth;young woman

public_health_relevance:
Metastatic melanoma is one of the deadliest cancers and although new treatments are promising somemelanomas do not respond to the treatments or develop resistance. This proposal examines the role of Ablkinases (proteins known to promote leukemia development) in melanoma identifying mechanisms by whichthey are activated and contribute to melanoma development and therapeutic resistance. The ultimate goal is totest whether FDA-approved drugs targeting Abl kinases can be utilized in combination with other agents totreat resistant disease.


application_id: 10221547
project_number: 5R01AG026307-15
project_title: Self-Regulation and Brain and Cognitive Health in Older Adults
administering_ic: NIA
award_notice_date: 2022-05-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: KING, JONATHAN W
project_start_date: 2006-07-15
project_end_date: 2024-09-30
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: SEGERSTROM, SUZANNE C.
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Summary The typical older adult experiences declines in brain structure and cognitive function but these mean declines occur in the context of what can be very different individual trajectories. The purpose of this project is to measure individual differences and changes in self-regulation (control of thoughts emotions behaviors and impulses) over time in older adults and to link self-regulation to physical activity inflammation and trajectories of neurocognitive health relevant to development of Alzheimers disease. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation exercise science neuropsychology neuroimaging Alzheimers disease and longitudinal design and analysis. The previous renewal period focused on relationships among facets of self-regulation and their relationship to immunological and cardiovascular health. The renewal continues assessment of these measures to provide continuity in this longitudinal dataset and adds innovation in the inclusion of repeated neuroimaging and assessment of infectious disease burden. Specifically the aims of the study are: (1) to test the effects of facets of self-regulation (conscientiousness self-regulation executive cognitive function and heart rate variability) on measures of neurocognitive health associated with aging and risk for Alzheimers disease; (2) to test the degree to which the relationship between self-regulation and neurocognitive health is mediated by physical activity and inflammation; (3) to test whether neurocognitive health associated with executive cognitive functions (e.g. dorsolateral frontal lobe volume) contributes to better self-regulation higher physical activity and lower inflammation; and (4) to test effects of infectious disease burden (latent viruses Toxoplasma gondii) on self-regulation inflammation and neurocognitive health and risk for Alzheimers disease. At 6-month intervals older adults (N = 175) will complete measures of self-reported self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. Physical activity BMI and waist circumference will be measured at each visit. Blood draws will be synchronized with these visits and assays performed on these samples will capture serum proinflammatory cytokines and antibodies against latent infections. The sample has follow-back data on many of these measures from 1-15 years and an eligible subset (N = 90) will already have baseline neuroimaging. Neuroimaging will be repeated twice at 2-year intervals. This renewal will be innovative in its longitudinal assessment of a dynamic system that includes brain behavior and immunity; integration of neuroimaging measures with other domains of healthy and unhealthy aging; and multimodal assessment of neurocognitive health including measures associated with risk for Alzheimers disease and other dementias: subjective cognitive health cognitive function volumetric imaging measures connectivity fractional anisotropy and resting cerebral blood flow.

project_terms:
Adult;Affect;Age;Aging;Alzheimer's Disease;Alzheimer's disease risk;Anisotropy;Antibodies;Back;Behavior;Biological Assay;Blood;Body mass index;Brain;Cerebrovascular Circulation;Cognition;Cognitive;Communicable Diseases;Cytomegalovirus;Data;Dementia;Development;Elderly;Emotions;Episodic memory;Exercise;Failure;Funding;Goals;Health;Hippocampus (Brain);Image;Immunity;Immunologic Factors;Impaired cognition;Individual;Individual Differences;Infection;Inflammation;Informal Social Control;Knowledge;Link;Longevity;Longitudinal Studies;Longitudinal cohort;Maintenance;Measures;Mediating;Mental Health;Motivation;Neurocognitive;Neuropsychology;Outcome;Parasites;Pathway interactions;Patient Self-Report;Physical activity;Prefrontal Cortex;Psychological Factors;Psychoneuroimmunology;Research;Rest;Risk;Risk Factors;Role;Sampling;Science;Serum;Short-Term Memory;Structure;Testing;Time;Toxoplasma gondii;Virus Latency;Visit;brain behavior;brain health;burden of illness;cardiovascular health;cognitive function;cohort;cytokine;dynamic system;executive function;experience;frontal lobe;heart rate variability;immune health;inflammatory marker;innovation;interest;latent infection;longitudinal analysis;longitudinal dataset;longitudinal design;multimodality;nervous system disorder;neuroimaging;physical conditioning;prospective;success;thought control;waist circumference

public_health_relevance:
NarrativeWith age come changes in the brain that can increase the risk of cognitive decline and neurological disease.However not all older adults experience these changes to the same degree. This project will continue to tracka cohort of older adults examining psychological and immunological factors that may be protective for brainand cognitive health and vice versa.


application_id: 10221505
project_number: 5R01AA028435-02
administering_ic: NIAAA
award_notice_date: 2021-08-06
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AA
serial_number: 028435
program_official: OROSZ, ANDRAS
project_start_date: 2020-08-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)M]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-08-01
project_terms:
Address;Affect;Alcohols;CRISPR/Cas technology;CXCL12 gene;CXCR4 gene;Cells;Cephalic;Congenital Abnormality;Cranial Nerves;Craniofacial Abnormalities;Data;Defect;Distant;Edible Plants;Embryo;Ethanol;Fetal Alcohol Spectrum Disorder;Grapes;Human;In Vitro;Knowledge;Laboratories;Life;Mediating;Mental Retardation;MicroRNAs;Mission;Modeling;Molecular;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Pathogenesis;Plants;Prevention;Prevention strategy;Public Health;Regulation;Repression;Research;Role;Signal Transduction;Site;Skeleton;Testing;Therapeutic;Therapeutic Intervention;Work;Zebrafish;alcohol effect;alcohol exposure;base;craniofacial;exosome;fetal;in vivo;innovation;insight;intercellular communication;migration;nanoparticle;novel;novel strategies;novel therapeutic intervention;prevent;preventive intervention;public health relevance;sensory system;teratogenesis;transcriptome sequencing


application_id: 10220036
project_number: 5R21ES031510-02
project_title: m6A Epitranscriptomics in Toxicant Associated Steatohepatitis
administering_ic: NIEHS
award_notice_date: 2021-05-21
opportunity_number: RFA-ES-19-002
application_type: 5
activity_code: R21
ic: ES
serial_number: 031510
program_official: TYSON, FREDERICK L
project_start_date: 2020-07-20
project_end_date: 2023-02-28
study_section: ZES1-LWJ-D(02)
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: CAVE, MATTHEW C
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractExposure to persistent environmental contaminants including polychlorinated biphenyls (PCBs) contributes tometabolic diseases including toxicant-associated steatohepatitis (TASH) a form of nonalcoholic fatty liverdisease (NAFLD). PCBs have been positively associated with TASH hepatocellular cancer altered liverenzymes and mortality in human cohorts. A complete understanding of the mechanisms by which PCBs act asa 1st hit in combination with a high fat Western diet (HFD) as a 2nd hit to increase triglyceride accumulationfibrosis and inflammation in the liver (hallmarks of TASH) remains elusive. Further although liver sexualdimorphism is well-established and sex-specific differences in human health outcomes after PCB exposure havebeen reported there are few mechanistic studies addressing these differences. N(6)-methyladenosine (m6A) isthe most common dynamic modification of transcribed RNAs. The regulation and role of m6A in liverepitranscriptomics and the impact of PCB exposure is unknown. This application addresses RFA-ES-19-002 byinvestigating the role of altered m6A and its writers readers and erasers in TASH in vivo using an establishedPCB exposure model. Preliminary RNA-seq data show that liver from HFD + Aroclor 1260 (PCB) exposed maleC57BL/6J mice have reduced transcript levels of the m6A methyltransferase complex protein Rbm15 and alteredlevels of the m6A readers Ythdf1 and Ythdc1/2. Whether these HFD + Aroclor 1260-induced changes are alsooccur in females and how they affect the m6A epitranscriptome and hepatocyte homeostasis or liver function isunknown. We recently reported increased PCB-induced hepatic inflammation and altered lipid metabolism infemale vs. male mice. The goal of this exploratory study is to determine the impact of PCB +/- HFD exposure invivo on the hepatic m6A epitranscriptome in male and female mice. We will test the hypothesis that altered m6Alevels of specific transcripts play a role in TASH in vivo. Integrated analysis will identify m6A epitranscriptome-mediated changes in signaling pathways regulating TASH pathophysiology. This goal will be achieved by 1)Identification of m6A-mediated transcriptome changes in HFD Aroclor 1260 (a mixture of non-dioxin-like (NDL)PCB subtypes that best mimics the PCB bioaccumulation in human adipose tissue) and HFD + Aroclor 1260 exposed male and female mouse liver; 2) Determination if HFD Aroclor 1260 or HFD + Aroclor 1260 exposurealter the expression of the writers readers and erasers of m6A in mouse liver. Integrated analysis will identifym6A epitranscriptome-mediated changes in signaling pathways regulating TASH pathophysiology that may betargets for therapeutic intervention. In the future knockdown or overexpression of key proteins identified in thisstudy will confirm their role in the observed m6A changes and in downstream signaling.

project_terms:
Address;Adenosine;Adipose tissue;Affect;Alternative Splicing;Animal Model;Antibodies;Aryl Hydrocarbon Receptor;Attenuated;Biological Markers;C57BL/6 Mouse;Cessation of life;Cirrhosis;Data;Diet;Dioxygenases;Disease;Dose;Environmental Exposure;Environmental Pollutants;Environmental Pollution;Enzymes;Epidermal Growth Factor;Euthanasia;Event;Exposure to;Fatty Liver;Fatty acid glycerol esters;Female;Fibrosis;Functional disorder;Future;Genes;Goals;Health;Hepatic;Hepatocyte;High Fat Diet;Histology;Homeostasis;Human;Hypertriglyceridemia;Immunoprecipitation;Inflammation;Knockout Mice;Liver;Liver Extract;Liver diseases;Measures;Mediating;Messenger RNA;Metabolic Diseases;Methyltransferase;MicroRNAs;Modeling;Modification;Mus;Necrosis;Nuclear Receptors;Nutrient;Nutritional;Outcome;Pathology;Pathway Analysis;Play;Polychlorinated Biphenyls;Positioning Attribute;Primary carcinoma of the liver cells;Protein Methyltransferases;Proteins;Proteome;RNA;RNA Splicing;Reader;Receptor Inhibition;Regulation;Reporting;Role;Sampling;Sex Differences;Signal Pathway;Signal Transduction;Steatohepatitis;Stress;Testing;Therapeutic Intervention;Time;Transcript;Translations;Untranslated RNA;Western Blotting;base;bioaccumulation;circulating microRNA;cohort;constitutive androstane receptor;epitranscriptome;epitranscriptomics;human subject;in vivo;knock-down;lipid metabolism;liver function;liver transplantation;mRNA sequencing;male;methyl group;mortality;non-alcoholic fatty liver disease;overexpression;pregnane X receptor;protein complex;protein expression;receptor;response;sex;sexual dimorphism;targeted treatment;toxicant;transcriptome;transcriptome sequencing;virtual;western diet

public_health_relevance:
Project NarrativeEnvironmental pollutants (polychlorinated biphenyls (PCB)) increase toxicant-associated steatohepatitis(TASH) in the context of a high fat diet. Whether PCB-induced modification of the epitranscriptome is involvedin TASH is unknown. The major goal of this exploratory project is to determine if PCBs alter the liverN(6)methyladenosine epitranscriptome in TASH resulting in sex-specific gene changes and disease pathology.


application_id: 10219957
project_number: 5R01AG068215-02
project_title: Sleep Fragmentation and Alzheimers Disease
administering_ic: NIA
award_notice_date: 2021-04-27
opportunity_number: PAR-18-497
application_type: 5
activity_code: R01
ic: AG
serial_number: 068215
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BACHSTETTER, ADAM D;DUNCAN, MARILYN J.;O'HARA, BRUCE FREDERICK;SUNDERAM, SRIDHAR
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
APP-PS1;Abeta clearance;Address;Affect;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Attenuated;Biological;Brain;Chronic;Cognition;Cognitive deficits;Correlative Study;Dementia;Demographic Factors;Deposition;Development;Disease;Disease Progression;Exhibits;Family;Frequencies;Human;Impaired cognition;Impairment;Inflammation;Knock-in;Knock-in Mouse;Life;Life Style;Light;Link;Mediating;Mediator of activation protein;Medical History;Microglia;Modeling;Moods;Mus;Nerve Degeneration;Noise;Pathology;Personal Satisfaction;Pharmaceutical Preparations;Pharmacology;Phase;Phase I Clinical Trials;Process;Rest;Risk;Role;Schedule;Sleep;Sleep Deprivation;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Societies;Synapses;System;Temperature;Testing;Time;Work;abeta accumulation;age related;beta amyloid pathology;circadian;circadian pacemaker;design;improved;middle age;mild cognitive impairment;mouse model;neuroinflammation;neuropathology;neurotoxic;novel;novel strategies;novel therapeutic intervention;pre-clinical;prevent;response;sleep quality;sleep quantity


application_id: 10219947
project_number: 5R01AG060056-04
project_title: APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2021-06-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 060056
program_official: BARRETT, PAUL JOHN
project_start_date: 2018-08-15
project_end_date: 2023-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTMetabolic dysfunction may contribute to the development of several age-related diseases includingAlzheimer's disease (AD). The gene Apolipoprotein E (APOE) encodes three major isoforms in the humanpopulation: E2 E3 and E4. E4 is the most significant genetic risk factor for sporadic AD while E2 isprotective. An understudied hallmark of AD patients  and of cognitively normal E4 individuals  is cerebralglucose hypometabolism. E4-associated reductions in glucose uptake begin decades prior to cognitiveimpairment however the mechanism by which it occurs and its relevance to AD risk remain unknown. Thebrain predominantly metabolizes glucose a substantial amount of which is shunted to the pentose phosphatepathway (PPP) in both neurons and astrocytes. The PPP generates antioxidant reducing factors such asNADPH and glutathione and decreased PPP activity increases oxidative stress and cell death. Interestinglyour novel preliminary data describe a murine model with human apoE that recapitulates an E4-associateddecrease in glucose metabolism and also documents decreases in multiple PPP metabolites. Thus the centralhypothesis of this proposal is that APOE influences neuronal function and survival through isoform-specificchanges in glucose metabolism. Specifically we hypothesize that E4 contributes to cognitive impairmentthrough metabolic reprogramming in which glucose uptake is decreased and redox management via the PPPis reduced. Our preliminary data in mice show a stepwise decrease in brain glucose uptake (E2>E3>E4) andin vitro results suggest these differences are due to changes in astrocytic uptake via GLUT-1. Therefore in thefirst Aim we will test the hypothesis that E4 decreases cerebral glucose uptake through downregulation of theastrocytic glucose transporter GLUT-1 using a scintillation proximity assay with targeted manipulation of apoEisoforms total protein concentrations and glucose transporters. To test the hypothesis that E4 decreasesglucose entry into the PPP we will quantitatively track glucose entry and metabolism in the cell through theunique precursor-product tracing afforded by Stable Isotope Resolved Metabolomics (SIRM) and translateour results through analysis of human brain tissue. Finally we will test the hypothesis that E4 exacerbatesoxidative damage and cell death due to a reduction in PPP-mediated management of oxidative stress. This willbe accomplished in vitro through pharmacological manipulation of PPP enzymes and in vivo by assessingcognitive function AD pathology and oxidative damage using redox proteomics analysis of brain tissue fromhuman apoE mice treated with a PPP stimulant. If successful this proposal will provide novel therapeutictargets to normalize glucose metabolism in high-risk individuals. Enhancing cerebral metabolism by increasingglucose uptake and entry into the PPP could have great impact in preventing or delaying the onset of AD.

project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Antioxidants;Apolipoprotein E;Astrocytes;Autopsy;Biological Assay;Brain;Cell Death;Cell Survival;Cells;Cerebrum;Coculture Techniques;Cognitive;Consensus;Data;Development;Disease;Down-Regulation;Enzymes;Genes;Genetic;Genotype;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glutathione;Glutathione Disulfide;Glycolysis;Human;Impaired cognition;In Vitro;Individual;Knowledge;Late Onset Alzheimer Disease;Link;Longevity;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mus;NADP;Neurons;Oxidation-Reduction;Oxidative Stress;Pattern;Pentosephosphate Pathway;Pharmacology;Population;Protein Isoforms;Proteins;Proteomics;Radiolabeled;Reduced Glutathione;SLC2A1 gene;Sampling;Small Interfering RNA;Testing;Time;Tissues;Translating;age related;aged;base;brain tissue;cell type;cognitive function;enzyme pathway;genetic risk factor;glucose metabolism;glucose uptake;high risk;human tissue;in vivo;inhibitor/antagonist;innovation;knock-down;metabolomics;mouse model;neuronal survival;new therapeutic target;novel;overexpression;oxidative damage;prevent;response;stable isotope;therapeutic target;uptake

public_health_relevance:
Project NarrativeAPOE*4 (E4) is the strongest genetic risk factor for late-onset Alzheimer's disease. This proposal aims tostudy how E4 negatively influences neuronal survival by studying a metabolic pathway that links glucosemetabolism and oxidative stress. If successful this will provide new therapeutic targets to normalize glucosemetabolism and potentially prevent or delay the onset of AD.


application_id: 10218271
project_number: 5R01HL152714-02
administering_ic: NHLBI
award_notice_date: 2021-04-27
opportunity_number: PAR-19-274
application_type: 5
activity_code: R01
ic: HL
serial_number: 152714
program_official: BROWN, ALISON GWENDOLYN MARY
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Dissemination and Implementation Research in Health Study Section[DIRH]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: SPRING, BONNIE
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-05-01
project_abstract:
ABSTRACT We propose a type 1 hybrid effectiveness-implementation study to test an adapted evidence-basedintervention and explore critical implementation issues including feasibility acceptability and costs thatinfluence scale-up and sustainment. We focus this adaptation effectiveness and implementation study onunderserved rural residents a population that maintains extremely high rates of suboptimal diet and sedentarybehaviors placing them at elevated risk for cardiovascular disease obesity diabetes cancer and otherchronic conditions. Within the vulnerable low socioeconomic status population of rural residents AppalachianKentuckians experience even worse health outcomes including among the highest rates of morbidity andmortality in the nation. Such adversity is exacerbated by and associated with inadequate community resources.Increasingly however Appalachian residents and other vulnerable populations are gaining access tomodalities that may be useful in addressing these health challenges including internet connectivity and nearlyubiquitous cell phone use. Despite this accelerating technology use the evidence base on personaltechnology-associated interventions (mHealth) in a rural high need population remains sparse. We proposefinalizing adaptation and testing an evidence-based multicomponent mHealth intervention Make BetterChoices 2 (MBC2) a behavioral program consisting of personalized health coaching an app accelerometerand financial incentives. In a recent randomized controlled trial among urban adults MBC2 produced largesustained diet and physical activity improvements by leveraging effective behavior change techniquesincluding goal-setting self-monitoring accountability and support. To prepare for the implementation of thissuccessful intervention with a new population marked by extreme health inequities and sparse resources ourteam has engaged in extensive foundational efforts based on the Dynamic Adaptation Process framework.These include: (1) completing focus groups and key informant interviews to assess the feasibility andacceptability for rural Appalachian residents to use the MBC2 program; (2) undertaking a comprehensivecommunity inventory to reveal existing and needed resources; (3) engaging stakeholders in community andacademic team meetings including community forums and CAB meetings; and (4) identifying MBC2programmatic and structural elements in need of adaptation. With this extensive preliminary activity we nowpropose a type 1 hybrid effectiveness-implementation trial in which we: (1) finalize adaptation by wireframe andusability testing MBC2 with local Appalachian residents; (2) conduct a RCT to test the effectiveness of theadapted MBC2 compared to an active control arm; and (3) explore implementation outcomes and contextualfactors with a focus on sustainment. This project aspires to demonstrate that systematic adaptation andimplementation of an evidence-based intervention can lead to meaningful and sustained behavioral changesand to prepare for potential scale-up and sustainment of the intervention to maximize its public health impact.

project_terms:
Accelerometer;Accountability;Address;Adult;Appalachian Region;Behavior;Behavioral;Blood Pressure;Body mass index;Budgets;Cardiovascular Diseases;Cellular Phone;Characteristics;Chronic;Chronic Disease;Clinical;Communities;Consolidated Framework for Implementation Research;Consumption;Data;Devices;Diabetes Mellitus;Diet;Elements;Equipment and supply inventories;Evidence based intervention;Fatty acid glycerol esters;Focus Groups;Foundations;Future;Goals;Health;Influentials;Intake;Internet;Intervention;Interview;Lead;Leisures;Life Style;Lipids;Malignant Neoplasms;Methods;Modality;Monitor;Morbidity - disease rate;Obesity;Outcome;Participant;Physical activity;Population;Process;Public Health;Randomized;Randomized Controlled Trials;Reporting;Research Activity;Resources;Rural;Rural Appalachia;Rural Population;Shapes;Structure;Techniques;Technology;Testing;Time;Training Support;Underserved Population;Unhealthy Diet;Vulnerable Populations;acceptability and feasibility;active control;active lifestyle;arm;attentional control;base;behavior change;cardiovascular disorder risk;contextual factors;cost;design;effectiveness evaluation;effectiveness implementation study;effectiveness implementation trial;effectiveness research;effectiveness testing;effectiveness trial;evidence base;experience;financial incentive;fruits and vegetables;good diet;health equity;health inequalities;hybrid type 1 design;implementation outcomes;implementation research;implementation science;improved;informant;information gathering;insight;intervention cost;intervention program;iterative design;knowledge base;low socioeconomic status;mHealth;meetings;mortality;physical inactivity;prevent;primary outcome;programs;rural dwellers;rural underserved;scale up;secondary outcome;sedentary;sedentary lifestyle;smartphone Application;stress management;successful intervention;tool;tv watching;usability;virtual;waist circumference

public_health_relevance:
PROJECT NARRATIVE Rural residents especially Appalachians have among the nations highest rates of cardiovasculardisease (CVD) diabetes and obesity all associated with unhealthy diet and lack of physical activity. Newtools including personal technology offers an opportunity to make long lasting behavioral changes andimprove health. We will test a culturally adapted evidence-based multicomponent mHealth intervention MakeBetter Choices 2 (MBC2) a behavioral program consisting of personalized health coaching an appaccelerometer and financial incentives and explore optimal implementation and sustainment approaches.


application_id: 10217139
project_number: 5P30ES030283-02
project_title: Integrated Toxicomics & Environmental Measurement Facility Core
administering_ic: NIEHS
award_notice_date: 2021-04-07
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6993
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Center for Integrated Environmental Health Sciences (CIEHS) goals are to understand how lifestyle factors interact with exposure to environmental toxicants in human health and disease and toenhance the capacity for environmental health research at the University of Louisville (UofL). UofLshared resource facility cores offer cutting edge scientific services enabling access to high-endequipment advanced techniques and specialized expertise that would typically be inaccessible for aninvestigator. It is essential for the modern environmental health scientist to understand the numerousavailable shared resource facility cores; in terms of accessibility effective experimental design data-acquisition and -analyses. The Integrated Toxicomics and Environmental Measurement Facility Core(ITEMFC) will create a central resource for CIEHS members allowing them to understand access andeffectively use environmental omics resources. The ITEMFC will coordinate activities between CIEHSmembers and the existing UofL shared resource facility cores. The ITEMFC will be comprised of sixdiscrete technology-centric components: genomics/ transcriptomics proteomics metabolomicsmetallomics metagenomics and controlled inhalation exposure studies. The ITEMFC will focus itsefforts on advising investigators on study design facilitating shared resource facility cores use andeducating Center members and trainees on these technologies. Additionally the ITEMFC will facilitatethe transfer of omics data to the Biostatistics and Informatics Facility Core (BIFC). It will accomplishthese goals through the following specific aims: Aim 1. Increase access and facilitate use of UofLshared resource facility cores. ITEMFC will serve our members by (a) explaining the various cores andhow they operate (b) establishing direct interactions with the right shared resource director to selectthe appropriate technology. We will aid in experimental design and closely collaborate with all FacilityCores to streamline sample handling and data analysis. The ITEMFC will also supplement the cost ofmember studies. Aim 2. Cultivate awareness interest and understanding of the ITEMFC sharedresource facility cores. The ITEMFC will support CIEHS members by (a) drawing attention to theshared resource facility cores (b) suggesting how the ITEMFC may enhance their approach inanswering their research questions and (c) support educating the next generation of environmentalscientists in the various technologies. Aim 3. Facilitate submission of CIEHS members grantapplications proposing to use ITEMFC Resources. The ITEMFC will support CIEHS members in theirgrant applications that include omics-based aims. The integrated services and expertise of the ITEMFCare essential to achieve CIEHS goals and to make progress with regard to understanding the diversepathological consequences of exposure to environmental toxicants together with lifestyle factors.

project_terms:
Applications Grants;Attention;Award;Awareness;Biometry;Budgets;Cells;Chronic Disease;Communities;Core Facility;DNA;Data;Data Analyses;Disease;Environmental Health;Equipment;Event;Experimental Designs;Exposure to;Funding;Genomics;Goals;Grant;Health;Health Sciences;Human;Informatics;Inhalation;Inhalation Exposure;Institution;Interest Group;Investments;Laboratories;Malignant Neoplasms;Measurement;Measures;Metabolic;Metagenomics;Metals;Modernization;National Institute of Environmental Health Sciences;Pathologic;Pilot Projects;Pollution;Proteins;Proteomics;RNA;Research;Research Design;Research Personnel;Resource Sharing;Resources;Running;Sampling;Scientist;Services;Suggestion;Techniques;Technology;Tissues;Toxic Environmental Substances;Toxicogenetics;Toxicology;Universities;Work;base;citizen science;community engagement;cost;data acquisition;environmental toxicology;faculty community;health science research;interest;lifestyle factors;medical schools;member;metabolomics;neurodevelopment;next generation;programs;shared attention;toxicant interaction;transcriptomics


application_id: 10217134
project_number: 5P30ES030283-02
project_title: University of Louisville Center for Integrative Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2021-04-07
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
program_official: THOMPSON, CLAUDIA L
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Agriculture;Alcohol consumption;Alcohols;Area;Basic Science;Biological Models;Biometry;Cardiovascular system;Chemicals;Childhood;Chronic;Chronic Disease;Clinical;Clinical Trials;Clinical Trials Unit;Collaborations;Communication;Communities;Complex;Core Facility;County;Development;Diabetes Mellitus;Diet;Disease;Disease Outcome;Ecosystem;Environment;Environmental Health;Environmental Risk Factor;Etiology;Exposure to;Funding;Gender;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Industrialization;Informatics;Interdisciplinary Study;Interest Group;Investigation;Kentucky;Knowledge;Laboratories;Leadership;Life;Malignant Neoplasms;Measurement;Mental disorders;Mentors;Mentorship;Metals;Modification;Obesity;Pathogenesis;Pilot Projects;Play;Pollution;Polychlorinated Biphenyls;Positioning Attribute;Predisposition;Program Development;Research;Research Personnel;Research Training;Resources;Role;Rural;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translating;Translations;United States;Universities;Vinyl Chloride;Vision;Youth;addiction;built environment;career development;citizen science;community based participatory research;community based research;community engagement;design;health science research;improved;lifestyle factors;man;member;metropolitan;multidisciplinary;next generation;pollutant;preventive intervention;programs;recruit;response;rural environment;rural healthcare;skills;socioeconomics;stressor;tobacco exposure;tobacco products;urban setting


application_id: 10216420
project_number: 4R00CA225633-03
administering_ic: NCI
award_notice_date: 2020-09-11
opportunity_number: PA-18-398
application_type: 4
activity_code: R00
ic: CA
serial_number: 225633
program_official: AMIN, ANOWARUL
project_start_date: 2020-09-11
project_end_date: 2023-08-31
study_section: NSS
contact_pi_person_id: 14359954
contact_pi: GUO, HOUFU
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-09-11
project_title:
Determining structural features of a collagen lysyl hydroxylase that promotes lung cancer metastasis

project_abstract:
Project Summary/Abstract:Candidate: Dr. Guo has received broad training in biochemistry and structural biology. He is a postdoctoralfellow at MD Anderson Cancer Center seeking to understand how collagen lysyl hydroxylase (LH) structuralfeatures regulate lung cancer metastasis. Dr. Guo is a highly productive investigator with 18 peer-reviewedpapers (6 of which as first or co-first author). As recognition of his achievements he received numerousawards during his doctoral and postdoctoral training.Career Development/Training: Dr. Guo's mentors at MD Anderson include Dr. Jonathan Kurie a physician-scientist with expertise in lung cancer biology and mouse modeling of human lung cancer and Dr. John Tainera renowned protein crystallographer studying macromolecular assemblies to inform drug design. AdditionallyDr. Guo will receive training from Dr. Mitsuo Yamauchi (UNC-Chapel Hill) a collagen biochemist who wasamong the first to elucidate how collagens are modified by LHs. These investigators have designed a trainingprogram centered on their key scientific disciplines that will strengthen Dr. Guo's abilities in their respectivefields and provide the skills needed for a smooth transition to independence.Research: Our group has shown that high expression of LH2 drives lung cancer metastasis and induces acollagen cross-link switch in tumor stroma. LH2 is a therapeutic target of interest but selective LH inhibitorsare not available a deficiency due in part to a lack of structural insight into LH2. The objective of my proposalis to elucidate LH2 structural features that promote lung cancer metastasis. In my preliminary results Idescribe new methods to produce human LH2 protein and assay its activity and the structure of the catalyticdomain of a viral LH homologue which revealed a homodimer stabilized by Fe+2-binding. I found that the twoactive sites flank a deep surface cleft on the dimer interface suggesting that dimerization creates a collagen-binding site and that basic residues adjacent to the active site are positioned to form salt bridges withtelopeptidyl acidic residues on collagen. From these findings I hypothesize that LH2 has telopeptidyl-LHactivity owing to unique features that allow it to form Fe2+-stabilized dimeric structures that interact withtelopeptidyl lysines on collagen. I will test this hypothesis by determining how LH dimer assemblies arestabilized by Fe2+-binding and interact with telopeptidyl lysine residues to regulate collagen cross-link formationand lung tumorigenesis.In sum my proposal will address the clinical problem of lung cancer metastasis. The novelty rests inpreliminary results that provide the first structural insights into a collagen LH hypotheses that challenge currentparadigms and technologies that facilitate quantification of LH enzymatic activity and evaluation of candidatemetastasis drivers.

project_terms:
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine;Acanthamoeba;Achievement;Active Sites;Address;Aldehydes;Alleles;Arginine;Aspartate;Award;Binding;Binding Sites;Biochemical;Biochemistry;Biological Assay;Biology;C-terminal;Cancer Biology;Cancer Center;Cartilage;Catalytic Domain;Charge;Clinical;Collagen;Complex;Crystallization;Crystallography;Development;Dimerization;Discipline;Disease;Drug Design;Enzymes;Epithelial;Epithelial Cells;Epithelium;Evaluation;Family member;Foundations;Future;Gelatinase B;Glutamates;Growth;Homologous Gene;Human;Hydrophobicity;Hydroxylysine;KRAS2 gene;Laboratories;Leucine;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lysine;Malignant neoplasm of lung;Mentors;Metastatic Neoplasm to the Lung;Methods;Mus;Mutation;N-terminal;Neoplasm Metastasis;Paper;Peer Review;Physicians;Positioning Attribute;Postdoctoral Fellow;Proline;Proteins;Reporting;Research;Research Personnel;Rest;Scientist;Sodium Chloride;Structure;Sum;Surface;Technology;Testing;Training;Training Programs;Tumor Tissue;Tumor-infiltrating immune cells;Tyrosine;Viral;bone;career development;clinical application;crosslink;design;dimer;human model;inhibitor/antagonist;insight;interest;lung tumorigenesis;macromolecular assembly;malignant breast neoplasm;mouse model;mutant;novel;post-doctoral training;prognostic value;protein structure;sarcoma;skills;structural biology;therapeutic target;tumor;tumor growth;tumorigenesis

public_health_relevance:
Project NarrativeBuilding on evidence from my mentors laboratory that the collagen modifying enzyme lysyl hydroxylase 2(LH2) induces a collagen cross-link switch in tumor stroma and thereby drives lung adenocarcinomametastasis I have generated a crystal structure of an informative viral homologue of LH2. The structuralfeatures of that enzyme are the basis for my hypothesis that LH2 has a novel dimerization interface and basicresidues adjacent to the active site that confer its unique collagen telopeptidyl LH activity. Testing thishypothesis will inform LH2 biology and may have broad clinical applicability because LH has been implicated inthe metastatic activity of multiple tumor types and the development of fibrotic diseases.


application_id: 10216310
project_number: 5R01GM130954-03
project_title: Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation
administering_ic: NIGMS
award_notice_date: 2021-07-19
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: GM
serial_number: 130954
program_official: BARSKI, OLEG
project_start_date: 2019-09-01
project_end_date: 2023-07-31
study_section: Molecular and Cellular Endocrinology Study Section[MCE]
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: RODGERS, DAVID W
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Insulin-degrading enzyme (IDE insulysin) is a primarily cytosolic peptidase shown to beimportant in the catabolism of insulin the amyloid beta peptide and likely other signaling andintracellular peptides. Its cellular physiology is therefore of considerable interest in the treatmentof disorders such as diabetes and Alzheimer's disease. However the site of IDE action on thesepeptides which are internalized into or otherwise present in the endosomal system is yet to befully understood. We propose to address the question of how this cytosolic enzyme encounterssubstrate peptides like insulin in the endosomal system exploring a novel mechanism for IDEsubcellular localization to this compartment. In particular we propose that IDE is trafficked toendosomes by binding to membrane anionic lipids particularly phosphoinositides through apolyanion-binding site. In the first aim we will test this hypothesis by using IDE polyanion sitemutants by altering levels of a key phosphoinositide and by expressing a phosphoinositidebinding competitor. We further propose to study in the second aim the participation ofendosomal IDE in insulin and amyloid(beta(peptide(catabolism. We will manipulate endosomalIDE levels using mutant forms of the enzyme with reduced endosome localization bydecreasing PtdIns(3)P levels and by increasing endosomal IDE by fusing it with a PtdIns(3)P-targeting domain. In the third aim we will study the polyanion-dependent activation of IDE andits role in affecting its catabolism of cytosolic peptides. We will use IDE mutants to test the effectof activation on hydrolysis of peptide substrates identified using a ligand trapping technique andpeptidomic analyses. We will also test for activation of cellular IDE by inositol phosphates andother potential endogenous activators. We will use our trapping technique to identify otherendogenous effectors. These studies will develop a clearer picture of how IDE carries out itsphysiological functions and greatly benefit efforts to treat IDE related pathophysiological states.(

project_terms:
Address;Affect;Affinity;Alzheimer's Disease;Amyloid beta-Protein;Binding;Binding Sites;Biological Assay;Catabolism;Cell Fractionation;Cell physiology;Cells;Cultured Cells;Development;Diabetes Mellitus;Disease;Endosomes;Enzyme Activation;Enzymes;Genetic study;Goals;Human Genetics;Hydrolysis;Inositol Phosphates;Insulin;Insulinase;Knowledge;Ligands;Link;Lipids;Membrane;Microscopy;Monitor;Peptide Hydrolases;Peptides;Phosphatidylinositols;Physiological;Play;Regulation;Role;Signal Transduction;Site;System;Techniques;Testing;Yeasts;base;endosome membrane;enzyme activity;enzyme substrate;inhibitor/antagonist;innovation;interest;mutant;novel;phosphatidylinositol 3-phosphate;polyanion;receptor internalization;receptor mediated endocytosis

public_health_relevance:
Numerous studies including human genetic studies link Insulin Degrading Enzyme (IDE) toboth diabetes and Alzheimer's disease likely through its role as a key regulator of insulininvolved in diabetes and amyloid beta peptide involved in Alzheimer's disease. This projectwill focus on how the physiological functions of Insulin Degrading Enzyme are affected by itsintracellular localization and by its regulation by polyanions.


application_id: 10216253
project_number: 5R01DK125801-02
administering_ic: NIDDK
award_notice_date: 2021-07-02
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 125801
program_official: KUCZMARSKI, ROBERT J
project_start_date: 2020-07-15
project_end_date: 2025-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 10552456
contact_pi: WILLIAMS, LOVORIA B
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-07-01
project_terms:
Address;Adherence;Adopted;Adult;African American;Aftercare;Age;Behavior;Blood Pressure;Body Weight decreased;Centers for Disease Control and Prevention (U.S.);Church;Clinical;Communities;Community Health Aides;Control Groups;Diet;Early Intervention;Equilibrium;Ethnic group;Expenditure;Future;Gender;Goals;Gold;Individual;Intervention;Intervention Studies;Life Style;Mediating;Mediation;Mediator of activation protein;Mission;Modeling;Morbidity - disease rate;Motivation;National Institute of Diabetes and Digestive and Kidney Diseases;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Obesity;Outcome;Outcome Measure;Participant;Pattern;Phase;Physical activity;Population;Prevalence;Psychosocial Factor;Public Health;Randomized;Research;Research Personnel;Risk Factors;Self Efficacy;Site;Social support;Socioeconomic Status;Standardization;Stress;Structure;Telephone;Time;Training;Translations;Treatment outcome;United States Centers for Medicare and Medicaid Services;Variant;Weight;Work;active control;arm;base;clinically significant;control trial;cost;cost effective;diabetes prevention program;dietary;experience;group intervention;improved;intervention cost;intervention effect;intervention program;lifestyle intervention;male;meetings;mortality risk;overweight adults;payment;personalized medicine;personalized strategies;primary outcome;programs;racial and ethnic;response;secondary outcome;sex;sociodemographic variables;standard care;success;treatment arm;treatment group;weight loss intervention


application_id: 10216188
project_number: 5R01CA217934-05
project_title: (PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment
administering_ic: NCI
award_notice_date: 2021-07-23
opportunity_number: RFA-CA-15-008
application_type: 5
activity_code: R01
ic: CA
serial_number: 217934
program_official: CHEN, WEIWEI
project_start_date: 2017-09-15
project_end_date: 2023-07-31
study_section: ZCA1-RTRB-E(M2)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: BONDADA, SUBBARAO ;BUTTERFIELD, D. ALLAN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThis application addresses the Provocative Question 9: "What are the molecular and/or cellular mechanismsthat underlie the development of cancer therapy-induced severe adverse sequelae?" focusing onChemotherapy-induced cognitive impairments (CICI). CICI is now a recognized toxicity syndrome that includesloss of executive function (confusion; memory issues) inability to multitask and impaired intellectualreasoning. While CICI caused by central nervous system (CNS)-directed therapies (such as radiation andintrathecal chemotherapy) is readily understood the mechanisms underlying a critical and shared toxicity ofchemotherapy that occurs after systemic cancer treatment with drugs that did not direct at the brain areunclear. The number of patients at risk for CICI from systemic therapy far exceeds the number of patientsexposed to CNS therapy but little is known about the mechanisms mediating the effect of systemic therapy onCICI and there is no clear vision of how to prevent this condition. We have previously shown that generationof reactive oxygen species (ROS) by cytotoxic chemotherapeutic drugs is an essential mediator of brain injuryeven though the drug itself did not get into the brain. It is also imperative to note that anticancer medicationsdesigned specifically to target cancer cells with specialized features such as the family of Bcl2 inhibitors alsogenerate ROS. However the effect of targeted therapy on CICI has never been addressed andconsequently their mechanisms of action are entirely unknown. The goal of this proposal is to test the overallhypothesis that therapy-induced ROS production in the target tissues leads to increased circulating TNFthrough extracellular vesicles (EVs)-mediated reactions and this pro-inflammatory cytokine crosses the bloodbrain barrier to elicit mitochondrial dysfunction and consequent neuronal injury leading to CICI. The followingspecific aims are designed to test the ROS hypothesis gain an understanding of the EVs-mediatedmechanisms and test the proof-of-concept in an experimental cancer therapy setting using two prototypechemotherapy agents (Doxorubicin and Venetoclax) that represent standard cytotoxic and experimentaltargeted drugs in a lymphoma model. Aim 1 will investigate the fundamental role of TNF in therapy-inducedneuronal injury to gain insights into mechanisms of CICI in the brain and demonstrate efficacy of chemotherapyin the presence of redox-active antioxidants. Aim 2 will determine the mechanistic links between circulatingextracellular vesicles and therapy-induced CICI. Aim 3 will define the cell(s) of origin of TNF produced duringchemotherapy that leads to cognitive impairment. These aims will be accomplished in vitro and in vivo usingstate-of-the-art technologies including magnetic resonance spectroscopy redox proteomics unique animalmodels and novel mitochondria targeting anti-oxidant MnP to ameliorate CICI without reducing the efficacy ofthe anti-cancer drugs. The results from this project will lay important groundwork for future clinical trials toimprove the quality of lives of cancer patients exposed to cytotoxic or targeted therapies.

project_terms:
4 hydroxynonenal;Address;Animal Model;Antibodies;Antineoplastic Agents;Antioxidants;Apoptotic;BCL2 gene;Biochemical;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Injuries;Cancer Patient;Cancer Survivor;Cells;Choline;Clinical;Clinical Trials;Cognition;Confusion;Cytotoxic Chemotherapy;Development;Doxorubicin;Drug Targeting;Drug usage;Etiology;Exposure to;Family;Functional disorder;Future;Generations;Goals;Immune;Impaired cognition;Impairment;In Vitro;Inflammatory;Injury;Intrathecal Chemotherapy;Knockout Mice;Link;Lymphoma;Lymphoma cell;Magnetic Resonance Spectroscopy;Mediating;Mediator of activation protein;Memory;Mitochondria;Modeling;Molecular;Mus;Neuraxis;Neuronal Injury;Oxidation-Reduction;Oxidative Stress;Pathology;Patients;Peripheral;Pharmaceutical Preparations;Plasma;Prevention;Production;Proteins;Proteomics;Publishing;Quality of life;Radiation;Reaction;Reactive Oxygen Species;Recommendation;Research;Respiration;Risk;Role;SOD2 gene;Symptoms;Syndrome;Systemic Therapy;TNF gene;Technology;Testing;Therapeutic Effect;Therapeutic Uses;Tissues;Toxic effect;Toxicity due to chemotherapy;Treatment Efficacy;United States;Vision;anti-cancer;antioxidant enzyme;blood-brain barrier permeabilization;cancer cell;cancer therapy;chemobrain;chemotherapy;cytokine;cytotoxic;design;executive function;experience;extracellular vesicles;improved;in vivo;inhibitor/antagonist;insight;macrophage;mimetics;mitochondrial dysfunction;multitask;neuron loss;nitration;novel;prevent;prototype;specific biomarkers;targeted treatment;tumor

public_health_relevance:
Project NarrativeChemotherapy-induced cognitive impairment (CICI) is a serious threat to the quality of life. This project isdesigned to identify practice-changing therapy by establishing a new paradigm which recognizes that ROS isthe initiator of CICI caused by both cytotoxic and targeted drugs. Results from these studies will lead to veryconcrete information potentially offering a specific course of action to develop effective clinical approachesspecifically designed to prevent CICI without reducing chemotherapeutic efficacy.


application_id: 10215786
project_number: 1R01MD016236-01
project_title: Researching Equitable Sleep Time (REST) in Appalachia
administering_ic: NIMHD
award_notice_date: 2021-09-26
opportunity_number: PAR-20-164
application_type: 1
activity_code: R01
ic: MD
serial_number: 016236
program_official: GILLMAN, ARIELLE SAMANTHA
project_start_date: 2021-09-26
project_end_date: 2026-06-30
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 14786675
contact_pi: MOLONEY, MAIREAD
other_pis: BADOUR, CHRISTAL L.
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Age;Alcohols;Anxiety;Appalachian Region;Attitude;Automobile Driving;Behavioral;Belief;Biological;Birds;C-reactive protein;Cardiovascular Diseases;Cardiovascular system;Caring;Child Sexual Abuse;Cirrhosis;Cognitive;Communities;County;Data Collection;Demographic Factors;Diabetes Mellitus;Disease;Distress;Economics;Emotional;Ethnic Origin;Eye;Face;Family;Financial Hardship;Glycosylated Hemoglobin;Glycosylated hemoglobin A;Health;Health Status Indicators;Health behavior;Heart Diseases;Heart Rate;Hour;Immunologics;Individual;Individual Differences;Interview;Kentucky;Knowledge;Lead;Link;Malignant Neoplasms;Measurement;Measures;Mediating;Memory;Mental Depression;Mental disorders;Metabolic;Methods;Modeling;Morbidity - disease rate;Neurocognitive Deficit;Obesity;Outcome;Overdose;Participant;Perception;Physical activity;Predictive Factor;Premature Mortality;Process;Productivity;Public Health;Race;Recording of previous events;Reporting;Research;Risk;Rural;Rural Appalachia;Rural Community;Rural Population;Scientific Advances and Accomplishments;Series;Sex Differences;Sleep;Sleep Deprivation;Smoking;Social support;Societal Factors;Southeastern United States;Stress;Substance Use Disorder;Substance abuse problem;Suicide;Surveys;System;Task Performances;Testing;Time;Trauma;United States;United States National Institutes of Health;Violence;Well in self;Work;base;cognitive task;cohort;cost;demographics;design;diet and exercise;economic impact;ethnic minority population;health disparity;health disparity populations;health inequalities;holistic approach;innovation;insight;interest;longitudinal design;low socioeconomic status;mortality;protective factors;racial and ethnic;racial minority;recruit;research study;rural dwellers;rural health disparities;rurality;self reliance;sex;sleep health;social;social determinants;social factors;substance use


application_id: 10215536
project_number: 5R21ES030334-02
project_title: Alternative splicing in arsenical skin carcinogenesis
administering_ic: NIEHS
award_notice_date: 2021-06-21
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: ES
serial_number: 030334
program_official: HUMBLE, MICHAEL C
project_start_date: 2020-07-14
project_end_date: 2023-06-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryChronic exposure to arsenic most commonly through contaminated drinking water plagues over 200 millionindividuals in over 70 countries including the USA. Arsenic is a multi-organ toxicant and chronic arsenicexposure causes several chronic diseases including cancer in multiple organs skin cancer being the mostcommon. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis aclear picture is yet to emerge. It is well known that chronic arsenic exposure radically changes thetranscriptomic and proteomic signatures but the underlying mechanism for such sweeping global changesare not yet clearly understood. Differential alternative splicing plays a role in carcinogenesis and may be atplay in arsenic-induced carcinogenesis. We employed state-of-the-art RNA-Seq analysis ina well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodiumarsenite for 32 weeks) in a longitudinal study to understand the global changes in splicing occurring during thetransformation process. Our data indicate >600 differential alternative splicing events occurred at each of thetime points studied (7 19 28 weeks of exposure). This differential splicing program by dramatically changingthe proteome could be a key player in the arsenic-induced transformation of skin cells. The present proposalaims to examine the contribution of significant differential splicing events at each time point towards theprocess of carcinogenesis. We will specifically scrutinize if the significant splicing events predicted by ourtranscriptomic studies can be correlated with protein isoform expression profiles. Furthermore we also aim tostudy if predicted significantly different spliced isoforms that take place in the 5' or 3' UTR of transcripts canbe correlated to expression profile in the mature mRNA samples from exposed and unexposed cells. Theoutcomes from this study will further our understanding of how alternative splicing shapes the cellular eventstaking place before during and after the time the HaCaT cells become malignant. In addition our study willlook to elaborate the mechanistic basis of how one change in an upstream regulatory alternative splicing factorcan cause genome-wide synchronized alternative splicing changes by signal amplification through successivesteps leading to altered proteome and ultimately adverse health effects.

project_terms:
3' Untranslated Regions;5' Untranslated Regions;Affect;Alternative Splicing;Area;Arsenic;Arsenicals;Arsenites;Attention;Automobile Driving;Biogenesis;Biological;Biological Process;Cell Cycle Regulation;Cell physiology;Cells;Chronic;Chronic Disease;Complex;Country;DNA Repair;DNA damage checkpoint;Data;Disease;Etiology;Event;Exposure to;Gene Expression;Gene Expression Regulation;Genome Components;Global Change;Health;Human;Individual;Lead;Longitudinal Studies;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Messenger RNA;MicroRNAs;Mitotic;Modeling;Oncogenic;Organ;Outcome;Outcome Study;Oxidative Stress;PLK1 gene;Paint;Pathway Analysis;Pathway interactions;Phenotype;Play;Post-Transcriptional Regulation;Process;Production;Protein Isoforms;Proteins;Proteome;Proteomics;RNA Splicing;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Shapes;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;System;Testing;Time;Transcript;arsenic-induced carcinogenesis;base;biological adaptation to stress;carcinogenesis;contaminated drinking water;differential expression;genome-wide;keratinocyte;programs;proteomic signature;public health relevance;response;sodium arsenite;toxicant;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;tumorigenesis;well water

public_health_relevance:
Public Health Relevance Statement/ Project NarrativeThis study will lead to a better understanding of the mechanisms at play by which chronic arsenic exposureleads to human skin cancer in human and will generate markers of early and late response to arsenicexposure. This study will contribute to the understanding of how one or a few cellular events lead to globalcoordinated alternative splicing events through amplification of splicing signal cascades.


application_id: 10215167
project_number: 1U18FD007239-01
project_title: Ion Chromatography System for sample analysis
administering_ic: FDA
award_notice_date: 2020-09-21
opportunity_number: PAR-18-604
application_type: 1
activity_code: U18
ic: FD
serial_number: 007239
program_official: CERIC, OLGICA
project_start_date: 2020-09-20
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZFD1 CVM-R (04)]
contact_pi_person_id: 16558681
contact_pi: ROMANO, MEGAN C
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Romano 2020 Project SummaryThe objective of this Food and Drug Administration (FDA) Veterinary Laboratory Investigation andResponse Network (VetLIRN) Capacity Building project is to support enhanced human and animal foodsafety by strengthening the capacity collaboration and integration of foodsafety laboratories andnetworks thereby facilitating an effective and coordinated response to future human and animal foodsafety issues. The overall goal of the program is to complement develop improve and use universitystate and federal veterinary diagnostic laboratory testing capabilities. The goal of this specificapplication is to obtain funding for an ion chromatography system used to analyze biological feedwater and other samples for anions including nitrate nitrite bromide fluoride chloride and otheranions. These analyses will be used to diagnose intoxications associated with feeds or drugs and toanalyze suspected source material. This will expand the laboratorys capability ad capacity to performfoodsafety related testing for the FDA VetLIRN program and investigate potential animal foodborneillness outbreaks.

public_health_relevance:
Romano 2020 Project NarrativeThis FDA VetLIRN Network Capacity Building project will strengthen the overall food safety system bydeveloping increased capacity and capabilities to detect adulteration which could affect animals raisedfor human consumption or companion animals consuming ingredients used in both animal and humanfood products.


application_id: 10214825
project_number: 1U18FD007241-01
project_title: Vet-LIRN Network Capacity-Building Projects
administering_ic: FDA
award_notice_date: 2020-09-21
opportunity_number: PAR-18-604
application_type: 1
activity_code: U18
ic: FD
serial_number: 007241
program_official: CERIC, OLGICA
project_start_date: 2020-09-20
project_end_date: 2021-12-31
study_section: Special Emphasis Panel[ZFD1 CVM-R (04)]
contact_pi_person_id: 15010137
contact_pi: REED, DEBBIE CAROL
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractVet-LIRN Network Capacity-Building ProjectsPAR-18-604 Breathitt Veterinary Center (BVC) seeks funding to maintain the high level of QualityManagement within the organization by purchasing new batteries for our Uninterrupted Power Supply. The UPS provides a bridge between normal electrical power and the generators that serve asback-up power for BVC. Power to equipment is maintained via a battery array that provides powerwhen the electricity supply is interrupted or the voltage drops to an unacceptable level. Highly sensitive diagnostic equipment such as the LC/MS/MS and the ICP/MS in toxicology theMALDI-TOF and SensiTitre in Bacteriology and the AU7500 and Quant5 Studio in Molecular Diagnosticshave several steps to properly shut them down without losing data. The operation of these units arealso sensitive to changes in voltage that would deteriorate sensitive electronic components. This couldlead to unexplained failures and impact the accuracy of data. The quality of test results is of utmost importance to our clients and is the basis of our QualitySystem. These batteries are necessary to guarantee the most accurate results. The cost of updated batteries for the UPS is $52000. BVC will accept partial funding of thisproject.

public_health_relevance:
Project NarrativeVet-LIRN Network Capacity-Building ProjectsPAR-18-604 Breathitt Veterinary Center (BVC) is one of two state veterinary diagnostic laboratories inKentucky. BVC is AAVLD accredited for all species. BVC is located in Hopkinsville Kentucky and isassociated with Murray State University in Murray Kentucky 60 miles distant. While Murray StateUniversity supports BVC by every means possible there are certain aspects of the maintenance of aveterinary diagnostic laboratory that are unique to laboratories. BVC retains its own grounds andcustodial staff and network administrator on site. Administrative faculty and technical staff conducttesting with a Quality Manager to scrutinize policies and work instructions. Maintaining the infrastructure required to operate a facility with the complexity of BVC is costlyand demanding. One of the items that must be maintained to ensure that quality standards are upheld is theUninterrupted Power Supply (UPS). This is a battery array that ensures many items in BVC never loseelectric power. The UPS provides a bridge between normal electrical power and the generators thatserve as back-up power for BVC. Servers on site at BVC and desktop computers together with computers that run testingequipment should never be subjected to voltage variations and electrical disturbances such as suddenloss of power. These variations can damage components and scramble data maintained on thecomputer system. Data loss could occur in addition to the damage caused to operating systems such asthe USALIMS laboratory management system and the QUALTRAX quality management system. Equipment at BVC such as the LC-MS/MS and the ICP/MS in toxicology the MALDI-TOF andSensiTitre in Bacteriology the ABI 7500 and Quant Studio 5 in Molecular Diagnostics all are verysensitive to power disturbances such as voltage sag or frequency variations. Any of these disturbancescan cause deterioration to sensitive electronic components resulting in unexplained failures andproblems with system performance and loss of important testing data. Protection of these expensive and critical pieces of equipment is essential. The LC-MS/MS andICP/MS are used to evaluate feed of all types for toxins of both chemical and biological origin.Mycotoxins pesticides and ionophores can be detected in feed samples on the LC/MS/MS. The ICP/MSis used to identify heavy metals and elemental toxins. The MALDI-TOF is a specially programed MSused to identify some bacteria quickly and accurately. The SensiTitre is used for the Anti-MicrobialResistance project that LRN sponsors. The ABI-7500 and Quant Studio5 are used to identify biologicalthreats in feed via real time polymerase chain reaction (rPCR). All of these are utilized on a daily basisfor routine diagnostic testing as well. UPS also would maintain systems within the BioSafety Level 3 (BSL 3) suite. This area needs tostay prepared for foreign animal and emerging disease testing. African Swine Fever (ASF) African HorseSickness (AHS) COVID-19 and Foot and Mouth Disease Virus (FMDV) are constant threats that wouldrequire use of the BSL 3. Avian Influenza (AI) testing would also be performed in the BSL 3 suite for theprotection of the public and the staff. While this falls outside the Vet-LIRN scope of funding programs itis important to remember that ASF FMDV and AI all impact the food industry. UPS batteries are required to be replaced periodically to ensure the strength of the batteryremains at full power. BVC requests funding to replace the current batteries. This request follows theFunding Opportunity Purpose 2. Support  quality assurance processes and support nationalcapacity/capability development. The cost of updated batteries for the UPS is $52000. BVC will accept partial funding of thisproject. Protection of data ensuring testing results are accurate and guarding the ability to ensure asafe and constant food supply are important parts of the Vet-LIRN mission.


application_id: 10213670
project_number: 5R37CA234002-02
project_title: Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors
administering_ic: NCI
award_notice_date: 2021-06-15
opportunity_number: PA-19-056
application_type: 5
activity_code: R37
ic: CA
serial_number: 234002
program_official: FORRY, SUZANNE L
project_start_date: 2020-07-09
project_end_date: 2025-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Attenuated;Automobile Driving;Binding;Bioavailable;Breast Adenocarcinoma;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Bypass;CDK4 gene;Cell Cycle;Cell Cycle Progression;Cells;Clinical;Clinical Trials;Cyclin D1;Cyclins;Development;ERBB2 gene;Enzymes;Estradiol;Estrogen Receptors;Estrogen receptor positive;FDA approved;Fructose;Genetic;Genetic Transcription;Glucose;Glycolysis;Growth;In Vitro;Malignant Neoplasms;Mediating;Metabolic;Metastatic breast cancer;Oncogenic;Oral;Pathway interactions;Patients;Pharmacology;Phase;Phase I/II Trial;Phosphorylation;Progression-Free Survivals;Relapse;Resistance;Resistance development;Retinoblastoma Protein;Role;Testing;Time;advanced breast cancer;base;blood glucose regulation;cancer cell;combinatorial;cyclin D3;design;early phase clinical trial;efficacious treatment;glucose metabolism;hormone receptor-positive;hormone therapy;improved;in vivo;inhibitor/antagonist;malignant breast neoplasm;mouse model;novel;novel strategies;overexpression;prevent;research clinical testing;response;targeted treatment;therapy resistant;treatment response;tumor


application_id: 10213118
project_number: 5R01HL138488-05
project_title: Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction
administering_ic: NHLBI
award_notice_date: 2021-06-19
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 138488
program_official: SOPKO, GEORGE
project_start_date: 2017-08-01
project_end_date: 2021-12-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTIschemic heart disease is the leading cause of morbidity and mortality in the U.S. population and is often causedby acute myocardial infarction (AMI). AMI initiates an inflammatory response leading to increased circulatinginflammatory bone marrow cells (BMCs) particularly monocytes (monocytosis). This response is crucial forremoving dead tissue and initiating the healing process. However exacerbated inflammatory response followingAMI can be detrimental and is associated with infarct expansion poor cardiac remodeling and adverse clinicaloutcomes. While most studies focus on monocyte production following AMI the mechanism(s) of monocyteegress from the bone marrow and early cardiac infiltration after AMI are poorly understood. Our preliminary datademonstrate the role of the signaling bioactive lipid lysophosphatidic acid (LPA) in the post-AMI mobilization ofBMCs. LPA produced by the enzyme autotaxin (ATX) plays a key role in activating inflammatory monocytesregulating their peripheral blood count and homing them to sites of inflammation. Preliminary studies alsoindicated that LPA levels are elevated early in PB and cardiac tissues after AMI in humans and mice. The long-term goal is to contribute to development of new clinically useful therapies for AMI injury. The overall objectiveof this application is to define LPA mediated signaling pathways linking AMI to the inflammatory BM response.The rationale for the proposed research is its potential to offer new approaches to reduce inflammation andimprove cardiac recovery after AMI. The central hypothesis is that LPA plays a key role in initiating andmaintaining the post-AMI inflammatory response thus impairing cardiac recovery. This hypothesis will be testedby pursuing three specific aims: 1) Identify the molecular mechanism(s) that result in elevated plasma LPA afterAMI 2) Determine the signaling systems by which ATX/LPA axis promotes monocytosis after AMI and 3) definethe association between LPA levels heritable genetic variability in LPA receptor 1 that predicts receptorexpression and monocytosis after AMI in humans. Results of these studies are expected to provide newmechanistic understanding of AMI-induced ATX/LPA signaling their contribution to AMI-associated systemicmonocytosis and cardiac inflammation and the role of heritable genetic mutations in monocytosis andinflammation in humans. To attain this goal the proposed project will combine human studies with animal modelswith genetic manipulation of key components of the ATX/LPA signaling. This group has extensive experience instudying heart/BM signaling after AMI as well as ATX/LPA signaling pathways. The overall impact of thesestudies derives from an innovative focus on the ATX/LPA signaling nexus as a critical mechanism in AMI-induc edinflammation and the potential to control post-AMI infarct expansion and subsequent heart failure by dampeningthis pathological response.

project_terms:
Acute;Acute myocardial infarction;Address;Adhesions;Affect;Animal Model;Atherosclerosis;Blood;Blood Vessels;Bone Marrow;Bone Marrow Cells;Cardiac;Cardiac Myocytes;Cells;Cessation of life;Chemotactic Factors;Clinical;Complement;Coupled;DNA Sequence Alteration;Data;Development;Endothelial Cells;Endothelium;Enzymes;Frequencies;GTP-Binding Proteins;Gap Junctions;Genetic;Goals;Healthcare;Heart;Heart failure;Heritability;Homing;Human;Impairment;Infarction;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Knowledge;Link;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mass Spectrum Analysis;Mediating;Metabolism;Mission;Modeling;Molecular;Monocytosis;Morbidity - disease rate;Mus;Myelopoiesis;Myocardial Ischemia;Myocarditis;Outcome;Pathologic;Pathway interactions;Patients;Pharmacology;Phosphoric Monoester Hydrolases;Plasma;Play;Population;Process;Production;Proteins;Public Health;Recovery;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Source;Spleen;System;Testing;Therapeutic;Tissues;Tracer;United States National Institutes of Health;Variant;base;cardiogenesis;chemokine;cytokine;experience;genetic manipulation;genetic variant;gustin;healing;improved;inhibitor/antagonist;innovation;lysophosphatidic acid;monocyte;mortality;mouse model;myocardial injury;novel strategies;peripheral blood;progenitor;receptor;receptor expression;repaired;response;role model;stable isotope

public_health_relevance:
The proposed research is relevant to health care in that ischemic heart disease following acute myocardialinfarction (AMI) continues to be the leading cause of mortality and morbidity in the U.S. The bone marrowresponds to myocardial injury by the production and mobilization of inflammatory cells that can exacerbate theinjury and our proposal aims at reducing this pathological inflammation and subsequent development of heartfailure. The proposed research is relevant to the NIHs mission pertaining to developing and applyingfundamental knowledge to protect and improve the health of the public.


application_id: 10212654
project_number: 3P20GM103436-20S1
project_title: ConProject-001
administering_ic: NIGMS
award_notice_date: 2020-09-21
opportunity_number: PAR-18-262
application_type: 3
activity_code: P20
ic: GM
serial_number: 103436
suffix: S1
program_official: ARORA, KRISHAN
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9(IN)
subproject_number: 7708
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
project_abstract:
The overarching goal of the Kentucky Institutional Development Award (IDeA) Network ofBiomedical Research Excellence (KY-INBRE) is to build capacity for health-related andbiomedical research in the Commonwealth of Kentucky. We will build a collaborative researchand research-training community throughout the state. Our primary collaborative network isrepresented by 2 research intensive universities 5 state-supported and one independentprimarily undergraduate institutions (PUIs). We provide outreach activities in support of manyother of our smaller state supported and independent institutions including community technicalcolleges. Overall our activities are designed to build on our established multi-disciplinary researchnetwork with a focus on functional genomics as a means to strengthen research infrastructureof the lead and partner institutions. One aim is to support the development of young researchfaculty investigators to help them become independently competitive for federal research grants.Another aim of our network is to provide a variety of research training opportunities for ourundergraduate and graduate students. These students represent the next generation of the healthcare and/or biomedical research industries and they need to be mentored to develop appropriatescientific research skills.

project_terms:
Award;Biomedical Research;Communities;Development;Educational workshop;Faculty;Goals;Health;Healthcare;Industry;Infrastructure;Institution;Interdisciplinary Study;Kentucky;Knowledge;Lead;Location;Mentors;Network Infrastructure;Postdoctoral Fellow;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Science;Students;Technology;Training;Universities;base;career;college;community college;design;experience;faculty research;functional genomics;graduate student;higher education;next generation;outreach;performance site;programs;skills;summer research;technical college;training opportunity;undergraduate student

public_health_relevance:
The health relatedness of this project lies with its goal to build capacity for health andbiomedical research throughout the Commonwealth of Kentucky. Moreover one of its primaryconcerns is to train the next generation of workers in the health care and biomedical researchindustries in Kentucky


application_id: 10212343
project_number: 5R01CA237643-03
project_title: Targeting epigenetic heterogeneity to improve lung cancer immunotherapy response
administering_ic: NCI
award_notice_date: 2021-06-07
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 237643
program_official: SOMMERS, CONNIE L
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. My central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing the PD-L1 expressing tumorpropagating cells (TPCs) and by depleting immunosuppressive tumor associated neutrophils. Theoverarching goal of the proposed study is to validate combining EZH2 inhibition with PD1/PD-L1 targetedimmunotherapy and learn the molecular mechanisms when the treatment is successful as well as when it is notsuccessful. In Aim 1 I will use both mouse models and human patient derived organoid cultures and serial orthotopictransplantation to examine NGFR and PD-L1 expression and tumor propagation abilities of lung SCC cells afterEZH2 inhibitor treatment. I will also test if non-TPC cells can de-differentiate and continue to fuel tumor growthby sorting for presence or absence of the putative TPC cell surface marker nerve growth factor receptor (NGFR).The epigenetic and transcriptional consequences of EZH2 inhibition on squamous lung tumor cells will beassessed by ChIP-seq and RNA-seq. In Aim 2 I will focus on the tumor associated neutrophils (TANs). I willcompare TANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migrationcapacity and ability to suppress T cells. I will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 I will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. I will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. Completion of these aims will solidify the efficacy of a promising therapeuticcombination and uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2inhibitors in squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibitionwith anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.

project_terms:
Affect;CXCL9 gene;Cancer Etiology;Cancer Patient;Cell surface;Cells;Cessation of life;ChIP-seq;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Gene Expression;Genes;Genetic Transcription;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Malignant neoplasm of lung;Methyltransferase;Molecular;Mus;NGFR Protein;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;Sorting - Cell Movement;Squamous Cell;Squamous cell carcinoma;T-Lymphocyte;Testing;Therapeutic;Time;Transplantation;Tumor stage;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;base;cancer immunotherapy;cell type;clinically relevant;combinatorial;conditional knockout;effector T cell;improved;inhibitor/antagonist;migration;mouse model;neoplastic cell;neutrophil;programmed cell death ligand 1;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
Lung cancer is the leading cause of cancer-related deaths worldwide and is a very complex disease withdifferent cell types that comprise each tumor. Immunotherapy is ground-breaking because it is able to cure somepatients with late stage tumors but the number of patients that have this great response is still low. In thisproposal we will test the combination of a second drug with immunotherapy to increase the likelihood thatsquamous lung tumors will respond to treatment.


application_id: 10212210
project_number: 5T32AG057461-05
project_title: Training in Translational Research in Alzheimer's and Related Dementias (TRIAD)
project_terms: Alzheimer's disease related dementia;Training;Translational Research
administering_ic: NIA
award_notice_date: 2021-08-26
opportunity_number: RFA-AG-17-063
application_type: 5
activity_code: T32
ic: AG
serial_number: 057461
program_official: LUO, YUAN
project_start_date: 2017-09-15
project_end_date: 2023-02-28
study_section: ZAG1-ZIJ-1(A1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: MURPHY, MICHAEL PAUL
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
7. PROJECT SUMMARY/ABSTRACTThis is an application for a T32 training grant titled Training in Translational Research in Alzheimer's Diseaseand Related Dementias (TRIAD) to support 4 predoctoral and 4 postdoctoral fellows. The overall goal of theproposed program is to provide cross-disciplinary training from bench to bedside to produce a newtranslational workforce that is critically needed to develop and advance effective treatments for Alzheimer'sdisease and related dementias. Trainees will receive rigorous and innovative translational research educationand training through a 3-cluster multidisciplinary and integrative mentoring program that spans the discoverycontinuum from molecular/biochemical methods preclinical translational approaches and clinical research. Thethematic focus is on risk factors for Alzheimer's disease and related dementias; these risk factors includecerebrovascular disease neuroinflammation Down syndrome and traumatic brain injury. The training programhas 18 faculty mentors with established and extensive interactions and collaborations and successful trackrecords in training. The faculty mentors encompass diverse areas of expertise from cell & molecular biologygenetics and data science through preclinical model systems therapeutic development neuroimagingneuropathology clinical trials and longitudinal clinical studies. The majority (13) of these mentors are housedwithin the University of Kentucky Sanders Brown Center on Aging which includes a long-standing NIA-fundedAlzheimer's Disease Center. All faculty with primary appointments in a Center also have academicappointments in other basic science or clinical departments at the University of Kentucky. Predoctoral traineeswill be recruited from our Integrated Biomedical Sciences graduate program and from the MD/PhD program inthe College of Medicine and postdoctoral trainees through targeted advertisement and recommendations fromcolleagues and other Alzheimer's Disease Centers. In addition to their individualized research program andcareer development plan each group of trainees will participate in a series of educational experiences thatinclude a dedicated AD101 course in Alzheimer's disease and related dementias seminars describingresearch and clinic ethics monthly research and career development seminars journal clubs Training theTrainers workshops and grant writing workshops. Each year trainees will be expected to present theirresearch at the annual Markesbery Symposium on Aging and Dementia. Postdoctoral trainees will be providedwith additional training opportunities including: 1) a short off-site externship at another laboratory that conductsAlzheimer's disease research and 2) presentations at the annual College of Medicine Postdoctoral PosterSession. Quantitative and qualitative metrics for evaluation of trainees and the training program will assure ahigh-quality and effective training experience. The outcomes of our program are intended to nurture highlyinnovative well-trained scholars who are dedicated and passionate about finding new approaches to preventor slow Alzheimer's disease and related dementias.

public_health_relevance:
8. PROJECT NARRATIVEOur training program for Translational Research in Alzheimer's Disease and Related Dementias (TRIAD) willprovide predoctoral and postdoctoral trainees with the cross-disciplinary knowledge and skills needed todiscover develop and advance new treatments for Alzheimer's disease and related dementias. Trainees willbe provided with expertise in cutting edge approaches from molecular methods to preclinical approaches andtranslation to clinical research. Our highly collaborative interdisciplinary and supportive team-basedenvironment at the University of Kentucky will produce the skilled workforce that is critically needed to meet thenational goal of developing a treatment for Alzheimer's by 2025.


application_id: 10210389
project_number: 5R01DK121797-03
project_title: Novel Liver Signaling Pathways Controlling Adiposity
administering_ic: NIDDK
award_notice_date: 2021-03-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 121797
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2020-07-03
project_end_date: 2025-03-31
study_section: Molecular and Cellular Endocrinology Study Section[MCE]
contact_pi_person_id: 9293438
contact_pi: HINDS, TERRY D
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adenovirus Vector;Adipocytes;Adipose tissue;Adult;Affect;Antioxidants;Attenuated;Bile fluid;Bilirubin;Biliverdin reductase;Biliverdine;Binding;Blood;Blood Glucose;Body Weight;Body Weight decreased;Cardiovascular Diseases;Cardiovascular system;Categories;Cell Size;Crigler-Najjar Syndrome;Data;Deposition;Diabetes Mellitus;Energy Intake;Energy Metabolism;Enzymes;Event;Excretory function;Expenditure;Fatty Liver;Fatty acid glycerol esters;Fenofibrate;Genes;Genetic;Genetic Polymorphism;Gilbert Disease;Glucose;Glucose Intolerance;Health;Hepatic;Hepatocyte;Hepatotoxicity;High Fat Diet;Hormones;Human;Hyperbilirubinemia;Icterus;Inflammatory;Inherited;Insulin;Insulin Resistance;Intestines;Investigation;Knock-out;Knockout Mice;Knowledge;Lead;Ligands;Lipids;Liver;Liver diseases;LoxP-flanked allele;Measures;Mediating;Medical;Metabolic;Metabolic hormone;Metabolism;MicroRNAs;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Receptors;Obese Mice;Obesity;Obesity Epidemic;Obesity associated disease;Outcome;Overweight;Oxidative Stress;PPAR alpha;Pathologic;Pathway interactions;Patients;Peripheral;Peroxisome Proliferator-Activated Receptors;Physiological;Plasma;Population Study;Process;Protein Isoforms;Publications;Resistance;Risk;Rodent;Serum;Signal Pathway;Signal Transduction;Signaling Molecule;Testing;Therapeutic;Tissues;Transactivation;UDP-Glucuronosyltransferase 1A1;Uncertainty;United States;Visceral fat;Weight Gain;carbohydrate metabolism;clinically relevant;cost;cytokine;fibroblast growth factor 21;hormonal signals;humanized mouse;improved;insulin sensitivity;lipid metabolism;mouse model;non-alcoholic fatty liver disease;novel;novel therapeutics;obese patients;oxidation;preference;promoter;recruit;transcription factor


application_id: 10210327
project_number: 5R01HL147381-02
project_title: Mechanisms regulating the atherogenic activities of serum amyloid A
administering_ic: NHLBI
award_notice_date: 2021-06-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 147381
program_official: LIU, LIJUAN
project_start_date: 2020-07-05
project_end_date: 2024-06-30
study_section: Special Emphasis Panel[ZRG1-VH-D(02)M]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: SHRIDAS, PREETHA
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but alsoplays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whoseconcentration in the plasma increases 1000-fold or more during a systemic inflammatory response beforereturning to near undetectable levels. However SAA is also persistently elevated in chronic inflammatoryconditions such as diabetes obesity rheumatoid arthritis etc. While the liver is the major source of SAAduring an acute inflammatory response extra-hepatic expression has also been documented. Most notablyadipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognizedfor decades that plasma levels of SAA predict cardiovascular risk in humans. More recently our groupdetermined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerousreports by multiple laboratories SAA exerts a myriad of effects in vitro that would be expected to exacerbateinflammation and atherosclerosis in vivo. However most of these published studies investigated lipid-free SAAoverlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances plasma SAA isfound associated with the high-density lipoprotein (HDL) fraction and accumulating evidence demonstratesthat HDL inhibits SAAs pro-inflammatory activity. Thus one function of HDL may be to sequester andneutralize SAA and limit the propagation of inflammation in vivo. Notably SAA can also be detected on apoBparticles particularly in human populations with increased risk for cardiovascular disease. Although thepathophysiological significance of the association of SAA with non-HDL lipoproteins is not known we haveshown that SAA on apoB-containing lipoproteins augments their proteoglycan binding which could lead toincreased vascular retention. Taken together these observations lead us to propose that the pro-inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium betweenHDL-SAA very low-density lipoprotein/low-density lipoprotein-SAA and lipid-free SAA. To test this hypothesiswe have developed critical research tools including novel mouse models with inducible tissue-specific SAAexpression to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodelingfactors (e.g. cholesterol ester transfer protein phospholipase A2 and oxidation) leads to the release ofbioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoBlipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA(liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. Theresults of this proposal will validate SAA as a therapeutic target in cardiovascular disease and will developSAA lipoprotein distribution as a potential biomarker of risk.

project_terms:
Acute;Acute-Phase Proteins;Adipose tissue;Age;Anti-Inflammatory Agents;Apolipoprotein E;Apolipoproteins;Apolipoproteins B;Atherosclerosis;Binding;Biological Markers;Biology;Blood Circulation;Blood Vessels;Cardiovascular Diseases;Cessation of life;Cholesterol Ester Transfer Proteins;Chronic;Clinical;Clinical Research;Development;Diabetes Mellitus;Dose;Equilibrium;Event;Extrahepatic;Family;Fatty acid glycerol esters;Generations;Goals;High Density Lipoproteins;Human;Impairment;In Vitro;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1 beta;Kidney;Laboratories;Lead;Lipids;Lipoprotein (a);Lipoproteins;Liver;Low-Density Lipoproteins;Methotrexate;Mus;Natural Immunity;Obesity;Pathologic;Pathway interactions;Phase;Phospholipase A2;Plasma;Play;Population;Process;Proteins;Proteoglycan;Publishing;Reporting;Research;Rheumatoid Arthritis;Risk;Risk Factors;Role;Series;Serum amyloid A protein;Signal Transduction;Site;Smoking;Source;Techniques;Testing;Tissues;Very low density lipoprotein;base;burden of illness;cardiovascular disorder risk;cardiovascular risk factor;experimental study;gain of function;high risk;in vivo;insight;loss of function;macrophage;mouse model;novel;oxidation;particle;potential biomarker;response;systemic inflammatory response;therapeutic target;tissue injury;tool;uptake

public_health_relevance:
Serum Amyloid A (SAA) plays a causal role in atherosclerosis in mice and predictscardiovascular disease (CVD) risk in humans. This proposal will investigate the mechanisms bywhich SAA causes atherosclerosis. Results are expected to validate SAA as a therapeutictarget in CVD and aid in the development of new biomarkers for identifying individuals who areat the highest risk.


application_id: 10209777
project_number: 1R01DK124774-01A1
administering_ic: NIDDK
award_notice_date: 2021-03-24
opportunity_number: PA-18-330
application_type: 1
activity_code: R01
ic: DK
serial_number: 124774
suffix: A1
program_official: SILVA, CORINNE M
project_start_date: 2021-04-01
project_end_date: 2026-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Age;Agonist;Behavior;Biological;Biology;Body Weight;Body Weight Changes;Cardiometabolic Disease;Circadian Dysregulation;Circadian Rhythms;Clinical;Clinical Trials Design;Complex;Control Groups;Cost of Illness;Cues;Data;Diabetes Mellitus;Diet;Disease;Eating;Eating Behavior;Estradiol;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Estrogen Therapy;Estrogens;Excision;Exposure to;Fasting;Fatty acid glycerol esters;Feeding behaviors;Female;Food;Functional disorder;GTP-Binding Proteins;Glucose;Glucose Intolerance;Health;Heart Diseases;Hepatocyte;High Fat Diet;Hour;Incidence;Insulin Resistance;Intervention;Knockout Mice;Life;Light;Liver;Measures;Menopause;Metabolic;Metabolic dysfunction;Metabolic syndrome;Metabolism;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Ovariectomy;Overweight;Pattern;Phase;Physiology;Postmenopause;Pre-Clinical Model;Prediabetes syndrome;Predisposition;Premenopause;Randomized;Randomized Controlled Clinical Trials;Research;Resistance;Rest;Risk;Risk Behaviors;Risk Factors;Sex Differences;Signal Transduction;Stroke;System;Testing;Text;Therapeutic;Time-restricted feeding;Tissues;United States;Woman;Women's Role;actigraphy;arm;base;cancer risk;cancer type;cardiometabolism;circadian;circadian pacemaker;circadian regulation;comorbidity;diet-induced obesity;estrophilin;experimental study;feeding;heart disease risk;high risk;improved;insulin sensitivity;male;men;molecular clock;mouse model;obesity risk;primary outcome;protective factors;receptor expression;therapeutic target;time use


application_id: 10208901
project_number: 5P30GM127607-04
project_title: Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2021-07-16
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2023-06-30
study_section: ZGM1-RCB-3
subproject_number: 5792
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Overarching goal of the Center is to understand the mechanisms of pathophysiology of diabetesand obesity and their cardiovascular complications. The Bioanalytics Core is an integral part ofthe Center and will play a key role in the evolution of COBRE in Phase III. The Core will renderservices for rigorous and comprehensive bioanalytical analysis of diabetic specimens. It willprovide intellectual input with experimental design and state-of-the-art technical expertise toaddress the needs of Center investigators. The Core consists of a group of outstanding scientistswith expertise in chromatography mass spectrometry clinical chemistry cardiovascularphysiology and diabetes. Director of the Core Dr. Sanjay Srivastava has more than twenty fiveyears of research experience in analytical biochemistry and pathology vascular inflammationatherosclerosis and diabetes. He will oversee all the Core operations and will work closely withCenter investigators and COBRE-supported pilot project leaders to fulfill their analyticalbiochemistry needs. Dr. Lorkiewicz technical director of the Core has extensive experience instable isotope labeling and mass spectrometric analyses of small molecular weight compounds.He will assist the Center investigators with their metabolomics mercapturomics and otherchromatography/mass spectrometry analyses. Drs. Srivastava and Lorkiewicz will provide handson training to junior investigators for bioanalytical assays. The training acquired at the Core willfacilitate them to grow as scientists and expand their repertoire of technical skills. The Core isequipped with state-of-the-art clinical chemistry and analytical biochemistry equipment and islocated in the Delia Baxter Building. In addition to address the current requirements of the COBREprojects the Core will continue to expand its knowledgebase and technical expertise to satisfythe future needs of the Center. Long term goal of the Core is to become a fiscally independententity capable of providing cutting-edge pathology and bio-analytical services to researchersinterested in diabetes and cardiovascular pathophysiology. Continued excellence in pathologicalanalyses will foster collaborations which will not only help the Core financially but will alsoadvance the field in combatting diabetic complications.

project_terms:
Acetylcysteine;Address;Alkaloids;Analytical Biochemistry;Applications Grants;Area;Atherosclerosis;Benzene;Biological Assay;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Charge;Chemicals;Chromatography;Clinical Chemistry;Collaborations;Communities;Complete Blood Count;Complications of Diabetes Mellitus;Continuing Education;Data Analyses;Diabetes Mellitus;Directed Molecular Evolution;Educational workshop;Ensure;Equipment;Evolution;Experimental Designs;Extramural Activities;Faculty;Fee-for-Service Plans;Fostering;Functional disorder;Funding;Future;Glucose;Goals;Grant;Hepatic;Human Resources;Infrastructure;Kidney;Lipids;Maintenance;Malondialdehyde;Mass Chromatography;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Molecular Weight;Neurotransmitters;Obesity;Participant;Pathologic;Pathology;Pathway Analysis;Phase;Pilot Projects;Plasma;Play;Procedures;Program Research Project Grants;Protocols documentation;Research;Research Personnel;Resolution;Resources;Role;Science;Scientist;Services;Specimen;Stable Isotope Labeling;Structure;Superfund;Technical Expertise;Techniques;Tobacco;Training;United States National Institutes of Health;Universities;Volatile Fatty Acids;Work;Xenobiotic Metabolism;cost;design;detection method;diabetic;experience;experimental study;instrument;interest;investigator training;knowledge base;mass spectrometer;member;metabolomics;monoamine;muconic acid;non-diabetic;novel;operation;oxidation;ranpirnase;research facility;stable isotope;symposium;toxicant;urinary;vascular inflammation;volatile organic compound;webinar


application_id: 10208417
project_number: 1R01CA251663-01A1
project_title: Targeting Mitochondrial Redox Capacity to Overcome Cancer Subtype that Regrowth After Radiation
administering_ic: NCI
award_notice_date: 2021-02-12
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 251663
suffix: A1
program_official: ESPEY, MICHAEL G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Animal Model;Antibiotics;Azithromycin;Biochemical;Biogenesis;Cell Death;Cell Survival;Cells;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Computer software;Coupled;Data;Dose;Electron Transport;Enzymes;Event;Exhibits;External Beam Radiation Therapy;FDA approved;Failure;Homeostasis;Hydrogen Peroxide;Image;Impairment;In Vitro;Macrolides;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolism;Microscopy;Mitochondria;Mitochondrial Proteins;Molecular;Mus;Normal Cell;Oxidation-Reduction;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Property;Prostate;Protein Array;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrence;Regulation;Research Design;Resistance;Resistance development;Resolution;Site;Testing;Therapeutic;Time;Translating;Translations;Treatment Efficacy;Xenograft Model;bioluminescence imaging;cancer cell;cancer heterogeneity;cancer recurrence;cancer subtypes;cancer survival;catalase;factor A;fractionated radiation;high risk;improved;in vivo;inhibitor/antagonist;insight;knock-down;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;mortality;novel;novel therapeutics;overexpression;patient derived xenograft model;prevent;prostate cancer cell;prostate cancer model;prototype;radiation delivery;radiation resistance;radioresistant;response;stable isotope;success;transcription factor;tumor;tumor growth;tumor heterogeneity


application_id: 10208353
project_number: 5P01NS097197-05
project_title: Core-003
administering_ic: NINDS
award_notice_date: 2020-08-04
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-01
project_end_date: 2023-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 7664
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Lafora Disease was originally described over 100 years ago by Dr. Gonzalo Rodriquez-Lafora as amyoclonus epilepsy with dementia. A hallmark of the disease identified by Lafora are inclusions in the brainnow known as Lafora bodies (LBs). LD is a rapidly progressing invariably fatal epilepsy. Onset is inadolescence in apparently healthy teenagers of both sexes with headaches and insidious decline in cognitivefunction. Myoclonic seizures staring spells and generalized convulsions follow and all escalate over time.Initial response to antiepileptic drugs is lost within three years and a constant myoclonus with atypical absencebegins. The young person then develops dementia often disinhibited and seizes with increased frequency.The patient becomes bedridden and death comes after a protracted decade of unceasing myoclonus in theform of a particularly massive seizure status epilepticus or aspiration pneumonitis.Identification of the genetic basis for LD by members of our group has ushered in a new era in ourunderstanding of the formation of LBs leading to LD. We have made rapid progress and have nowdemonstrated that eliminating LBs wholly cures LD in mouse models opening up the real possibility of a cure.To that end we propose the establishment of the Lafora Epilepsy Cure Initiative (LECI) Center. We haveassembled an international group of pioneers and leaders in the field. We propose to attack the disease frommultiple angles targeting the full spectrum of molecular and cellular causes of LD and believe that we areuniquely positioned to realize the dream of treating and curing LD patients.The overall focus of this Program Project Grant is to: Diagnose Treat and eventually Cure LD. Fourcomplimentary projects and three integrated core facilities form the basis of this proposal. Our projects are:Project #1: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD.Project #2: Genome editing mRNA suppression and glycogen chain termination to inhibit glycogen storage astherapy for LD.Project #3: Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to LD.Project #4: Defining the therapeutic window for the treatment of LD.LD offers a unique window into both normal neuronal glycogen metabolism and epileptic disease when theprocess is perturbed. While this project aims at defining the basic mechanisms of LD and translating this workinto therapeutics and cures our work is likely to reveal pathogenic mechanisms common to other epilepsies.The collective effort of the LD experts will both define LD therapy options and generate abundant newcollateral data that will uncover pathways connecting the bioenergetics of the brain with the generation ofseizures and epilepsy. These insights may be particularly informative to the most daunting aspect of epilepsynamely intractability that afflicts over 30% of patients.

project_terms:
Adolescence;Antiepileptic Agents;Antisense Oligonucleotides;Bioenergetics;Biological;Biological Assay;Biological Models;Biological Products;Biology;Brain;Carbohydrates;Cessation of life;Chemistry;Child;Clinic;Clinical Research;Clinical Trials;Collaborations;Communities;Convulsions;Core Facility;Coupled;Cytoplasm;Data;Defect;Dementia;Dendrites;Development;Diagnosis;Diagnostic;Disease;Dreams;Enzymes;Epilepsy;Frequencies;Gene Expression;Generations;Genes;Genetic;Glycogen;Grant;Headache;Hormones;International;Intractable Epilepsy;Knowledge;Lafora Disease;Life;Medicine;Messenger RNA;Methods;Modality;Modeling;Molecular;Molecular Target;Mutation;Myoclonic Epilepsies;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurodegenerative Disorders;Neurons;Neurosciences;Outcome;Pathogenicity;Pathology;Pathway interactions;Patients;Persons;Pharmaceutical Chemistry;Pharmacology;Phase;Phosphoric Monoester Hydrolases;Physicians;Plants;Positioning Attribute;Process;Production;Program Research Project Grants;Pulmonary Inflammation;RNA;Reagent;Refractory;Research;Research Personnel;Scientist;Seizures;Shapes;Starch;Status Epilepticus;Structural Biochemistry;Techniques;Technology;Teenagers;Testing;Therapeutic;Time;Training;Translating;United States National Institutes of Health;Vision;Work;base;brain cell;career;clinical application;cognitive function;genome editing;glycogen metabolism;induced pluripotent stem cell;innovation;insight;interdisciplinary approach;member;mouse model;novel;personalized diagnostics;proteostasis;response;sex;small molecule;small molecule inhibitor;spelling;success;sugar;therapeutic evaluation;ubiquitin-protein ligase

public_health_relevance:
Lafora disease is a catastrophic epilepsy that strikes healthy teenagers and leads to constant ever-worseningseizures until it results in death after 10 years. The collaboration in this Program Project Grant brings togetherthe clinician-scientists and researchers who discovered the causes of this disease: the shape of glycogenbecomes abnormal in this disease in fact it becomes similar to plant starch and builds up in the patients braincells. We will utilize state of the art technologies including techniques to manipulate genes introducingbiological agents to interfere with gene expression utilization of hormones and carbohydrate-poor dies smallmolecules and sugar-mimics to down-regulate glycogen production. Our research is in a state where we see aclear track to develop effective methods to diagnose treat and ultimately cure LD. Our vision is that one day aphysician having diagnosed a child with this horrendous epilepsy would have the medicines and technologiesto stop the disease in its tracks so that the child is able to resume development and life a healthy and normallife.


