# projects

application_id: 10530638
project_number: 5R01AR073906-05
project_title: Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling
administering_ic: NIAMS
award_notice_date: 2023-01-19
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AR
serial_number: 073906
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2020-02-25
project_end_date: 2024-11-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 10909082
contact_pi: KIKANI, CHINTAN K
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 SummaryMuscle trauma is one of the most common and repetitive types of injury in humans. Owing to theregenerative functions of Muscle Stem Cells (MuSCs) the injured myotome can fully regain its structural andfunctional integrity within just a few days. In addition to this remarkable regenerative function MuSCs also playa significant role in the maintenance of muscle homeostasis under the normal condition. On the other hand thedecline in MuSCs function is implicated in muscle wasting diseases and several forms of musculardystrophy. The functions of MuSCs are influenced by the niche it occupies. For example the niche emitssignals to regulate MuSCs quiescence in the uninjured state or activation when regeneration is required.Understanding how these signaling pathways control quiescence and activation of MuSCs is essential to devisethe next generation of therapeutic approaches for diseases of MuSCs dysfunction. We recently described anovel signaling pathway in MuSCs that stimulates regenerative myogenesis by epigenetically activating thetranscription of the Myog promoter. In this pathway Per-Arnt-Sim domain Kinase (PASK) phosphorylatesWD40-domain repeat 5 (Wdr5) at the onset of the myogenesis program. Phosphorylated Wdr5 stimulatesthe Myog transcription by inducing histone H3 trimethylation at lysine 4 (H3K4me3) and the recruitmentof the MyoD transcription factor at the Myog promoter. We present evidence that PASK expression and activityis induced in regenerating myoblasts by signaling cues such as insulin and nutrients in mTOR complex 1dependent manner. Functionally loss of Pask in mice retards regenerative myogenesis and over-expressionof PASK depletes the stem cells. Thus we hypothesize that PASK plays a role balancing self-renewal vsdifferentiation during regeneration. Building upon these data in this proposal we will investigate howPASK expression and activity is regulated in the regenerating myoblast (Specific Aim 1). In activatedMuSCs PASK phosphorylated Wdr5 induces H3K4me3 modification MyoD recruitment and nucleosomalremodeling on the Myog promoter yet the mechanism is not clear. In Specific Aim 2 we will extensivelystudy two interacting partners of Wdr5 which could remodel the Myog promoter for its activation. Uponinduction of Myogenin Pax7 expression is down-regulated and terminal differentiation is established. SincePASK is an upstream regulator of the Myog expression we are interested determining how loss or gainof PASK affects the self-renewing population during regeneration and normal aging process which we willstudy in Specific Aim 3. Ultimately these aims will allow us to understand how niche signaling cues controlthe balance between self-renewal and differentiation and how it can be exploited for improvement ofphysiological conditions such as sarcopenia.

project_terms:
Acetylation;Acute;Adult;Affect;Aging;Binding;Cell Count;Cell physiology;Cells;Collaborations;Complex;Cues;Data;Disease;Epigenetic Process;Equilibrium;FRAP1 gene;Functional disorder;Genetic Transcription;Goals;Histone H3;Histones;Homeostasis;Human;Injury;Insulin;Legal patent;Lysine;Maintenance;Messenger RNA;Metabolism;Methylation;Modeling;Modification;Molecular;Mus;Muscle;Muscle Cells;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myoblasts;Myogenin;Myopathy;Natural regeneration;Nucleosomes;Nutrient;Pathway interactions;Phosphorylation;Phosphotransferases;Physiological;Play;Population;Process;Proliferating;Property;Protein Kinase;Proteins;Publishing;Reagent;Repression;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Testing;Therapeutic;Transcription Process;Transferase;Trauma;WD Repeat;Wasting Syndrome;age-related muscle loss;hormonal signals;human disease;improved;in vivo;inhibitor;injured;interest;member;mouse model;muscle aging;myogenesis;normal aging;novel;novel therapeutics;overexpression;programs;promoter;recruit;regeneration function;regeneration potential;regenerative;response;sarcopenia;self-renewal;stem cell differentiation;stem cell fate specification;stem cell function;stem cells;transcription factor

public_health_relevance:
Project NarrativeDysregulation of Muscle Stem Cell (MuSC) function contributes to many human diseases. Here we describea novel signaling pathway that stimulates MuSC differentiation while suppressing selfrenewal. Wepropose that this pathway can be therapeutically exploited for the treatment of ageassociated musclewasting.


application_id: 10529483
project_number: 2R01CA207772-06A1
project_title: Roles of Hsp47 in Breast Cancer Progression
administering_ic: NCI
award_notice_date: 2022-09-09
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: CA
serial_number: 207772
suffix: A1
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2027-05-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
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
project_terms:
3-Dimensional;Adipocytes;Adipose tissue;Binding;Bioinformatics;Biological Assay;Blood Platelets;Breast;Breast Cancer Risk Factor;Breast cancer metastasis;Cardiovascular Diseases;Cells;Co-Immunoprecipitations;Coculture Techniques;Collagen;Data;Deposition;Diabetes Mellitus;Epithelial;Extracellular Matrix;Fibrosis;Funding;Genetic Transcription;High Fat Diet;Human;Immune;Infiltration;Inflammation;Knockout Mice;Knowledge;Link;Malignant Neoplasms;Mammary Neoplasms;Mesenchymal;Modeling;Molecular;Molecular Chaperones;Mus;Nature;Neoplasm Metastasis;Non obese;Obesity;Obesity associated cancer;Pathologist;Pathway interactions;Play;Positioning Attribute;Proteins;Proteomics;Regulation;Research;Role;Scheme;Signal Transduction;Surface Plasmon Resonance;Testing;Tissue Sample;Tissues;Transgenic Organisms;Transitional Cell;Tumor Tissue;adipocyte differentiation;asporin;base;breast cancer progression;cancer cell;cancer recurrence;diet-induced obesity;digital;experimental study;in vivo;inhibitor;insight;macrophage;malignant breast neoplasm;mammary gland development;mouse model;multidisciplinary;nano-string;novel;obesity development;recruit;second harmonic generation imaging;single-cell RNA sequencing;stemness;survival outcome;tissue culture;tumor growth;tumor progression


application_id: 10528089
project_number: 1R21ES033334-01A1
project_title: Benzene Exposure and Heart Failure
administering_ic: NIEHS
award_notice_date: 2022-06-23
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: ES
serial_number: 033334
suffix: A1
program_official: SCHUG, THADDEUS
project_start_date: 2022-07-01
project_end_date: 2024-06-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9705355
contact_pi: ZELKO, IGOR N.
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:
Project SummaryLong-term exposure air pollutant exposure is recognized as a risk factor for cardiovascular diseases includingmyocardial ischemia and heart failure. Recent epidemiological and experimental data indicate that many volatileorganic compounds including benzene contribute to worsening outcomes in patients with progressive heartdisease. Benzene is the most abundant air pollutant mostly generated from automobile exhaust and tobaccosmoke. Despite high prevalence of benzene in air-pollutants little is known about the direct effects of inhaledbenzene on heart failure morbidity and mortality in well-controlled animal studies. Our recent studies show thatbenzene exposure resembling moderate to high levels of human exposure worsens cardiac function in pressureoverload-induced mice. The benzene-induced worsening of cardiac functions was accompanied by endothelialactivation and infiltration of granulocytes in the heart and upregulation of gene expression for CXCL1 chemokineand alarmin S100A8/A9 complex which promotes neutrophil and monocyte chemotaxis and adhesion throughTLR4 and RAGE signaling. Our new preliminary data show that ambient benzene exposure causes endothelialactivation/injury in humans and chronic low dose exposure stimulates endothelial activation/injury in mice. Usinganimal model of pressure overload-induced cardiac dysfunction we will examine the effects of environmentalbenzene exposure on cardiac dysfunction (echocardiography cardiac hypertrophy analysis of composition andactivation status of infiltrating immune cells) during heart remodeling (Aim 1) and examine the molecularmechanisms by which benzene exacerbate cardiac dysfunction (Aim 2). Successful completion of these studieswill for the first time show how benzene affect cardiac function in patients with progressing heart failure andprovide mechanistic insight into this process.

project_terms:
Adhesions;Affect;Air Pollutants;Animal Model;Animals;Anti-Inflammatory Agents;Automobile Exhaust;Benzene;Benzene Exposure;Bone Marrow;C57BL/6 Mouse;CXCL1 gene;Cardiac;Cardiac Output;Cardiotoxicity;Cardiovascular Diseases;Cells;Chemicals;Chemotaxis;Cholesterol;Chronic;Clinical Research;Complex;Data;Development;Dichloromethylene Diphosphonate;Dose;Echocardiography;Endothelial Cells;Endothelium;Endotoxins;Environmental Pollutants;Epidemiology;Exposure to;Flow Cytometry;Gene Expression;Genetic Transcription;Goals;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;High Prevalence;Histology;Hospitalization;Human;Hypertrophy;Immune;Immunohistochemistry;Infiltration;Inflammation;Inflammatory;Inhalation;Injury;Insulin Resistance;LCN2 gene;Left;Left ventricular structure;Liposomes;Mediating;MicroRNAs;Molecular;Morbidity - disease rate;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardial dysfunction;Neutrophil Infiltration;Outcome;Pathologic;Patients;Persons;Plasma;Process;Risk;Risk Factors;Role;S100A8 gene;S100A9 gene;Signal Transduction;Site;Source;Styrenes;TLR4 gene;Testing;Time;Tissues;Tobacco smoke;Toluene;Tumor-infiltrating immune cells;United States;Up-Regulation;Ventricular;Ventricular Remodeling;Xylene;acute coronary syndrome;air filter;base;cardiovascular health;cardiovascular risk factor;chemokine;cigarette smoke;endothelial stem cell;ethylbenzene;exposed human population;granulocyte;heart function;improved;inhibitor;insight;macrophage;mimetics;monocyte;mortality;mouse model;myocardial injury;neutrophil;patient prognosis;preclinical study;pressure;recruit;sex;small molecule;small molecule inhibitor;toxicant;transcriptome sequencing;volatile organic compound

public_health_relevance:
Project NarrativeBenzene is the most abundant air pollutant mostly generated from automobile exhaust and tobacco smoke.Despite high prevalence of benzene in air-pollutants direct effects of inhaled benzene on heart failure morbidityand mortality in well-controlled animal studies have not been investigated. The goal of this project is to elucidatethe contribution of benzene on cardiac dysfunction and heart failure.


application_id: 10527587
project_number: 1R21AI166233-01A1
project_title: Functional Role of the Enterococcal Polysaccharide Antigen
administering_ic: NIAID
award_notice_date: 2022-05-20
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 166233
suffix: A1
program_official: HUNTLEY, CLAYTON C
project_start_date: 2022-05-20
project_end_date: 2024-04-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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
project_abstract:
Enterococci represent one of the leading causes of infections among hospitalized patients andresidents of long-term care facilities. In the USA there were over 50000 cases of enterococcalinfections in 2017 with ~10% fatality rate. The majority of infections are caused byEnterococcus faecalis and E. faecium which include bacteremia urinary tract and surgical sitesinfections and endocarditis. E. faecalis and E. faecium display high levels of natural andacquired antibiotic resistance that severely limits the treatment options. The major component ofstreptococcal cell wall is the Enterococcal Polysaccharide Antigen (EPA). The recently solvedstructure of EPA consists of a polyrhamnose backbone decorated with a polyribitol phosphate-containing teichoic acid. While a hypothetical mechanism of EPA biosynthesis has beenproposed studies are required to test it. The goal of this application is to decipher the criticalsteps of EPA polyrhamnose and teichoic acid assembly. In addition we will examine the role ofEPA in binding to the enterococcal autolysins and the resistance mechanism to hostantimicrobial protein expressed in the intestinal epithelial cells ReGIII. We will utilize acombination of genetic analytical and biochemical methods to answer these questions. Theenzymes of EPA biosynthetic pathway constitute promising targets for the development of novelantimicrobials to combat enterococcal infections. Thus the proposed experiments will provide abetter understanding of cell wall biogenesis in enterococci to enable the development ofalternative approaches to treat drug-resistant infections. Furthermore the proposed studies willenhance our understanding of the functions of EPA in antimicrobial resistance and persistenceof enterococci in gut microbiota.

project_terms:
Acetylgalactosamine;Adherence;Anabolism;Antibiotic Resistance;Antibiotics;Antigens;Antimicrobial Resistance;Autolysin;Autolysis;Automobile Driving;Bacteremia;Bacteria;Bacteriophages;Binding;Biochemical;Biogenesis;Biological Assay;Biological Process;Cell Wall;Cell membrane;Cells;Cellular Morphology;Complement;Daptomycin;Data;Development;Drug Controls;Drug resistance;Endocarditis;Enterococcus;Enterococcus faecalis;Enterococcus faecium;Enzymatic Biochemistry;Enzymes;Epithelial Cells;Essential Genes;Evolution;Exhibits;Fatality rate;Future;Genes;Genetic;Genome;Glycobiology;Goals;Health care facility;Hospitals;Host Defense;Human;In Vitro;Infection;Intestines;Ions;Life;Lipids;Long-Term Care;Mediating;Methods;Microbial Biofilms;Microscopy;Modeling;Molecular;Molecular Genetics;Mucous body substance;Multi-Drug Resistance;Muramidase;New Agents;Outcome;Pathway interactions;Patients;Peptidoglycan;Permeability;Phagocytes;Phospholipase A2;Physiology;Play;Polysaccharides;Proteins;Resistance;Resistance to infection;Role;Side;Site;Streptococcus;Structure;Surface;Surgical Wound Infection;Teichoic Acids;Testing;Thick;Urinary tract;Vancomycin Resistance;Vertebral column;Virulence;antimicrobial;antimicrobial peptide;beta-Lactams;combat;experimental study;gut microbiota;inorganic phosphate;intestinal epithelium;novel;novel therapeutics;pathogen;polyribitol phosphate;resistance mechanism;therapeutic target;trait

public_health_relevance:
Enterococcus faecalis and Enterococcus faecium are important nosocomial pathogens thatcause life-threatening infections. The goal of the proposed studies is to determine themechanism and the function of the Enterococcal Polysaccharide Antigen to enable thedevelopment of alternative approaches to treat these drug-resistant infections.


application_id: 10526797
project_number: 1R21CA267152-01A1
project_title: Circulating HPV DNA as a Prediagnostic Marker of Oropharyngeal Cancer
administering_ic: NCI
award_notice_date: 2022-07-29
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: CA
serial_number: 267152
suffix: A1
program_official: WANG, WENDY
project_start_date: 2022-07-29
project_end_date: 2024-06-30
study_section: Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: FADEN, DANIEL
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
project_abstract:
PROJECT SUMMARYThe incidence of HPV-driven oropharyngeal cancer (HPV-OPC) a type of head and neck cancer is rapidly increasing inthe United States (US). HPV-OPC recently surpassed cervical cancer as the most common HPV-associated malignancy.Unlike cervical cancer there are no methods of early detection for HPV-OPC. HPV16 E6 antibody positivity has beenidentified as a promising early biomarker of HPV-OPC. Previous work from our group showed that HPV16 E6 antibodiesare present in up to 90% of HPV-OPC patients and appear more than 10 years prior to diagnosis. However given thelong lag time between HPV16 E6 seroconversion and cancer diagnosis HPV16 E6 seropositive individuals may need to befollowed for a decade or more before the cancer is clinically diagnosable. Thus early detection biomarkers that indicatethe presence or absence of tumor are needed before considering HPV16 E6 antibody testing for clinical use. Circulatingtumor (ct)HPV DNA detection is a promising marker for detection of HPV-OPC. Work from our group has demonstratedthat ctHPVDNA is 98.4% sensitive and 98.6% specific for HPV-OPC at the time of diagnosis. Prior studies of ctHPVDNAhave focused on the utility of ctHPVDNA for diagnosing HPV-OPC and monitoring for recurrence post-treatment. Todate the potential of ctHPVDNA for early detection of HPV-OPC has not been explored. A major barrier to evaluatingctHPVDNA in a pre-diagnostic setting is that assays developed to date require a high volume of blood (>1ml) which hasprecluded nested studies in prospective cohorts given that blood samples collected prior to HPV-OPC diagnosis arelimited and precious. Leveraging our experience in ctDNA we have re-optimized our droplet digital PCR (ddPCR) basedassay for detecting ctHPVDNA in small volumes of archived specimen. The objective of this study is to conduct the firstlarge study to evaluate the kinetics of ctHPVDNA prior to diagnosis and to compare this biomarker to HPV16 E6seropositivity. A nested case-control study will be conducted within the Prostate Lung Colorectal and Ovarian (PLCO)Cancer Screening Trial a prospective cohort study of 154935 middle aged men and women from across the US. Pre-diagnostic blood samples from 81 OPC cases and 162 matched controls (1:2 ratio) will be tested for ctHPVDNA. All serialsamples from ctHPVDNA positive cases will also be tested to evaluate kinetics of the marker leading up to diagnosis. Wehypothesize that ctHPVDNA will be detectable prior to cancer diagnosis and that ctHPVDNA will be more sensitive thanHPV16 E6 seropositivity. This proposal is innovative given the use of a novel ctHPVDNA assay specifically optimized forsmall volumes of archived specimen which will allow us to conduct the first study to evaluate ctHPVDNA in a pre-diagnostic setting. This research may lead to better methods for early detection of HPV-OPC and directly responds to thejoint Notice of Special Interest issued by the National Cancer Institute (NCI) and National Institute for Dental andCraniofacial Research (NIDCR): Advancing Head and Neck Cancer Early Detection Research (AHEAD); NOT-CA-20-031.

project_terms:
Aftercare;Antibodies;Archives;Biological Assay;Biological Markers;Blood;Blood Volume;Blood specimen;Cancer Patient;Clinical;Cohort Studies;Colorectal;Communities;Custom;DNA;Data;Detection;Development;Diagnosis;Diagnostic;Early Diagnosis;Genotype;Gold;HPV oropharyngeal cancer;Head and Neck Cancer;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papillomavirus 16;Incidence;Individual;Joints;Kinetics;Lead;Logistic Regressions;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of nasopharynx;Methods;Monitor;Monitoring for Recurrence;Morbidity - disease rate;National Cancer Institute;National Institute of Dental and Craniofacial Research;Nested Case-Control Study;Ovarian;Patients;Plasma;Prospective cohort;Prospective cohort study;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Research;Risk;Sampling;Screening for cancer;Specificity;Testing;Time;Tumor Burden;United States;Virus;Woman;Work;base;biological specimen archives;cancer cell;cancer diagnosis;cancer recurrence;case control;cohort;digital;early detection biomarkers;experience;high risk;innovation;interest;liquid biopsy;malignant oropharynx neoplasm;men;middle age;novel;response;screening;seroconversion;seropositive;tool;tumor;validation studies;viral DNA;viral detection;virtual

public_health_relevance:
PROJECT NARRATIVEHuman papillomavirus-driven oropharyngeal cancer (HPV-OPC) a type of head and neck cancer is rapidly increasing inincidence and has surpassed cervical cancer as the most common HPV-associated malignancy in the United States;however unlike cervical cancer there are no methods for early detection of HPV-OPC. The proposed research will studyif circulating tumor HPV DNA is detectable in the blood before patients are diagnosed with HPV-OPC using a customliquid biopsy developed by our team. This research may lead to new methods for early detection of HPV-OPC.


application_id: 10525127
project_number: 1K23AG075262-01A1
administering_ic: NIA
award_notice_date: 2022-08-26
opportunity_number: PA-20-206
application_type: 1
activity_code: K23
ic: AG
serial_number: 075262
suffix: A1
program_official: LYONS, ELIZABETH ANNE
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Career Development for Clinicians/Health Professionals Study Section [AGCD-3]
contact_pi_person_id: 16198324
contact_pi: RHODUS, ELIZABETH
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_terms:
Active Learning;Address;Adoption;Adult;Advisory Committees;Aggressive behavior;Aging;Agitation;Alzheimer's Disease;Alzheimer's disease related dementia;Analysis of Covariance;Anxiety Disorders;Behavior;Behavior Therapy;Behavior assessment;Behavioral;Behavioral Mechanisms;Behavioral Model;Behavioral Symptoms;Caregiver Burden;Caregivers;Caring;Client satisfaction;Clinic;Clinical;Clinical Trials Design;Clinical assessments;Communities;Country;Cues;Data;Dementia;Dementia caregivers;Development;Development Plans;Diagnosis;Dimensions;Elderly;Environment;Extramural Activities;Faculty;Fellowship;Fostering;Foundations;Funding;Future;Goals;Grant;Health;Health Services Accessibility;Home;Home environment;Individual;Institutes;Institution;Intervention;Interview;Kentucky;Letters;Measurement;Measures;Medicine;Mental Depression;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Morbidity - disease rate;Neurology;Neurosciences;Pamphlets;Performance;Persons;Physiological;Population;Positioning Attribute;Protocols documentation;Proxy;Psychiatrist;Psychophysiology;Quality of life;Randomized Controlled Trials;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Residencies;Rural;Rural Appalachia;Rural Community;Safety;Scholarship;Science;Scientist;Single-Blind Study;Sleep Disorders;Stimulus;Surveys;Teacher Professional Development;Testing;Time;Training;Underrepresented Populations;United States National Institutes of Health;Universities;Work;aging in place;arm;base;behavior change;behavioral response;career;career development;caregiver education;college;community based research;dementia care;environmental intervention;evidence base;experience;feasibility trial;follow-up;health disparity;health equity;improved;in-home care;innovation;knowledge base;mortality;novel strategies;patient home care;programs;psychiatric symptom;response;rural area;satisfaction;sensor;social;standard of care;supportive environment;symptom management;telehealth;tenure track;therapy development;tool


application_id: 10524504
project_number: 5P20GM121327-05
project_title: Targeting Glutamine Uptake via ASCT2 Inhibition in MYCN-amplified Neuroblastomas
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: MCGUIRL, MICHELE
project_start_date: 2021-11-10
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
subproject_number: 9851
contact_pi_person_id: 12051773
contact_pi: RELLINGER, ERIC JAMES
other_pis: ZHOU, BINHUA P
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_terms:
3-Dimensional;Animal Model;CRISPR/Cas technology;Cancer Cell Growth;Cancer Center;Cell Survival;Combined Modality Therapy;Dropout;Glutamine;In Vitro;Kentucky;Knock-out;MYCN gene;Malignant Neoplasms;Metabolic;Metabolic Pathway;Metabolism;Neoplasm Metastasis;Neuroblastoma;Oncogenes;Organoids;Patients;Pediatric Neoplasm;Primary Neoplasm;Proto-Oncogenes;Role;Solid Neoplasm;Universities;Xenograft Model;Xenograft procedure;angiogenesis;childhood cancer mortality;design;high risk;in vivo;inhibitor/antagonist;metabolomics;neuroblastoma cell;small molecule;stable isotope;subcutaneous;tumor growth;tumor metabolism;tumor progression;uptake

public_health_relevance:
High-risk neuroblastomas are responsible for a disproportionate number of childhood cancer deaths despite aggressive multimodal therapy. Nearly half of all high-risk neuroblastomas feature amplification of MYCN a cancer promoting gene that increases glutamine uptake and metabolism. Herein we seek to determine whether blocking glutamine uptake halts neuroblastoma tumor progression in advanced animal models and uncovers vulnerabilities to be exploited in the design of combination therapies.


application_id: 10523897
project_number: 1R21AG074146-01A1
project_title: Oxidative stress-induced vascular pathology and dysfunction in Alzheimers disease
administering_ic: NIA
award_notice_date: 2022-07-28
opportunity_number: PAR-19-071
application_type: 1
activity_code: R21
ic: AG
serial_number: 074146
suffix: A1
program_official: NEWMAN, ELIZABETH
project_start_date: 2022-08-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1 MDCN-M (91)]
contact_pi_person_id: 10287198
contact_pi: SOMPOL, PRADOLDEJ
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_abstract:
PROJECT SUMMARY/ ABSTRACTVascular contributions to cognitive impairment and dementia (VCID) is highly comorbid with Alzheimer'sdisease (AD) where it exacerbates and hastens functional deficits. Mechanistic studies of vascular pathologyformation and its effects on brain function especially in AD is limited. Developing translational imaging forapplication to mixed pathology models is necessary to understand the complex pathophysiological processesthat link VCID and AD. Recently we modified and optimized the oxidative stress-induced photothrombosisprotocol (I.e. photoactivation of IV-injected Rose Bengal dye) for targeting individual capillaries in rodents. Themajor advantage of this novel vascular oxidative stress model is that vessel stalls occlusion andmicrohemorrhage can be followed in single capillaries in living mice in real time using multiphoton imaging. Inthis R21 we aim to apply this technique to 5xFAD mice to generate and characterize a novel AD/VCID mousemodel en route to determining fibronectin a matrix protein that supports vascular structure and integrityasan indicator for the oxidative stress that arises from both cerebrovascular disease and AD. Our ongoing workon postmortem human brain specimens has revealed that astrocyte-derived fibronectin strongly colocalizeswith the oxidative stress marker nitrotyrosine (NT) especially around cerebrovessels and A deposits.Photothrombosis of small cerebral arterioles revealed accumulation of fibronectin/NT colocalization atintravascular and nearby perivascular regions similar to what we observe in human AD brain tissue. Here wepropose to use cutting edge physiology approaches combined with human postmortem brain specimens fromour world class brain bank at the Sanders-Brown Center on Aging to test the hypothesis that oxidativestressindicated by NT incorporation into fibronectin exacerbates cerebrovascular and synapticdysfunction in the context of AD. In Aim 1 we will determine the effect of microvascular oxidative stress onneurovascular function in WT and 5xFAD mice. Multiphoton imaging techniques will be used to apply and toobserve in real-time the development of microvascular pathologies including blood vessel stalls vesselocclusion (infarct) and microhemorrhage as well as their effects on neurovascular coupling. Mouse braintissues and postmortem samples from humans with confirmed vascular pathology and AD pathology will alsobe used to assess fibronectin/NT interactions with blood vessels and to cross-validate our novelphotothrombotic mouse model of mixed AD/VCID pathology. In Aim2 we will test the hypothesis that oxidativestress-induced microvascular pathology in 5xFAD mice leads to the global exacerbation of cognition andsynaptic function in the context of AD-like pathology. The proposed studies will fill a critical knowledge gapsurrounding the convergence of pathologic sequelae in cerebrovascular disease and AD. Moreoverestablishment of a novel mouse model for mixed AD/VCID pathology will help inform new strategies for treatingindividuals with both AD and vascular pathology.

project_terms:
3-nitrotyrosine;Age;Aging;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease pathology;Alzheimer's disease therapeutic;Amyloid beta-Protein;Animal Model;Animals;Astrocytes;Autopsy;Award;Basement membrane;Biological Markers;Blood Vessels;Blood capillaries;Blood flow;Brain;Cell Adhesion;Cerebrovascular Disorders;Cerebrum;Cognition;Complex;Confocal Microscopy;Contralateral;Dementia;Deposition;Development;Disease Progression;Dyes;Electrophysiology (science);Endothelial Cells;Extracellular Matrix Proteins;Extravasation;Fibronectins;Frequencies;Functional disorder;Future;Hemorrhage;Hippocampus (Brain);Human;Hyperemia;Image;Image Analysis;Imaging Techniques;Impaired cognition;Impairment;Individual;Infarction;Knowledge;Label;Laser Speckle Imaging;Lead;Link;Long-Term Potentiation;Measures;Mediating;Memory;Modeling;Monitor;Mus;Neuronal Dysfunction;Nitrogen;Oxidative Stress;Oxygen;Pathologic;Pathology;Peripheral;Peroxonitrite;Physiology;Pre-Clinical Model;Process;Proteins;Protocols documentation;Research Project Grants;Resolution;Resources;Rodent;Role;Rose Bengal;Route;Saline;Sampling;Slice;Specimen;Stimulus;Structure;Synapses;Synaptic plasticity;Techniques;Testing;Three-Dimensional Image;Thrombosis;Time;Tissue Harvesting;Tissues;Tyrosine;Validation;Vascular Diseases;Vibrissae;Work;amyloid pathology;arteriole;barrel cortex;brain tissue;cerebrovascular;cerebrovascular pathology;cognitive function;comorbidity;experimental study;imaging approach;insight;intravital imaging;macromolecule;microscopic imaging;microvascular pathology;mouse model;multiphoton imaging;multiphoton microscopy;neocortical;neurovascular;neurovascular coupling;non-demented;novel;oxidative damage;photoactivation;pre-clinical;synaptic function;thrombotic;time use;treatment strategy;two-photon;vascular cognitive impairment and dementia;vascular injury;vector

public_health_relevance:
Project NarrativeThis research project will reveal a fundamental mechanism of how oxidative stress disrupts the smallestcerebrovessels and subsequently alters the vascular-related matrix protein fibronectin en route to impairingsynaptic and cognitive function in the context of Alzheimer's disease. Furthermore this study will provide anovel mixed Alzheimer/vascular translational mouse model for future studies.


application_id: 10523782
project_number: 1K23AR079583-01A1
project_title: Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness
administering_ic: NIAMS
award_notice_date: 2022-08-08
opportunity_number: PA-20-205
application_type: 1
activity_code: K23
ic: AR
serial_number: 079583
suffix: A1
program_official: CARIFI, EMILY FORAN
project_start_date: 2022-08-08
project_end_date: 2027-07-31
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 14923231
contact_pi: MAYER, KIRBY P
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL 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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute respiratory failure;Address;Adult;Applied Research;Basic Science;Biogenesis;Biopsy;COVID-19;Cell fusion;Cell physiology;Cells;Characteristics;Clinical;Clinical Investigator;Clinical Sciences;Clinical Trials;Complex;Critical Illness;Data;Deuterium Oxide;Development;Disabled Persons;Environment;Functional disorder;Future;Gait speed;Goals;Grant;Health;Hospitalization;Hospitals;Human;Immunohistochemistry;Impairment;Inflammatory;Intensive Care Units;Intervention;Knowledge;Label;Lead;Learning;Lower Extremity;Measures;Mechanical ventilation;Mentors;Mentorship;Methodology;Microscopy;Mitochondria;Mitochondrial Proteins;Morphology;Muscle;Muscle Fatigue;Muscle Proteins;Muscle Weakness;Muscle function;Muscle satellite cell;Outcome;Patient-Focused Outcomes;Patients;Pattern;Performance;Pharmacology;Phase;Phenotype;Physical Function;Physical Rehabilitation;Property;Protein Biosynthesis;Proteins;Proteolysis;Quality of life;RNA;Recovery;Recovery of Function;Regression Analysis;Rehabilitation therapy;Research;Research Training;Respiration;Ribosomes;Sepsis;Severity of illness;Skeletal Muscle;Stable Isotope Labeling;Statistical Data Interpretation;Survivors;Technical Expertise;Testing;Time;Training;Translating;Walking;Western Blotting;cell type;disability;effective therapy;experimental study;functional disability;functional outcomes;improved;inflammatory milieu;longitudinal analysis;macrophage;muscle form;muscle strength;novel;patient subsets;physically handicapped;prevent;protein degradation;proteostasis;rehabilitation research;rehabilitation strategy;satellite cell;skeletal muscle wasting;skills;stem


application_id: 10520481
project_number: 1U01DE031223-01A1
project_title: Susceptibility Patterns for Grade C Periodontitis in Young Individuals
administering_ic: NIDCR
award_notice_date: 2022-09-22
opportunity_number: PAR-20-060
application_type: 1
activity_code: U01
ic: DE
serial_number: 031223
suffix: A1
program_official: WANG, LU
project_start_date: 2022-09-22
project_end_date: 2027-08-31
study_section: Special Emphasis Panel[ZDE1 YM (12)]
contact_pi_person_id: 8964577
contact_pi: SHADDOX, LUCIANA MACCHION
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Academy;Actinobacillus actinomycetemcomitans;Adopted;Affect;African ancestry;Age;American;Bacteria;Characteristics;Clinical;Communities;Complex;DNA;DNA sequencing;Data;Development;Diagnosis;Dideoxy Chain Termination DNA Sequencing;Disease;Disease Progression;Economics;Elderly;Environment;Environmental Exposure;Epithelial Cells;Esthetics;Etiology;European;Exhibits;Family;Genes;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Gingival Crevicular Fluid;Goals;Immune response;Incisor;Individual;Inflammation Mediators;Inflammatory;Inflammatory Response;Life;Link;Metagenomics;Molecular;Multicenter Studies;Names;Oral;Pathogenesis;Pathway Analysis;Pathway interactions;Pattern;Periodontitis;Phenotype;Population;Predisposition;Property;Public Health;Rehabilitation therapy;Saliva;Sampling;Series;Shotguns;Siblings;Site;Susceptibility Gene;Taxonomy;Terminology;Testing;Tooth structure;Variant;Virulence;Virulent;Work;base;candidate identification;case control;cohort;disease diagnosis;early onset;exome sequencing;gene interaction;genetic association;genetic variant;genome-wide;high risk;individualized medicine;metagenome;microbial;microbial colonization;microbial community;microbiome;neutrophil;oral cavity epithelium;oral microbiome;peripheral blood;social;targeted treatment;transcriptome;transcriptome sequencing


application_id: 10519298
project_number: 1R01CA266579-01A1
project_title: Targeting Polo-Like Kinase 1 in Prostate Cancer to Enhance Therapeutic Efficacy
administering_ic: NCI
award_notice_date: 2022-06-21
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 266579
suffix: A1
program_official: XU, WANPING
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2]
contact_pi_person_id: 10992448
contact_pi: LI, ZHIGUO
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:
Alleles;Androgens;Apoptosis;Autophagocytosis;Biometry;Breeding;Cancer Etiology;Cancer Patient;Cell Survival;Cells;Cellular biology;Cessation of life;Clinic;Clinical Research;Data;Disease;Enterobacteria phage P1 Cre recombinase;Fostering;Genetically Engineered Mouse;Goals;Health;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunosuppression;Immunotherapy;Infiltration;Investigation;Lead;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Mediating;Membrane;Mission;Molecular;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Oncology;Outcome;Oxidative Stress;PDL1 inhibitors;PDL1 pathway;PLK1 gene;Pathology;Patient-Focused Outcomes;Patients;Pharmacology;Phosphorylation;Phosphotransferases;Play;Prognosis;Prostate Cancer therapy;Public Health;Reactive Oxygen Species;Refractory;Regulation;Research;Residual state;Role;Signal Pathway;Signal Transduction;Survival Rate;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Time;Treatment Efficacy;Tumor Escape;Tumor Immunity;Up-Regulation;Work;advanced prostate cancer;androgen deprivation therapy;anti-PD-L1 therapy;base;cancer cell;castration resistant prostate cancer;cell growth;comparative efficacy;design;effective therapy;improved;inhibitor;innovation;men;mortality;mouse model;neoplastic cell;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;programmed cell death ligand 1;programs;promoter;prostate cancer cell;receptor;response;targeted treatment;therapeutically effective;tumor;tumor growth;tumor microenvironment;tumor xenograft;tumor-immune system interactions


application_id: 10519108
project_number: 5R01CA221867-06
project_title: Nucleus Accumbens-Associated Protein-1 in Melanoma Immunotherapy
administering_ic: NCI
award_notice_date: 2022-11-16
opportunity_number: PAR-16-228
application_type: 5
activity_code: R01
ic: CA
serial_number: 221867
program_official: KUO, LILLIAN S
project_start_date: 2018-07-03
project_end_date: 2024-11-30
study_section: Special Emphasis Panel[ZRG1-OTC-Y(55)R]
contact_pi_person_id: 7598539
contact_pi: YANG, JIN-MING
other_pis: SONG, JIANXUN JIM
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 SUMMARY/ABSTRACTAs melanoma mostly expresses tumor-specific neo-antigens (Ags) immunotherapy such as adoptive celltransfer-based therapy (ACT) is considered a promising treatment option for this notoriously deadly disease.Nevertheless due to various factors that may weaken therapeutic immunity the clinical outcomes and benefitsof this remedy remain less satisfactory. Importantly accumulating evidence suggests that the metabolic statusof both immune cells and tumor cells has a significant impact on the potency of ACT and that metabolicreprogramming may represent a viable target for reinforcing immunotherapy. Nucleus accumbens-associatedprotein-1 (NAC1) is a transcription co-regulator belonging to the BTB/POZ gene family and is highly expressedin several types of cancer including melanoma. Published studies including our own have shown that NAC1not only bestows oncogenic potential but also undermines therapeutic outcomes through its transcription-dependent or -independent functions. More recently we discovered that NAC1 can promote glycolysis throughits interaction with HIF-1a and is critically required for development survival and function of T cells as well astumor cells. We also found that NAC1 negatively affects the tumoral expression of major histocompatibilitycomplexes (MHCs); the alteration of NAC1 gene expression occurs during differentiation of the pluripotentstem cell (PSC)-derived T cells and this alteration is accompanied by changes in the expressions of a numberof other genes. Based on these intriguing findings we hypothesize that NAC1-mediated metabolicreprogramming suppresses anti-tumor immunity; targeting NAC1 would hasten death or reduce resilience ofboth tumor and suppressor immune cells and modulate the expression of tumor Ags checkpoint moleculesand the related proteins thereby relieving immune-suppression and reinforcing the efficacy of ACT againstmelanoma. To test these hypotheses the current multiple PI application proposes the following highlyinteractive specific aims: (1) To determine the novel role of NAC1 in T cells; (2) To determine the role oftumoral NAC1 in melanoma immune escape; and (3) To determine the impact of targeting NAC1 in ACTagainst melanoma. This multiple PI project combines the Yang laboratorys strength in cancer biology with theSong laboratorys expertise in tumor immunology. We have already established the mouse and human PSC-derived antigen-specific CD8+ T lymphocytes and the murine syngeneic and humanized (NOD-scid IL2rgnull)mouse melanoma models for the proposed studies and are well poised to accomplish the above aims.Completion of this project will not only uncover NAC1 as a unique molecular determinant of tumor-specificimmune responses and shed new light on the importance of NAC1 in cancer pathobiology but also providenovel therapeutic opportunities to enhance ACT against melanoma through the NAC1-targeted strategy.

project_terms:
Adoptive Cell Transfers;Affect;Antigens;Autophagocytosis;Biological Models;CD8-Positive T-Lymphocytes;CTLA4 gene;Cancer Biology;Cells;Cessation of life;Clinical;Cytotoxic T-Lymphocytes;Development;Disease;FASN gene;Gene Expression;Gene Family;Genes;Genetic Transcription;Glycolysis;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunology;Immunosuppression;Immunosuppressive Agents;Immunotherapy;In Vitro;Induction of Apoptosis;Laboratories;Literature;Major Histocompatibility Complex;Malignant Neoplasms;Mediating;Melanoma Cell;Memory;Metabolic;Metabolism;Metastatic Melanoma;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Neoplasms;Nucleus Accumbens;Oncogenic;Outcome;Patients;Play;Pluripotent Stem Cells;Proteins;Publishing;Recurrent Malignant Neoplasm;Refractory;Regulation;Regulatory T-Lymphocyte;Role;Skin Cancer;Small Interfering RNA;T memory cell;T-Cell Development;T-Lymphocyte;Testing;Therapeutic;Tumor Antigens;Tumor Immunity;Tumor-associated macrophages;cancer recurrence;cancer type;cytokine;cytotoxic CD8 T cells;design;effector T cell;gene product;human pluripotent stem cell;immunogenicity;improved;improved outcome;in vivo Model;innovation;melanoma;nanoliposome;negative affect;neoantigens;neoplastic cell;novel;novel strategies;novel therapeutics;nutrition;programmed cell death ligand 1;programmed cell death protein 1;resilience;response;therapy outcome;tumor;tumor immunology;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
PROJECT NARRATIVEMelanoma one of the most aggressive and fatal neoplasms is responsible for over 80% of skincancer-related deaths. By determining the role and importance of NAC1 a cancer recurrence-associated gene product and a transcription co-regulator in regulating antitumor immunity we proposeto design and develop a novel and effective strategy to reinforce immunotherapy for patients with thisdevastating disease. Thus this proposal is immediately relevant to Cancer Moonshot and mayultimately have a large impact in improving melanoma treatment.


application_id: 10518440
project_number: 1R01CA266004-01A1
project_title: Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis
administering_ic: NCI
award_notice_date: 2022-06-13
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 266004
suffix: A1
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2022-07-01
project_end_date: 2022-10-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 11838914
contact_pi: SUN, RAMON C.
other_pis: GENTRY, MATTHEW S.
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
project_abstract:
Abstract:Lung adenocarcinoma (LUAD) is the major histological subtype of lung cancer and the leading cause ofcancer-related mortalities worldwide. For a substantial number of LUAD patients the only treatment optionsavailable are traditional multi-agent chemotherapy coupled with surgery and/or radiation. For these patientsthe 5-year survival remains disappointingly low. Additional molecular mechanisms driving LUAD proliferationand tumorigenesis remain a critical knowledge gap in lung cancer research and a major barrier for thedevelopment of personalized therapies. Recent reports including our own reveal critical roles for glycogen inlung tumor progression. Building on these foundational studies we developed a robust and precisiontechnology to visualize glycogen in situ with 50 m spatial resolution using mass spectrometry imaging thatprovides 1000x increased sensitivity compared to previous methods. Using this technology we definedglycogen levels in 122 NSCLC patients treated at the University of Kentuckys NCI Designated Cancer Center.Our preliminary data demonstrate that: 1) significantly elevated glycogen is observed in LUAD and not innormal lung tissue. 2) Elevated glycogen is a LUAD tissue-specific hallmark and is not observed in lungsquamous cell carcinoma. 3) LUAD-glycogen is structurally unique with increased phosphorylation andbranching. 4) This LUAD phenotype correlated with marked protein decreases in the glycogen phosphataselaforin. Strikingly laforin knockout in model lung cell lines and the KrasG12D/p53-/- LUAD mouse model drives: 1)glycogen hyper-phosphorylation 2) increased affinity with the master metabolic regulator AMP-activatedprotein kinase (AMPK) 3) decreased AMPK activity and 4) accelerated tumor proliferation and progression.We hypothesize that the structurally unique LUAD-glycogen is a critical component of LUAD metabolismproliferation and progression. The overall objective of this study is to define the etiology of LUAD-glycogen onboth cancer metabolism and tumor progression. To achieve this we will: Define the LUAD-glycogen clinicalcourse and its interaction with AMPK (Aim 1). Then we will define the signaling role of LUAD-glycogen incellular metabolism through AMPK (Aim 2). Finally we will establish the role of LUAD-glycogen in tumorprogression and early transformation in vivo (Aim3). This proposal builds on exciting and rigorous preliminarydata and presents an integrated approach to define this unique LUAD hallmark of excess glycogen utilizingrobust complementary and state-of-the-art methodologies such as mass spectrometry imaging protein andglycogen biochemistry and targeted metabolomics. The salient findings from this proposal will significantlyadvance the knowledge base regarding the roles of glycogen in LUAD biology and progression and drive thediscovery of personalized therapies that can be leveraged for the LUAD population that only qualify forconventional chemotherapy.

project_terms:
5'-AMP-activated protein kinase;Affinity;Apoptosis;Automobile Driving;Binding;Biochemical;Biochemistry;Biological Assay;Biology;Biophysics;Cancer Biology;Cancer Etiology;Cancer Patient;Carbon;Cell Cycle;Cell Line;Clinical;Coupled;Data;Development;Diagnosis;Etiology;Foundations;Future;Genetic;Glucose;Glycogen;Goals;Histologic;In Situ;KRASG12D;Kentucky;Knock-out;Knowledge;Lipids;Longitudinal Studies;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;Metabolism;Metastatic Neoplasm to Lymph Nodes;Methodology;Methods;Modality;Modeling;Molecular;Monitor;Mus;Mutate;Mutation;NCI-Designated Cancer Center;Non-Small-Cell Lung Carcinoma;Nucleotides;Oncogenic;Operative Surgical Procedures;Organoids;Pathogenicity;Patients;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Population;Precision therapeutics;Property;Protein Kinase;Proteins;Quality of life;Radiation;Reporting;Resolution;Role;STK11 gene;Sampling;Signal Transduction;Squamous Cell Lung Carcinoma;Staging;Structure of parenchyma of lung;TP53 gene;Technology;Testing;Tissues;Transgenic Mice;Tumor Biology;Tumor Pathology;Universities;anticancer research;base;chemotherapy;cohort;fatty acid oxidation;genetically modified cells;glucose metabolism;in vivo;knowledge base;mass spectrometric imaging;metabolomics;mortality;mouse model;mutant;novel;personalized medicine;pre-clinical;prevent;stable isotope;tumor;tumor metabolism;tumor progression;tumorigenesis

public_health_relevance:
Project NarrativeDiagnosis of non-precision medicine targetable lung cancer represents a bleak future with lower chance ofsurvival and a poor quality of life. For many lung cancer patients the only treatment options available aretraditional multi-agent chemotherapy coupled with surgery and/or radiation. This project will explore thepathogenic roles of glycogen in lung cancer biology and progression and drive the discovery of personalizedtherapies that can be leveraged for the lung cancer patients that only qualify for conventional chemotherapy.


application_id: 10518172
project_number: 1R01NS120882-01A1
project_title: Neuronal IL-1R1 Signaling in Mild Closed Head Injury
administering_ic: NINDS
award_notice_date: 2022-06-30
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 120882
suffix: A1
program_official: AWWAD, HIBAH OMAR
project_start_date: 2022-07-01
project_end_date: 2027-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: NORRIS, CHRISTOPHER MARK
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
project_terms:
Acute;Address;Age;Animal Disease Models;Anti-Inflammatory Agents;Attention;Autoimmune Diseases;Axon;Behavior;Behavioral Assay;Brain;Cells;Chronic;Closed head injuries;Complex;Data;Development;Electrophysiology (science);Exhibits;FDA approved;Formulation;Functional disorder;Gene Expression Profile;Genes;Goals;Inflammation;Inflammatory;Inflammatory Response;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Intervention;Knockout Mice;Knowledge;LoxP-flanked allele;Maintenance;Mediating;Memory;Modeling;Mus;Nature;Nerve Degeneration;Nervous System Trauma;Neurodegenerative Disorders;Neuroglia;Neurons;Pathway interactions;Peripheral;Phase;Phenotype;Physiology;Process;Receptor Signaling;Recovery;RiboTag;Role;Signal Transduction;Synapses;Synaptic plasticity;System;Testing;Therapeutic;Tissues;Traumatic Brain Injury;cell type;cognitive function;cognitive recovery;cytokine;experimental study;genetic approach;inflammatory milieu;interleukin-1 receptor accessory protein;knock-down;mouse model;nerve injury;nervous system disorder;neuroinflammation;neuroregulation;novel;preservation;response;synaptic function


application_id: 10517568
project_number: 2R01AT008617-06A1
project_title: Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation
administering_ic: NCCIH
award_notice_date: 2022-07-19
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: AT
serial_number: 008617
suffix: A1
program_official: KIM, HYE-SOOK
project_start_date: 2015-12-01
project_end_date: 2027-05-31
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
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_terms:
Acids;Affect;Aging;Bacteria;Binding;Biological;Brain;Brain Diseases;Calmodulin;Cells;Chronic;Clinical;Consumption;Custom;Data;Development;Diet;Disease;Edible Plants;Encephalitis;Foundations;Garlic;Health Status;Human;Immune Tolerance;In Vitro;Individual;Inflammation;Inflammatory;Interleukin-1;Interleukin-10;Interleukin-6;Intervention;Intestines;Knock-out;Knowledge;Lipids;Mediating;Microglia;Modeling;Molecular;Mus;Neuroimmune;Oral;Oral Administration;Pathway interactions;Phosphatidic Acid;Physiological;Physiology;Plants;Play;Prevention;Prevention strategy;Probiotics;Process;Production;Protein Analysis;Proteins;Publishing;RNA;Role;Sorting - Cell Movement;TNF gene;Testing;Therapeutic;Untranslated RNA;aged;aging brain;base;brain tissue;c-myc Genes;clinical application;cytokine;design;exosome;good diet;gut-brain axis;improved;in vivo;insight;macrophage;murine colitis;nanoparticle;neuroinflammation;new therapeutic target;prebiotics;prevent;protective effect;protein expression;transcriptome sequencing;translational study


application_id: 10517197
project_number: 1R01DK131442-01A1
project_title: The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation
administering_ic: NIDDK
award_notice_date: 2022-06-01
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 131442
suffix: A1
program_official: GARCIA, MARTHA
project_start_date: 2022-06-01
project_end_date: 2027-03-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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:
There is an increasing evidence that demonstrates a critical pathogenic role for the gut-liver axis in thedevelopment of nonalcoholic fatty liver diseases (NAFLD). Gut-derived endotoxin leakiness is increased underpathological conditions including high fat diet (HFD) consumption. Gut fucosylation is a key force in maintaininga homeostatic relationship between the gut and its microbiota. Nevertheless it is unclear how host fucosylationmachinery contributes to obesity-associated intestinal barrier function microbial translocation and inflammation.Glycosphingolipids (GSLs) are major constituents of enterocytes and consist of glycans conjugated to a lipid(ceramide) core. Ceramide is at the center of sphingolipid metabolism and is hydrolyzed to generate sphingosineand fatty acid by ceramidases including neutral ceramidase (NcDase). However whether gut NcDasecontributes to intestinal fucosylation in NAFLD is unclear. We found that deletion of intestinal epithelial cells(IECs) NcDase induced marked upregulation of intestinal fucosylation in response to HFD exposure. Ourpreliminary studies further demonstrated that HFD-fed NcDase-/- mice have increases in intestinal AhR activityIL-22 secretion and the production of fucosylated gangliosides (fucosyl-GM1). We also found that fucosyl-GM1can bind to DC-SIGN a C-type lectin expressed in hepatic macrophages and can induce anti-inflammatory M2macrophage. This has led to the central hypothesis that gut NcDase regulates the intestinal fucosylationand subsequent barrier function via IEC AhR signal; and that IECs NcDase-derived fucosylatedglycosphingolipids induce hepatic macrophage polarization via fucosyl-GM1/DC-SIGN pathway andprevent the development of NAFLD. Importantly the proposal also pursues translational studies that examinethe efficacy of prebiotic 2-FL feeding and fucosyl-GM1 treatment targeted at intestinal fucosylation and hepaticinflammatory macrophages in mitigating gut-liver axis changes. Following specific aims will be carried out: Aim1: Determine the impact of NcDase on the gut fucosylation and the effects of this impact on intestinal barrierintegrity. We will determine the impact of NcDase-related gut microbiota on the gut fucosylaton and barrierfunction. Aim 2: Determine whether NcDase regulation of IEC AhR contributes to gut fucosylation via microbialmetabolite in response to HFD exposure. Aim3: Determine whether IEC NcDase-derived fucosylatedgangliosides contribute to the induction of liver tolerogenic macrophages and evaluate the efficacy offucosylation-based therapeutic interventions in NAFLD. Our studies on the NcDase-mediated gut fucosylationand prebiotic intervention will likely bring new mechanistic understanding and identify new therapeutic targetsfor the prevention and treatment of NAFLD.

project_terms:
Alcohols;Anti-Inflammatory Agents;Apical;Aryl Hydrocarbon Receptor;Bacteria;Binding;Butyrates;C-Type Lectins;CD209 gene;Cells;Ceramidase;Ceramides;Chronic;Complex;Consumption;Data;Development;Endotoxemia;Endotoxins;Enterocytes;Epithelial;Epithelial Cells;Farber's lipogranulomatosis;Fatty Acids;Fatty Liver;Functional disorder;Gangliosides;Glycolipids;Glycosphingolipids;Hepatic;High Fat Diet;Immune;Immune system;Inflammation;Inflammatory;Intervention;Intestines;Lead;Ligands;Lipids;Liver;Mediating;Metabolism;Mucins;Mucous body substance;Mus;Obesity;Pathogenicity;Pathologic;Pathway interactions;Polysaccharides;Prevention;Production;Receptor Activation;Receptor Signaling;Regulation;Role;Sampling;Secretor blood group alpha-2-fucosyltransferase;Sphingolipids;Sphingosine;Stimulus;Stress;Therapeutic Effect;Therapeutic Intervention;Tight Junctions;Toll-like receptors;Up-Regulation;Xenobiotics;adherent junction;base;efficacy evaluation;feeding;galactosylgalactosylglucosylceramidase;gastrointestinal epithelium;gene product;glycosylation;gut inflammation;gut microbiota;gut-liver axis;interleukin-22;intestinal barrier;intestinal epithelium;liver inflammation;liver injury;macrophage;microbial;microbial host;microbiota;new therapeutic target;non-alcoholic fatty liver disease;pathogenic bacteria;prebiotics;prevent;response;sphingosine kinase;symbiont;translational study

public_health_relevance:
Project NarrativeThis proposal provides the basis for a better understanding of the mechanisms for NcDase-induced gutfucosylation and glycosphingolipid-regulated macrophages in the development of NAFLD and may lead to theidentification of novel therapeutic targets.


application_id: 10516461
project_number: 4R00HL145117-03
project_title: Macrophage Pyroptosis in Abdominal Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2021-11-29
opportunity_number: PA-18-398
application_type: 4
activity_code: R00
ic: HL
serial_number: 145117
program_official: CHARETTE, MARC F
project_start_date: 2021-12-01
project_end_date: 2024-11-30
study_section: NSS
contact_pi_person_id: 14992976
contact_pi: WU, CONGQING
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 purpose of this K99/R00 application is to (1) provide me with necessary training in research andcareer development for my transition to a successful independent researcher; (2) study the role ofpyroptosis a novel form of programmed cell death in the rupture of Abdominal Aortic Aneurysm (AAA).AAA is a progressive pathological dilation and weakening of the aorta. AAA is associated with extremerates of death (up to 80%) in the event of aortic rupture. There has no medical therapy to prevent or treataortic rupture which is largely attributed to that mechanisms underlying AAA rupture have not beendefined. AAA is characterized by inflammation and frequent presence of thrombus. Inflammatory lesionsoften contain dead cells. Until recently programmed cell death was thought to occur only in one formcalled apoptosis. In 2015 and 2016 four Nature publications from three groups revealed gasdermin D(GSDMD)-dependent mechanisms of pyroptosis. GSDMD forms pores on cell surface and ruptures cellmembrane. In ruptured cell membrane phosphatidylserine which is exclusively located in the innermonolayer in living cells freely flip into outer monolayer and forms a procoagulant surface for tissuefactor by facilitating the assembly of proteins of clotting cascade. We recently discovered thatmacrophage pyroptosis caused septic death through tissue factor release which triggered disseminatedintravascular coagulation in mice. My preliminary data show that genetic deficiency of GSDMD protectsagainst AAA rupture in angiotensin II-infused mice. In this proposal I will test the hypothesis thatmacrophage pyroptosis promotes AAA rupture through tissue factor-dependent thrombus propagation.Two aims will be addressed to test this hypothesis. In Aim 1 I will profile macrophage pyroptosis inangiotensin II-induced AAA rupture using caspase-1 and Caspase-11 deficient mice (K99 PHASE). InAim 2 I will determine how macrophage pyroptosis through tissue factor-mediated mechanismscontributes to AAA rupture (R00 PHASE). Together I will examine the causal relationship betweenthrombus and AAA rupture and test the concept of a feedforward loop between macrophage pyroptosisand tissue factor/thrombus until AAA rupture. This project is important because GSDMD and pyroptosismay represent a therapeutic target. This project is innovative because it defines a novel procoagulantmechanism in AAA. I will also examine macrophage biology and pyroptosis in human aortic aneurysmtissues available in Dr. LeMaires Aortic Disease Biobank at Baylor College of Medicine to enhance thetranslational aspects of my proposed research.

project_terms:
Abdominal Aortic Aneurysm;Address;Angiotensin II;Aorta;Aortic Aneurysm;Aortic Diseases;Aortic Rupture;Apoptosis;Biology;CASP1 gene;Caspase;Cell membrane;Cell surface;Cells;Cessation of life;Coagulation Process;Data;Death Rate;Disseminated Intravascular Coagulation;Event;Genetic;Human;Inflammation;Inflammatory;Lesion;Mediating;Medical;Medicine;Mus;Nature;Pathologic;Phosphatidylserines;Proteins;Publications;Research;Research Personnel;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Surface;Testing;Thromboplastin;Thrombus;Tissues;Training;biobank;career development;college;innovation;macrophage;monolayer;novel;prevent;release factor;research and development;septic;therapeutic target


application_id: 10516074
project_number: 5R01ES032396-03
project_title: A university-community partnership to reduce exposure to disinfection byproducts in Appalachia
administering_ic: NIEHS
award_notice_date: 2022-11-01
opportunity_number: RFA-ES-20-002
application_type: 5
activity_code: R01
ic: ES
serial_number: 032396
program_official: O'FALLON, LIAM
project_start_date: 2021-01-01
project_end_date: 2025-10-31
study_section: ZES1-ARL-K(R)
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
other_pis: HOOVER, ANNA GOODMAN
congressional_district: 06
department: OTHER BASIC 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_terms:
Acids;Address;Appalachian Region;Businesses;Cardiovascular system;Characteristics;Chemicals;Chemistry;Chloramines;Chlorates;Chlorine;Coal;Collaborations;Communication;Communities;Congenital Abnormality;Consultations;County;Data;Disinfectants;Disinfection;Economics;Environmental Health;Exposure to;Funding;Goals;Grant;Halogens;Health;Home;Human;Infrastructure;Intervention;Kentucky;Knowledge;Laws;Location;Malignant neoplasm of urinary bladder;Methods;Modeling;National Institute of Environmental Health Sciences;Ozone;Participant;Persons;Pilot Projects;Population;Process;Public Health;Reaction;Regulation;Research;Research Personnel;Resources;Risk;Risk Reduction;Route;Rural Community;Sampling;Scientist;Source;Surface;System;Testing;Training and Infrastructure;Trihalomethanes;Trust;Ultraviolet Rays;United States;United States Environmental Protection Agency;Universities;Variant;Virginia;Water;West Virginia;citizen science;community partnership;drinking water;exposure route;ground water;health communication;health literacy;improved;indoor air;predictive modeling;public drinking;rural America;rural dwellers;social;water quality

public_health_relevance:
PROJECT NARRATIVEAppalachian Kentuckians in Martin and Letcher Counties are grappling with a health-threateningdrinking water crisis arising from exposures to disinfection by-products (DBPs). DBPs includecompounds that have been associated with a variety of adverse health effects includingincreased risk of bladder cancer and cardiovascular birth defects. This study which builds onfindings from two community-engaged NIEHS P30-funded pilot studies and one P30-fundedcommunity grant uses a multi-method approach stakeholder-engaged approach to reduce DBPexposures and improve public health in target counties.


application_id: 10515406
project_number: 1R01AG078702-01
project_title: Deciphering the Glycan Code in Human Alzheimers Disease Brain
administering_ic: NIA
award_notice_date: 2022-09-14
opportunity_number: RFA-AG-22-019
application_type: 1
activity_code: R01
ic: AG
serial_number: 078702
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2022-09-15
project_end_date: 2022-10-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
contact_pi_person_id: 11838914
contact_pi: SUN, RAMON C.
other_pis: ANGEL, PEGGI M;BENDALL, SEAN CURTIS;DRAKE, RICHARD R.
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:
Abstract:Alzheimers disease (AD) is a devastating diagnosis and there is a critical need to understand the fundamentalmolecular pathogenesis of AD to design effective therapies. In addition to the well-known AD pathologiesperturbed glucose metabolism is also a clinical feature of AD. Glycogen and N-linked glycans are two criticallyimportant but understudied facets of glucose metabolism. Both glycogen and N-linked glycans are complexcarbohydrates that play vital roles in brain physiology such as cognition memory formation and life span.Despite the importance of these pathways in normal brain function whether complex carbohydrate metabolismare perturbed during AD disease progression remains a critical knowledge gap in neurobiology. In excitingpreliminary data we discovered profound glycogen accumulation and protein hyperglycosylation in theprefrontal cortex of both mouse models of AD and human AD specimens. Further we found a positivecorrelation between increased glycogen and Braak staging in an analysis of a 97-patient cohort. Finally oralglucosamine supplement a precursor to UDP-N-acetylglucosamine biosynthesis building block of N-linkedglycans further exacerbated hyperglycosylation and led to poorer cognitive performance in the 5xFAD mousemodel of AD. Based on these preliminary data we hypothesize that aberrant complex carbohydratemetabolism are pathogenic processes during AD disease progression. The major objective of this study is tosystematically resolve cellular and extracellular origins of perturbed complex carbohydrate metabolism usingstate-of-the-art single cell technologies. We will achieve this through synergistic integration of multi-parametersingle-cell mass spectrometry imaging methodologies. First we will define complex carbohydrates with clinicalcourse and disease progression in patient samples (Aim 1). Then we will interrogate cellular and extra-cellulararchitecture in normal and AD patient samples (Aim 2). Finally we will apply multimodal integration to trackcellular and extracellular origins of complex carbohydrate perturbation in AD (Aim 3). This study will providecritical new information regarding ideal cell- region- and temporally-specific opportunities for therapeuticmodulation of AD. Collectively we believe the resultant findings from this proposal will be highly salient formultiple related fields of Alzheimers disease and other neurodegenerative disorders.

project_terms:
3-Dimensional;Age;Algorithms;Alzheimer associated neurodegeneration;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Anabolism;Anatomy;Architecture;Astrocytes;Biological;Brain;Brain region;Carbohydrates;Cell physiology;Cells;Central Nervous System Diseases;Clinical;Clinical Course of Disease;Co-Translational Protein Processing;Code;Cognition;Complex;Data;Dementia;Development;Diagnosis;Dimensions;Disease;Disease Progression;Education;Endothelium;Event;Extracellular Matrix;Glucosamine;Glycogen;Goals;Heterogeneity;Hippocampus (Brain);Human;Image;Impaired cognition;Knowledge;Link;Longevity;Measures;Memory;Metabolic;Metabolism;Metadata;Methodology;Microglia;Molecular;Multiplexed Ion Beam Imaging;Multivariate Analysis;Neighborhoods;Neuraxis;Neurobiology;Neurodegenerative Disorders;Neuroglia;Neurons;Oral;Pathogenesis;Pathogenicity;Pathology;Pathway interactions;Patients;Physiology;Play;Polysaccharides;Prefrontal Cortex;Process;Proteins;Proteomics;Research Personnel;Role;Sampling;Slice;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Staging;Study models;Therapeutic;Time;Tissue imaging;Tissues;analysis pipeline;base;carbohydrate metabolism;cellular imaging;cerebrovascular pathology;cognitive performance;cohort;design;effective therapy;extracellular;glucose metabolism;glycosylation;human disease;imaging approach;imaging platform;insight;mass spectrometric imaging;mouse model;multimodality;nanoscale;neuron loss;protein folding;sex;single cell technology

public_health_relevance:
Project NarrativeGlycosylation is an abundant and complex co-translational modification of proteins that impacts protein foldingmaturation stability subcellular localization and enzymatic activity. While critical roles of N-linkedglycosylation are beginning to emerge in the brain its involvement in Alzheimer's disease (AD) remains largelyunknown. We provided preliminary data in support of N-linked glycan alterations as a driver of AD diseasepathology the goal of this proposal is to define the cellular and extracellular events underlying altered N-linkglycan metabolism in AD.


application_id: 10514689
project_number: 3P30CA177558-10S1
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2022-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S1
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
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
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) was established more than 35 years ago as a university-based matrixcancer center at the University of Kentucky (UK) Kentucky's flagship institution of higher education. MCC isthe only National Cancer Institute (NCI)-designated Cancer Center in Kentucky a state of 4.4 million that leadsthe nation for all-site cancer incidence and mortality and serves as the MCC's catchment area. Over $347M instate institutional and philanthropic investment since recruitment of MCC Director Dr. B. Mark Evers (CS) in2009 have supported significant research and resource expansion enabling substantial new facultyrecruitment program development renovation of clinical and shared resource space and new state-of-the artinstrumentation as well as statewide education and community outreach efforts. The 119 MCC members drawfrom 28 departments in 8 UK colleges with 28 new faculty recruited since 2013. Cancer-relevant researchfunding to MCC investigators exceeds $38.7M in total annual costs an increase of $10.3M since 2012. Overthe last 4 years 9357 subjects have been accrued to interventional trials. Members have published 851cancer-focused publications since 2013 reflecting 28% intra-programmatic 16% inter-programmatic and 58%inter-institutional collaborations. Research is conducted within 4 MCC Research Programs: Cancer CellBiology and Signaling; Cancer Prevention and Control; Drug Discovery Delivery and TranslationalTherapeutics; and Genomic Instability Epigenetics and Metabolism. Five Shared Resource Facilities (SRFs)facilitate cutting-edge research by providing robust infrastructure for specialized expertise and advancedmethods: Biospecimen Procurement and Translational Pathology; Biostatistics and Bioinformatics; CancerResearch Informatics; Flow Cytometry and Cell Sorting; and Redox Metabolism. Two new SRFs (Behavioraland Community-Based Research and Oncogenomics) are in development. Significant achievements include:development of an NCI-sponsored early therapeutics program including an active Molecular Tumor Board andPrecision Medicine Center; expansion of the MCC Network from 8 to 24 sites; establishment of a regionalMetabolomics Center (U24); award of 2 new cancer-related centers  a Center of Biomedical ResearchExcellence (COBRE) in Cancer and Metabolism and a Center for Appalachian Research in EnvironmentalSciences; and expansion of community outreach/education initiatives across the state. MCC research focuseson Kentucky's most serious cancer burdens with emphasis on the distressed Appalachian Kentucky regionwhere cancer incidence and mortality rates surpass those for the entire state. The MCC brings unique basicclinical and population research strengths to this mission. These strengths are integral to all MCC programsand collectively provide robust capacity to deliver transformative interventional research to an importantunderserved priority population thereby contributing to national efforts to conquer cancer through discoveryand clinical translation cancer prevention and community outreach.

project_terms:
Achievement;Address;Appalachian Region;Area;Award;Basic Science;Behavioral Research;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Centers of Research Excellence;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Community Healthcare;Community Networks;Community Outreach;Community Physician;Comprehensive Cancer Center;County;Coupled;Data Sources;Development;Disease;Distress;Early Diagnosis;Education;Education and Outreach;Environmental Risk Factor;Environmental Science;Epigenetic Process;Faculty Recruitment;Fellowship;Flow Cytometry;Foundations;Funding;Genetic;Genomic Instability;Genomics;Health Professional;Healthcare;Immunotherapy;Incidence;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Studies;Intervention Trial;Investments;Kentucky;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolism;Methods;Minority Graduate Student;Minority Groups;Mission;Molecular;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Obesity;Obesity associated cancer;Oncology;Outcome;Oxidation-Reduction;Pathology;Patients;Phenotype;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention therapy;Preventive;Program Development;Publications;Publishing;Quality of life;Radon;Registries;Research;Research Personnel;Resistance;Resource Sharing;Resources;Risk Factors;Role;SEER Program;Science;Scientist;Screening for cancer;Services;Signal Transduction;Site;Strategic Planning;Target Populations;Therapeutic;Training;Transcend;Translating;Translational Research;Translations;Underserved Population;Universities;anticancer research;authority;base;bench to bedside;biomedical informatics;cancer care;cancer genomics;cancer health disparity;cancer prevention;cancer research center director;cancer site;cancer survival;cancer therapy;career development;clinical development;clinical translation;cohort;college;community based research;community engagement;cost;drug discovery;early phase clinical trial;genetic epidemiology;health assessment;health disparity;high school;higher education;improved;innovation;instrumentation;inter-institutional;medically underserved;meetings;member;metabolomics;mortality;multidisciplinary;next generation;novel anticancer drug;outreach;personalized diagnostics;personalized intervention;population health;precision medicine;precision medicine clinical trials;programs;prospective;recruit;repository;response;screening;standard of care;synergism;targeted treatment;translational therapeutics;treatment response;tumor;tumor metabolism;undergraduate student;underserved community

public_health_relevance:
PROJECT NARRATIVE The Markey Cancer Center the only NCI-designated Cancer Center serving 4.4 million Kentuckians in itsstatewide catchment area has the institutional authority for all cancer-relevant activities at the University ofKentucky (UK) and within the UK HealthCare enterprise. The center's mission is to reduce cancer incidenceand mortality through an integrated comprehensive program of cancer research treatment educationprevention and community engagement. Thus the Markey Cancer Center delivers in-depth and impactfulresearch programs in basic translational and population science including the development of clinical trials toaddress Kentucky's unique cancer burden and to accelerate bench-to-bedside translational outcomes thatwill reduce serious health disparities and significantly impact patients the state and the nation.


application_id: 10512933
project_number: 1R21CA256385-01A1
project_title: Investigating the Role of PFKFB4 in the Immune Regulation of Lung Cancer
administering_ic: NCI
award_notice_date: 2022-07-13
opportunity_number: PAR-20-292
application_type: 1
activity_code: R21
ic: CA
serial_number: 256385
suffix: A1
program_official: SOMMERS, CONNIE L
project_start_date: 2022-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZCA1 SRB-A (M1)]
contact_pi_person_id: 9475582
contact_pi: TELANG, SUCHETA
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:
PROJECT SUMMARYLung cancer is responsible for the highest number of cancer-related deaths in the world. Non-small cell lungcancers (NSCLC) form the majority of lung tumors. These tumors are often discovered at an advanced stagewhen options are limited and survival is poor. Effective strategies are desperately needed to improve outcomesfrom this devastating cancer.NSCLCs universally exhibit a high rate of glycolysis to support their rapid growth and spread. A key rate-limitingstep in the glycolytic pathway is catalyzed by the enzyme 6-phosphofructo-1-kinase (PFK1). PFK1 is activatedby fructose-26-bisphosphate (F26BP) - produced by the 6-phosphofructo-2-kinase/fructose-26-bisphosphatasefamily of enzymes (PFKFB1-4). In previous studies we found that the PFKFB4 enzyme is highly expressed inNSCLCs and established its requirement in the regulation of glucose metabolism and growth in these tumors.We have developed a potent novel small molecule inhibitor of PFKFB4 MPN-22 that selectively inhibitsPFKFB4 and decreases NSCLC glycolysis and proliferation and tumor growth in vivo. In recent studies we havefound that immunosuppressive Th17 and T17 cells express F26BP and PFKFB4 and that MPN-22administration in lung tumor-bearing mice decreases the frequency and activity of these cells. We hypothesizethat PFKFB4 is required for Th17/T17 activity and that MPN-22 will decrease their activity resulting in anincrease in activated CD4+ and CD8+ T cells. We further postulate that MPN-22 will potentiate the antitumoractivity of immune checkpoint inhibitors (ICIs) to effectively decrease NSCLC growth. We propose to examinethe effects of PFKFB4 inhibition with MPN-22 on Th17/T17 cell development and activity in vitro andadditionally determine the effects of MPN-22 on immune cells and tumor progression and its efficacy incombination with ICIs in relevant oncogene-driven models of lung cancer. We anticipate that MPN-22 willsignificantly decrease the activity of immunosuppressive T cell subsets and increase the efficacy of ICIs inNSCLC. The ultimate goal of our studies is to develop an effective therapeutic strategy to successfullytreat and improve outcomes in advanced NSCLC.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cells;Cessation of life;Data;Deoxyglucose;Development;Diagnosis;Disease;Enzymes;Evaluation;Exhibits;Family;Frequencies;Fructose;Fructose-26-bisphosphatase;Genetic Transcription;Glucose;Glycolysis;Goals;Growth;Hypoxia;IL17 gene;Immune;Immune checkpoint inhibitor;Immunosuppression;In Vitro;Interleukin-17;KRASG12D;Knock-out;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Mus;Myeloid-derived suppressor cells;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Oral;Outcome;Pathway interactions;Patients;Play;Positron-Emission Tomography;Production;Pyruvate;Regulation;Role;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;TP53 gene;Therapeutic;United States;advanced disease;analog;anti-PD-1;anti-PD1 antibodies;base;blood glucose regulation;cell growth;clinically relevant;directed differentiation;effective therapy;effector T cell;fluorodeoxyglucose positron emission tomography;glucose metabolism;growth promoting activity;immunoregulation;improved outcome;in vivo;inhibitor;lung cancer cell;mortality;neoplastic cell;normoxia;novel;novel therapeutic intervention;phase I trial;rapid growth;response;small molecule;small molecule inhibitor;systemic toxicity;therapeutically effective;tumor;tumor growth;tumor progression

public_health_relevance:
NARRATIVELung cancer is the most frequent cause of cancer-related death and non-small cell lung cancer (NSCLC) is themost commonly diagnosed lung cancer. Despite therapeutic advancements outcomes from NSCLC remainpoor. We anticipate that our studies will demonstrate the importance of the PFKFB4 enzyme in the activity ofimmunosuppressive T cells and the efficacy of PFKFB4 inhibition in augmenting effects of immune checkpointinhibitors and decreasing tumor progression in NSCLC. Accordingly the proposed studies seek to providerationale to support the targeting of PFKFB4 (in combination with immune checkpoint inhibitors) as a noveltherapeutic strategy to reduce the high mortality associated with NSCLC.


application_id: 10512548
project_number: 1R21CA263107-01A1
project_title: Mechanisms underlying radiation-induced dysphagia
administering_ic: NCI
award_notice_date: 2022-07-25
opportunity_number: PAR-20-292
application_type: 1
activity_code: R21
ic: CA
serial_number: 263107
suffix: A1
program_official: BAKOS, ALEXIS DIANE
project_start_date: 2022-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZCA1 TCRB-9 (M1)]
contact_pi_person_id: 10207355
contact_pi: KING, SUZANNE N.
other_pis: Not Applicable
congressional_district: 03
department: MISCELLANEOUS
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:
ABSTRACT Radiation-induced dysphagia is a devastating complication of chemoradiation treatment for head and neckcancer. Deficits in oral and pharyngeal movement during swallowing are the most prevalent cause of radiation-induced dysphagia. The adverse effects of these swallowing problems can lead to long-term dietaryrestrictions malnutrition and placement of a feeding tube to prevent aspiration. Recent evidence in otherareas of the body demonstrate that radiation can damage peripheral nerves resulting in changes in motorfunction. However the neural mechanisms underlying radiation-induced dysphagia are unknown. Anunderstanding of the pathophysiology of radiation-induced dysphagia is needed to develop more effectivetherapeutic targets aimed at preserving post chemoradiation swallowing function. Swallowing is a coordinatedactivity controlled by a neural pattern-generating circuitry in the brainstem that relies heavily on sensoryinformation. Nociceptors are a subset of sensory neurons that are sensitized by tissue injury. When nociceptorsensory axons are damaged they trigger protective responses that can drive changes in neural control leadingto disturbances in coordinated motor output. We propose that nociceptor activity interfering with swallowingfunction may be another potential mechanism at play after chemoradiation muscle injury. In the proposedstudy we will characterize how oropharyngeal swallowing is affected by chemoradiation and determinewhether injury of sensory neurons can contribute to dysphagia post-treatment. We hypothesize thatchemoradiation-induced axon injury is associated with changes in oral and pharyngeal swallowing kinematicsafter treatment. This research has two specific aims that are strongly supported by preliminary data. In Aim 1we will determine the effect of chemoradiation to the mylohyoid muscle on the movement of the oral andpharyngeal structures during swallowing. Kinematic analysis and force measures will be used to quantifyfunctional deficits. In Aim 2 we will determine the nerve injury/stress-like response induced in trigeminalsensory neurons following chemoradiation to the mylohyoid muscle. We will identify sensory neurons in thetrigeminal ganglion projecting from the mylohyoid and measure their expression of injury/stress-inducedmarkers. We will also test alternative mechanisms and develop a predictive model to quantify the complicationrisk of treatment to tissue and behavioral outcomes. The proposed experiments will establish the feasibility of anovel neural-based mechanism underlying radiation-induced dysphagia and define specific points ofswallowing dysfunction after chemoradiation in the rat that will serve as targets for assessing future treatments.

project_terms:
Adverse effects;Affect;Afferent Neurons;Aftercare;Area;Behavior Therapy;Behavioral;Bolus Infusion;Brain Stem;Cancer Survivor;Chemotherapy and/or radiation;Collagen;Complement;Complex;Complication;Data;Deglutition;Deglutition Disorders;Devices;Diet Modification;Eating Behavior;Enteral Feeding;Fibrosis;Functional disorder;Future;Goals;Grant;Head and Neck Cancer;Immunofluorescence Immunologic;Impairment;Injury;Intervention;Investigation;Larynx;Lead;Malnutrition;Measurement;Measures;Modality;Modeling;Motor;Motor output;Movement;Muscle;Nociceptors;Normal tissue morphology;Oral;Oropharyngeal;Outcome;Peripheral;Pharyngeal structure;Play;Radiation;Rattus;Research;Risk;Risk Estimate;Sensory;Statistical Models;Stress;Structure of trigeminal ganglion;Sublingual Region;Testing;Time;Tissues;Tongue;Trigeminal System;United States;Work;activating transcription factor 3;afferent nerve;axon injury;base;behavioral outcome;chemoradiation;chemotherapy;clinically relevant;dietary restriction;drinking behavior;experimental study;head and neck cancer patient;high risk;improved;injured;irradiation;kinematics;nerve injury;neural patterning;neuromechanism;neuroregulation;novel;peripheral nerve damage;predictive modeling;preservation;prevent;relating to nervous system;response;screening;sensory input;therapeutic target;therapeutically effective;tissue injury;treatment risk;treatment strategy

public_health_relevance:
Project NarrativeSwallowing disorders are a major complication after chemoradiation treatment for head and neck cancer. Thisgrant examines how chemoradiation treatment alters swallowing movement and establishes if sensory nerveinjury is associated with swallowing dysfunction after treatment. Successful completion of the proposedexperiments will provide fundamental information that will facilitate subsequent projects testing therapies aimedat preventing or improving swallowing outcomes for head and neck cancer survivors.


application_id: 10510245
project_number: 1R01DA056646-01
project_title: Ghrelin Deacylase as a Treatment for Opioid Polysubstance Abuse
administering_ic: NIDA
award_notice_date: 2022-06-10
opportunity_number: RFA-DA-22-031
application_type: 1
activity_code: R01
ic: DA
serial_number: 056646
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2022-07-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZDA1 IXR-Q (09)]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: ZHENG, FANG
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:
With currently available medications for opioid use disorder (OUD) the relapse rate is very high. Further co-use of an opioid and a stimulant such as methamphetamine (METH) undermines success in treatment for OUD.It is highly desired to develop novel therapeutic options for treatment of OUDs including polysubstance usedisorders (PSUDs). Recently reported studies have revealed an interesting role of ghrelin in drug abuse andreward-relevant behaviors. Ghrelin is known as a growth-hormone-releasing acylated peptide from stomach a28 amino-acid peptide with the third residue (Ser3) acylated by n-octanoic acid. Ghrelin is produced in thestomach travels to the brain through blood circulation and acts on ghrelin (or growth hormone secretagogue)receptor (GHSR) to stimulate the mesolimbic dopamine reward pathway and increase rewarding behaviors inrodents. GHSR antagonism has been shown to attenuate rewarding effects induced by various substancesincluding METH amphetamine fentanyl morphine heroin cocaine nicotine and alcohol. For exampleadministration of a selective GHSR antagonist significantly reduced the fentanylseeking/relapselike behaviorin rats. On the other hand GHSR has diverse regulatory roles associated with its constitutive activity (the activityin the absence of ghrelin ligand) and hence GHSR antagonism could also result in unwanted adverse effects.Thus alternative strategies targeting ghrelin itself could be more interesting. However whether targeting ghrelinitself would be effective to attenuate the drug rewarding effects remains controversial in literature as ghrelinlevels before and after treatment were not measured in previous animal studies targeting ghrelin itself. It isunclear whether any of the previously used approaches was able to decrease the ghrelin level significantlyenough to attenuate the substance reward. We propose to use our recently identified ghrelin deacylase (a mutantof human butyrylcholinesterase or BChE) as a safe and effective ghrelin modulator to attenuate substancerewarding effects. Such a ghrelin modulator is expected to be as effective as a GHSR antagonist in treatment ofsubstance use disorders (SUDs) including PSUDs but without interacting with any brain receptors/transporters.Specifically in this investigation we will first evaluate the BChE mutant for its in vivo potency in modulatingghrelin and attenuating the rewarding and reinforcing effects of representative opioids (fentanyl and heroin) andtheir combinations with METH in various rodent models. Then we will design and discover a new BChE mutantas a more potent ghrelin deacylase with further improved catalytic activity for ghrelin diacylation develop itslong-acting fusion protein form and examine the long-term in vivo effects of the long-acting ghrelin deacylase.Accomplishment of this investigation will determine whether ghrelin itself is a truly effective target and whethera potent ghrelin deacylase as a ghrelin modulator is truly effective for treatment of PSUDs. If the answers are allpositive the most effective long-acting ghrelin deacylase (recombinant protein) to be tested and developed mayalso serve as a promising therapeutic candidate for treatment of PSUDs.

project_terms:
Acute;Adverse effects;Affect;Aftercare;Alcohols;Amino Acids;Amphetamines;Animals;Attenuated;Behavior;Binding;Biological Assay;Blood Circulation;Brain;Butyrylcholinesterase;Chimeric Proteins;Chronic;Cocaine;DR1 gene;Data;Dependence;Development;Disease;Dopamine;Dopamine Receptor;Down-Regulation;Drug Exposure;Drug abuse;Enzymes;Esthesia;Euphoria;Feeling;Fentanyl;G-Protein-Coupled Receptors;Gastric Acid;Heroin;High Prevalence;Human;Hydrolase;Hyperactivity;Hypesthesia;In Vitro;Ingestion;Investigation;Lead;Ligands;Literature;Methamphetamine;Morphine;National Institute of Drug Abuse;Neurons;Nicotine;Octanoic Acids;Opioid;Pathway interactions;Peptides;Perception;Pharmaceutical Preparations;Play;Presynaptic Terminals;Process;Production;Property;Proteins;Rattus;Receptor Signaling;Recombinant Proteins;Relapse;Reporting;Research;Rewards;Rodent;Rodent Model;Role;Self Administration;Side;Signal Transduction;Site-Directed Mutagenesis;Somatotropin;Stimulant;Stimulus;Stomach;Structure;Substance Use Disorder;Substance of Abuse;Synapses;System;Testing;Therapeutic;Travel;Withdrawal;Work;animal data;antagonist;base;behavioral study;conditioned place preference;deacylation;design;dopamine system;dopamine transporter;dopaminergic neuron;drug reward;effective therapy;enzyme activity;ghrelin;growth hormone secretagogue receptor;improved;in vivo;in vivo evaluation;methamphetamine effect;methamphetamine use;mutant;novel;novel therapeutic intervention;novel therapeutics;opioid use disorder;opioid user;pleasure;polysubstance abuse;polysubstance use;protein expression;protein purification;rational design;receptor;receptor expression;response;substance use;substance use treatment;success;therapeutic candidate;treatment strategy

public_health_relevance:
Accomplishment of this investigation will validate a potentially promising new target and may eventuallylead to development of a novel therapeutic approach to treatment of substance use disorders.


application_id: 10509828
project_number: 1R03CA267326-01A1
project_title: Alterations in DNA Damage following Major Surgery and Hyperthermic Intraperitoneal Chemotherapy
administering_ic: NCI
award_notice_date: 2022-08-05
opportunity_number: PAR-20-052
application_type: 1
activity_code: R03
ic: CA
serial_number: 267326
suffix: A1
program_official: THURIN, MAGDALENA
project_start_date: 2022-08-05
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZCA1 PCRB-E (M1)]
contact_pi_person_id: 7907525
contact_pi: KIM, JOSEPH
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
project_abstract:
ABSTRACT/SUMMARYNearly 10% of patients with metastatic colorectal cancer (mCRC) have progression of disease involving thespread of metastatic cancer to the peritoneal cavity. These patients generally have the worst outcomes for allpatients with mCRC. A recent phase III multicenter clinical trial has shown that single-agent immune checkpointinhibitor (ICI) has greater efficacy and better safety profile than standard cytotoxic chemotherapy regimens forpatients with mCRC. Importantly indications to receive ICI therapy are dependent on the measurement of hightumor mutation burden (TMB) neoantigen burden and microsatellite instability (MSI) status. These direct andindirect measures of genomic instability predict clinical response to ICIs however only 5% of patients arecurrently eligible to receive these therapies.Patients with mCRC with peritoneal spread of disease may undergo major cytoreductive surgery (CRS) duringwhich all gross sites of disease are resected. CRS is combined with heated intraperitoneal chemotherapy(HIPEC) with mitomycin C at 43C to eradicate microscopic disease. We hypothesize that major surgicalinflammation from CRS and the heat and chemotherapy of HIPEC altogether increase genomic instability.Surgical inflammation is known to activate heat shock proteins (Hsps) which may destabilize its regulatory controlover mismatch repair (MMR) proteins leading to deficient DNA repair. This condition combined with the DNAdamaging effects of mitomycin c and heat may lead to high TMB increased neoantigens and altered MSI inoccult microscopic mCRC cells. Our overarching hypothesis is that patients undergoing CRS/HIPEC will beeligible to receive and will benefit from ICI therapy.We propose to obtain blood samples and surgical tissues before and after CRS/HIPEC from patients with mCRC.These specimens will be assessed for changes in TMB and neoantigens (Aim 1) and MMR/MSI (Aim 2). Fromthe surgical tissues we will also create paired patient-derived organoids (PDOs) from which we will investigateHsps MMR proteins and MSI. Our prior studies using PDOs from CRS/HIPEC patients support their use toassess sensitivities to ICI therapies before and after CRS/HIPEC. We propose the following specific aims:Specific Aim 1. To measure alterations in TMB and neoantigens as a result of the heat and DNA damagingeffects of mitomycin C in mCRC patients undergoing CRS/HIPEC.Specific Aim 2. To determine whether surgical inflammation combined with heat and DNA damaging effects ofmitomycin C from CRS/HIPEC disrupt Hsp-stabilization of MMR proteins to increase MSI.

project_terms:
Adjuvant;Bathing;Blood specimen;Cell Line;Chemotherapy-Oncologic Procedure;Clinical;Cytotoxic Chemotherapy;Cytotoxic agent;DNA;DNA Damage;DNA Mismatch Repair Protein MLH1;DNA Repair;Data;Defect;Deposition;Disease;Disease Progression;Disseminated Malignant Neoplasm;Excision;Exhibits;Genomic Instability;Greater sac of peritoneum;Heat shock proteins;Human;Immune System Diseases;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Inflammation;Inflammatory Response;Lead;MLH1 gene;MSH2 gene;Malignant Neoplasms;Measurement;Measures;Microsatellite Instability;Microscopic;Mismatch Repair;Mitomycin C;Monoclonal Antibodies;Multi-Institutional Clinical Trial;Mutation;Neoplasm Metastasis;Operative Surgical Procedures;Organoids;Outcome;Pathway interactions;Patients;Peritoneal;Phase;Physiological;Process;Prognosis;Progression-Free Survivals;Proteins;Randomized Controlled Trials;Regimen;Relapse;Research;Resected;Safety;Site;Specimen;Stress;Testing;Tissue Sample;Tissues;Toxic effect;Tumor Debulking;anti-PD-1;base;cancer cell;cancer survival;checkpoint therapy;chemotherapy;clinical predictors;colon cancer patients;cytokine;drug sensitivity;experience;improved;inhibitor therapy;intraperitoneal therapy;member;metastatic colorectal;neoantigens;operation;pembrolizumab;programmed cell death protein 1;response;tumor

public_health_relevance:
PROJECT NARRATIVEOur proposal examines whether the major inflammation heat and chemotherapy of cytoreductive surgery (CRS)and heated intraperitoneal chemotherapy (HIPEC) increases the genomic instability of patients with metastaticcolorectal cancer (mCRC). Our ultimate objective is to identify changes in tumor mutation burden neoantigensor microsatellite instability as a result of CRS/HIPEC so that patients with mCRC are eligible to receiveefficacious and safe immune therapies.


application_id: 10508652
project_number: 1R03HD109497-01
project_title: The Impact of Leukocyte-Derived OSM on Ovulation and Luteinization in the Human Ovary
administering_ic: NICHD
award_notice_date: 2022-08-15
opportunity_number: PA-20-200
application_type: 1
activity_code: R03
ic: HD
serial_number: 109497
program_official: TAYMANS, SUSAN
project_start_date: 2022-08-15
project_end_date: 2024-07-31
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 14509280
contact_pi: CHOI, YOHAN
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:
ABSTRACTS The ovulatory process is the mid-cycle gonadotropin surge-induced acute inflammatory response.Leukocytes are critical effectors in the inflammatory response. However the mechanisms of leukocyterecruitment and the specific roles of leukocytes in the ovulatory follicle remain elusive especially in humans.The current study proposes to elucidate how the mid-cycle LH surge coordinates leukocyte recruitment and theexpression of genes in preovulatory follicular cells to bring about successful ovulation and luteinization in thehuman ovary. From our pilot single-cell transcriptome analyses using human follicular aspirates from womenundergoing in vitro fertilization we discovered that OSM (oncostatin-M) is exclusively expressed in specifictypes of leukocytes whereas its receptors OSMR and LIFR (leukemia inhibitory factor receptor) and their co-receptor IL6ST (IL6 family signal transducer) are present predominantly in granulosa cells. Similarly ingranulosa cells of dominant follicles collected from normally cycling women throughout the periovulatoryperiod we found that OSMR mRNA levels were markedly increased after hCG stimulation. In addition ourpreliminary data showed that hCG increased the expression of OSM receptors OSMR and IL6ST in primaryhuman granulosa cell cultures mimicking in vivo up-regulation of OSMR. Our preliminary data also revealedthat OSM could activate specific signaling pathways and stimulate progesterone and prostaglandin E2production two crucial mediators of ovulation. Based on these novel data we hypothesized that 1) the LH surge induces the recruitment of OSM-expressing leukocytes while increasing the expression of its receptors (OSMR LIFR IL6ST) in follicular cellsof preovulatory follicles and 2) leukocyte-derived OSM upon binding to its receptors in preovulatory follicularcells activates specific signaling pathways and regulates the expression of specific ovulatory genes therebypromoting necessary ovulatory changes. These hypotheses will be tested by first characterizing expressionprofiles of OSM in leukocytes and its receptors OSMR LIFR and IL6ST in follicular cells of the dominantfollicles collected throughout the periovulatory period and examining the regulatory mechanisms involved in theexpression of OSM receptors in human granulosa cells (Specific Aim 1). Next we will delineate OSM-activated intracellular signaling pathways in human granulosa cells (Specific Aim 2). Lastly we will elucidatethe impact of leukocyte-derived OSM on the periovulatory process by identifying OSM-regulated downstreamgenes (RNA-seq analysis) and evaluating cellular/biological impacts on affected pathways using humangranulosa cell cultures. The proposed study will demonstrate for the first time OSM as a novel ovulatoryfactor of leukocyte-origin and identify its specific roles in the human ovary thus filling the gap in ourunderstahopteanding of the role of leukocytes in the ovulatory process.

project_terms:
Acute;Affect;Aspirate substance;Binding;Bioinformatics;Biological;Cell Culture Techniques;Cells;Data;Dinoprostone;EGF gene;Family;Fertility;Fertilization in Vitro;Gene Expression;Genes;Gonadotropins;Granulosa-Lutein Cells;Human;Human Chorionic Gonadotropin;IL6 gene;IL6ST gene;Infertility;Inflammation;Inflammatory Response;Knowledge;LIFR gene;Leukocytes;Luteinization;MAPK3 gene;Mediator of activation protein;Messenger RNA;OSMR gene;Ovary;Ovulation;PTGS2 gene;Pathway interactions;Phase;Procedures;Process;Production;Progesterone;Progesterone Receptors;Proteins;Recombinants;Role;Sampling;Signal Pathway;Signal Transduction;Signaling Molecule;Stat3 Signaling Pathway;Supplementation;Testing;Time;Tissues;Transducers;Up-Regulation;Woman;base;design;differential expression;female fertility;fertility improvement;granulosa cell;improved;in vivo;leukemia inhibitory factor receptor;male;novel;oncostatin M;ovarian dysfunction;proliferative phase Menstrual cycle;receptor;receptor expression;recruit;single-cell RNA sequencing;spatiotemporal;transcriptome;transcriptome sequencing

public_health_relevance:
PROJECT NARRATIVEThe successful ovulation is essential for female fertility; however there are large gaps in our understanding ofmechanisms underlying the ovulatory process particularly in humans. The proposed study will demonstrateoncostatin-M as a novel ovulatory factor of leukocyte-origin and elucidate its action and roles in humanperiovulatory follicles. Therefore this study will enhance our knowledge on the ovulatory process which can beapplied in designing better strategies to improve womens fertility.


application_id: 10508346
project_number: 1R21AG078601-01
project_title: Novel experimental models to study the effect of extracellular vesicles on neurons
administering_ic: NIA
award_notice_date: 2022-08-16
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AG
serial_number: 078601
program_official: DIBATTISTA, AMANDA
project_start_date: 2022-08-17
project_end_date: 2024-07-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
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:
Extracellular vesicles (EVs) have taken center stage in almost every area of biological research includingneurobiology. EVs are secreted vesicles that transport lipids RNA/DNA and proteins from a donor to a recipientcell including pathogenic peptides and proteins such as A tau and synuclein. Therefore spreading ofpathogenic factors by EVs in Alzheimers disease (AD) and Parkinsons Disease (PD) is the focus of many recentstudies. However the physiological significance of endogenously generated EVs and mechanism of function arelargely unknown. A critical knowledge gap and barrier to progress is our lack of understanding of thephysiological and pathological function of EVs due to the scarcity of in vivo models.We showed that EVs secreted by astrocytes and enriched with the sphingolipid ceramide (astrosomes) aretaken up by neurons and transported to mitochondria. We discovered that genetic deficiency of neutralsphingomyelinase 2 (nSMase2) an enzyme generating ceramide by hydrolysis of sphingomyelin reducesastrosomes and upregulates transcript clusters associated with neuronal development and signal transductionsuggesting that astrosomes regulate neuronal function.To test the regulation of neurons by astrosomes we propose to establish novel techniques and models forEV functional analysis. We developed mouse models with-astrocyte specific nSMase2 deficiency (loss-of-function) models and secretion of fluorescently labeled astrosomes (reporter models). We will primarily usethese models to understand the significance of endogenous astrosomes for normal neuronal function. We willincorporate pilot studies to understand the function of astrosomes in (changing) physiological conditions (e.g.aging).Our overall goal is to establish novel techniques to determine the in vivo function of astrosomes. Onceestablished these techniques can be adapted to determine the function of EVs from other cell types (neuronsmicroglia or any other tissue and cell type) as well

project_terms:
Affect;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Apoptosis;Area;Astrocytes;Binding;Brain;CASP3 gene;Cell Death;Cells;Ceramides;Cognition;Communication;DNA;Data;Dependovirus;Enzymes;Experimental Models;Gene Expression;Generations;Genetic;Genus Hippocampus;Goals;Hydrolysis;Impairment;In Vitro;Individual;Intracellular Transport;Knock-out;Knowledge;Label;Length;Lipids;MicroRNAs;Microglia;Mitochondria;Modeling;Monitor;Mus;Neurobiology;Neurons;Nuclear;Organelles;Parkinson Disease;Pathogenicity;Pathologic;Peptides;Pharmacology;Physiological;Pilot Projects;Population;Prevention;Process;Processed Genes;Prostate;Proteins;Publishing;RNA;Regulation;Reporter;Satellite Viruses;Signal Transduction;Sphingolipids;Sphingomyelinase;Sphingomyelins;Synapses;Synaptic Transmission;System;Techniques;Testing;Tissues;Transcript;Up-Regulation;Vesicle;Virulence Factors;base;biological research;cell type;experimental study;extracellular vesicles;improved;in vivo;in vivo Model;lipid transport;loss of function;middle age;mouse model;neuron development;neuron loss;neurotoxicity;neurotransmission;novel;prevent;response;synuclein;tau Proteins;transcriptome sequencing;uptake;vesicle transport

public_health_relevance:
Astrocytes are cells in the brain that interact with neurons. They secrete small vesicles that affect neuronalfunction particularly mitochondria  organelles that generate energy  and the expression of genes that areimportant for neuronal communication. We will develop novel experimental models to study the effect ofastrocyte-derived vesicles on neurons.


application_id: 10507809
project_number: 1R03NS128748-01
project_title: Curation of the Seattle ALS Patient
administering_ic: NINDS
award_notice_date: 2022-07-20
opportunity_number: PA-20-200
application_type: 1
activity_code: R03
ic: NS
serial_number: 128748
program_official: GUBITZ, AMELIE
project_start_date: 2022-08-01
project_end_date: 2023-06-30
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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:
SUMMARYData sharing allows new applications and hypotheses to be applied to existing data sets honoring theindividuals who contributed data and often public funding of the project that generated the data. Data sharingis particularly important for uncommon diseases such as amyotrophic lateral sclerosis (ALS). The Seattle ALSPatient Profile Database (SALSPPD) is a rich longitudinal dataset of ALS patients (n = 143) and their partners(spouses significant others or caregivers; n = 123) from clinics in Seattle WA; San Francisco CA; andPhiladelphia PA. The purpose of the study was to characterize the psychological and physical natural historyof ALS and the interactions between them. Participants were interviewed in their homes every 3 months for upto 18 months between March 1987 and August 1989. Follow-up phone calls were completed in 1990 1994and 2008 primarily to ascertain patient outcomes. In 2009 we were granted ownership of these data for ouruse with the intention that the data would be made publicly available. However the data are not in usableform.These are valuable data that include information on patient characteristics (e.g. medical and family historypatient-reported outcomes disease outcomes treatments) partner characteristics (e.g. partner-reportedoutcomes) family characteristics (e.g. family structure) and disease outcomes (e.g. forced vital capacitysurvival). Under this proposal the data would be formatted and validated (e.g. variable names and valuesvalue labels and syntax); documented (data dictionary missing data analysis variable descriptive statistics);and the data and documentation made publicly available and their use promoted to scientists. Sharing theSALSPPD will provide a rich resource to scientists interested in the natural history of ALS psychosocial effectson ALS outcomes and vice versa and psychosocial and disease outcomes of treatments.

project_terms:
ALS patients;Accidents;Age;Amyotrophic Lateral Sclerosis;Biometry;Caregivers;Cessation of life;Characteristics;Child;Clinic;Code;Consultations;Data;Data Analyses;Data Set;Databases;Diagnosis;Disease;Disease Outcome;Divorce;Documentation;Factor Analysis;Family;Family Characteristics;Funding;Grant;Health;Health behavior;Heart Diseases;Home;Individual;Infection;Intention;Interview;Label;Letters;Malignant Neoplasms;Marital Status;Medical;Mental Depression;Muscular Dystrophies;Names;Natural History;Operative Surgical Procedures;Outcome;Ownership;Participant;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Personality;Pharmaceutical Preparations;Philadelphia;Physical therapy;Psychology;Recording of previous events;Reporting;Research Personnel;Resources;Respirators;San Francisco;Scientist;Sclerosis;Severities;Site;Social Interaction;Spouses;Structure;Sum;Symptoms;Telephone;Time;Treatment outcome;Treatment/Psychosocial Effects;Visit;Vital capacity;Work;alternative treatment;coping;data de-identification;data dictionary;data sharing;demographics;family structure;file format;follow-up;indexing;interest;longitudinal dataset;meetings;nervous system disorder;profiles in patients;psychologic;psychosocial;residence;search engine;statistics;syntax

public_health_relevance:
NARRATIVESharing data among scientists honors the individuals who contributed data and often public funding of theproject that generated the data. Data sharing is particularly important for uncommon diseases such asamyotrophic lateral sclerosis (ALS). The Seattle ALS Patient Profile Database (SALSPPD) contains detailedassessments of ALS patients and their partners (spouses significant others or caregivers) but is not in usableform and this project would make the data usable and available to other scientists.


application_id: 10506115
project_number: 1K99AR081367-01
project_title: Contribution of ribosome specialization to the pathophysiology of muscular dystrophy
administering_ic: NIAMS
award_notice_date: 2022-08-17
opportunity_number: PA-20-188
application_type: 1
activity_code: K99
ic: AR
serial_number: 081367
program_official: CARIFI, EMILY FORAN
project_start_date: 2022-08-17
project_end_date: 2024-07-31
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 12197125
contact_pi: WEN, YUAN
other_pis: Not Applicable
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: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ATP Synthesis Pathway;Address;Adult;Biological Assay;Cells;Chronic;Contractile Proteins;Cytoplasm;Data;Disease;Disease Progression;Dose;Drops;Duchenne muscular dystrophy;Equilibrium;Exercise;Failure;Functional disorder;Generations;Genes;Genetic Diseases;Genetic Transcription;Glucocorticoid Receptor;Glucocorticoids;Growth;Hindlimb;Image;Impairment;In Vitro;Knock-out;Knockout Mice;Learning;Maintenance;Measurement;Measures;Mechanics;Mediating;Mentors;Mentorship;Mitochondria;Mitochondrial Proteins;Modeling;Morphology;Muscle;Muscle Proteins;Muscle function;Muscular Atrophy;Muscular Dystrophies;Oxygen Consumption;Pathogenesis;Pathology;Patients;Performance;Phase;Phenotype;Production;Protein Biosynthesis;Proteins;Regulation;Respiratory Diaphragm;Ribosomal Proteins;Ribosomes;Role;Running;Skeletal Muscle;Specificity;Steroid therapy;Steroids;Stress;Striated Muscles;System;Techniques;Testing;Tetanus Helper Peptide;Time;Tissues;Training;Transcript;Translating;Translations;Up-Regulation;Ventilator;Yeasts;base;career;design;effective therapy;exercise training;functional decline;functional loss;improved;in vivo;mdx mouse;mitochondrial dysfunction;mouse model;muscle strength;new therapeutic target;novel;novel therapeutics;paralogous gene;postnatal development;protein expression;restoration;standard of care;transcriptome sequencing


application_id: 10505311
project_number: 1R21DA055028-01A1
administering_ic: NIDA
award_notice_date: 2022-08-08
opportunity_number: PAR-19-064
application_type: 1
activity_code: R21
ic: DA
serial_number: 055028
suffix: A1
program_official: HARTSOCK, PETER
project_start_date: 2022-08-15
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZDA1 SXC-G (19)]
contact_pi_person_id: 12261498
contact_pi: VICKERS, RACHEL ANN
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_title:
Dealers Detectives and People Who Use Drugs: Triangulating Perspectives to Understand COVID-19s Impact on the Rural Appalachian Drug Market and Mitigate Downstream Overdose Risk

project_abstract:
Abstract: From June 2019 to May 2020 the US saw the highest number of OD deaths ever recorded in a 12-month period with a heightened increase from March-May 2020 when control measures were firstimplemented. This translated to a 30% increase in the number of overdose deaths from 2019 to 2020.Kentucky an epicenter of the opioid epidemic had a 56% increase in the number of overdose deaths over thesame period: the second greatest increase nationwide and the highest number of fatal overdoses the statehas ever recorded. Various factors have likely played a role in this surge. For example stay-at-home ordersand social distancing practices may result in PWUD using drugs in isolation more often  a risk factor for fatalOD given the limit to bystanders ability to administer naloxone and/or call emergency services. Earlyindications from data on COVID have some positing that drug market changes may impact individual levelvulnerability to OD. In Kentucky there was a 102% increase in fentanyl-involved OD deaths from Jan-Sept2020 compared to the same period in 2019 suggesting that an influx of fentanyl in the drug supply has driventhe recent increase in ODs. In response to the urgent need for intervention the goal of this proposal is tounderstand the changes in the illicit fentanyl market brought about by COVID and simultaneously work toidentify harm reduction strategies to reduce PWUD vulnerability and foster resilience to these changes. Thisproposal is timely not only in that it responds to an urgent COVID-related surge in fatal ODs but also becauseit aligns with a period of mass scale-up of SAMHSA-funded fentanyl test strip (FTS) services in Kentucky. Theproposed mixed-methods community-engaged R21 study led by a scientific team with extensive experiencein rural substance use research will yield urgently needed local data on harm reduction strategies that couldcurb the historic spike in fentanyl-related ODs in rural Appalachia by achieving the following aims: Aim 1.Characterize COVIDs effect on the illicit fentanyl market and potential fentanyl-related harm reductionstrategies (i.e. FTS) in Appalachian Kentucky through qualitative interviews with state and local lawenforcement and local harm reduction staff. Aim 2. Identify individual-level characteristics of rural PWUD mostvulnerable and resilient to pre-/post-COVID changes in fentanyl use and OD risk through an analysis ofexisting longitudinal data spanning the pre-/post-COVID period. Aim 3. Describe COVIDs impact on the localillicit fentanyl market and OD risk and explore attitudes toward potential harm reduction strategies (e.g. FTSpeer- and dealer-driven distribution of FTS) through qualitative interviews with people who sell drugs andPWUD identified as most vulnerable and most resilient to COVID-related changes in the Aim 2 analysis.Subaim 3a. Examine acceptability of an FTS intervention among Aim 3 participants using a small pilot with preand 1-month post qualitative interviews.

project_terms:
Address;Affect;Appalachian Region;Area;Attenuated;Attitude;COVID-19;COVID-19 impact;COVID-19 pandemic;Centers for Disease Control and Prevention (U.S.);Characteristics;Collaborations;Communities;Data;Detection;Disease Outbreaks;Drug usage;Drug user;Emergency medical service;Fentanyl;Fostering;Funding;Goals;Harm Reduction;Health;Home;Individual;Intervention;Interview;Kentucky;Law Enforcement;Life;Measures;Methods;Naloxone;Natural Disasters;Overdose;Participant;Persons;Pharmaceutical Preparations;Play;Policies;Recommendation;Recording of previous events;Research;Research Infrastructure;Risk;Risk Factors;Role;Rural;Rural Appalachia;Services;Social Distance;Time;Translating;United States Substance Abuse and Mental Health Services Administration;Work;acceptability and feasibility;analog;community partnership;community transmission;coronavirus disease;drug market;drug use vulnerability;experience;high risk;improved;novel;opioid epidemic;overdose death;overdose risk;peer;post-COVID-19;resilience;response;scale up;substance use;test strip;tool

public_health_relevance:
Narrative: The COVID-19 pandemic and related control policies have been associated with substantialincreases in fentanyl-related overdoses (ODs). PWUD in rural Appalachia may be especially impacted whereaccess to needed services was limited even before COVID-19. The proposed mixed-methods community-engaged study will yield urgently needed local data on harm reduction strategies that could curb the historicspike in fentanyl-related ODs in rural Appalachia.


application_id: 10501326
project_number: 1R01NR020478-01
administering_ic: NINR
award_notice_date: 2022-08-31
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: NR
serial_number: 020478
program_official: HUSS, KAREN
project_start_date: 2022-08-31
project_end_date: 2026-06-30
study_section: Clinical Management in General Care Settings Study Section[CMGC]
contact_pi_person_id: 11595895
contact_pi: WU, JIA-RONG
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: 2022-08-31
project_title:
Improving medication adherence using family-focused and literacy-sensitive strategies in patients with heart failure

project_abstract:
Project SummaryMedication adherence is thought by many providers and researchers to be the most important self-carebehavior yet it is also the most problematic. Poor medication adherence can cause poor quality of life (QoL)hospitalization and death. In the United States approximately 125000 deaths per year are due to poormedication adherence and up to 50% of heart failure (HF) patients are re-hospitalized within 6 months of aprevious HF exacerbation and one of the most common causes is poor medication adherence. Lifelong andusually complex medication regimens are needed for patients with HF yet 40-60% of HF patients havesuboptimal medication adherence. Health literacy plays a significant role in suboptimal medication adherence.Support by a care partner (CP; usually a family member) can improve adherence and reduce hospitalizations.Although some interventions have improved HF patients adherence improvements were small and effectswere not sustained. To enhance and sustain intervention effects we will use an approach that is literacy-sensitive and incorporates social support. Using easy-to-understand language for patients and CPs we willtest an interactive behavioral family-focused and literacy-sensitive (FamLit) intervention delivered by nursesincorporating evidence-based multi-components (e.g. teach-back coaching role-playing goal setting) toengage both patients and CPs in improving and sustaining medication adherence and health outcomes. Wewill conduct a randomized controlled trial to evaluate the efficacy of FamLit intervention on medicationadherence hospitalization death and QoL. We will randomly assign 164 dyads of patients and their primaryCPs (patients-CPs) to either the FamLit intervention or an attention-control group. Both groups will have an in-person session (delivered on the day of a clinic appointment for regular follow-up) one month after baselineand phone boosters every other week for up to 3 months. FamLit group sessions will focus on improvingmedication adherence and control group sessions will focus on general health issues. Our aims are to: 1) testthe efficacy of the FamLit intervention compared to an attention control group on outcomes (i.e. primary:medication adherence and secondary: a) HF hospitalization or all-cause death b) QoL c) social support andd) communication) over 12 months; 2) determine if TPB-related intermediate outcomes (attitudes subjectivenorms perceived behavioral control) mediate the effects of the intervention on medication adherence; 3)examine whether each dyad members a) health literacy b) social support and c) communication moderatethe effect of the FamLit intervention on medication adherence; and 4) determine how each dyad membersattitudes subjective norms perceived behavioral control social support and communication affect their ownand their partners QoL over 12 months using the innovative Actor-Partner Interdependence Model. TheFamLit intervention if efficacious holds potential to improve/sustain medication adherence and reducehospitalizations and death. We will follow up with an effectiveness-implementation hybrid trial as our next step.

project_terms:
Address;Adherence;Adverse effects;Affect;Appointment;Attitude;Back;Behavior;Behavior Control;Behavioral;Caring;Cause of Death;Cessation of life;Chronic;Clinic;Communication;Complex;Control Groups;Educational Materials;Event;Family;Family member;Friends;Goals;Happiness;Health;Health Promotion;Heart failure;Hospitalization;Individual;Instruction;Intervention;Language;Learning;Link;Mediating;Medical;Modeling;Morbidity - disease rate;Motivation;Nurses;Outcome;Partner Communications;Patient Care;Patients;Persons;Pharmaceutical Preparations;Planning Theory;Play;Prevention;Primary Health Care;Provider;Quality of life;Randomized;Randomized Controlled Trials;Reading;Regimen;Research;Research Personnel;Role;Role playing therapy;Self Care;Social support;Spouses;Symptoms;Telephone;Testing;Time;Treatment Efficacy;United States;Work;attentional control;base;comparison intervention;compliance behavior;effectiveness implementation study;efficacy evaluation;efficacy testing;evidence base;follow-up;fourth grade;group intervention;health literacy;high risk;improved;innovation;interest;intervention effect;literacy;medication compliance;member;mortality;multi-component intervention;older patient;pilot test;post intervention;primary outcome;secondary outcome;skills

public_health_relevance:
Project NarrativePeople with heart failure who do not take their medications as prescribed are at high risk of complicationsleading to hospitalization death and poor quality of life. In the proposed intervention nurses will use easy-to-understand language to coach patients and their care partners to help them work together and build skills toovercome their individual barriers to adherence in order to improve and sustain patient medication adherence.If effective this intervention will support long-term medication adherence thus reducing hospitalizations anddeaths related to heart failure.


application_id: 10498895
project_number: 1R01DK133184-01
project_title: The Role of DENND5B in Dietary Lipid Absorption
administering_ic: NIDDK
award_notice_date: 2022-07-06
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 133184
program_official: SENGER, STEFANIA
project_start_date: 2022-07-15
project_end_date: 2027-05-31
study_section: Nutrition and Metabolism in Health and Disease Study Section[NMHD]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
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_terms:
AGFG1 gene;Acute;Address;Affect;Apolipoproteins B;Atherosclerosis;Autophagocytosis;Biogenesis;Bioinformatics;Blood Circulation;Body Composition;Body mass index;Cardiometabolic Disease;Cardiovascular Diseases;Cell membrane;Cells;Chylomicrons;Co-Immunoprecipitations;Complex;Conscious;Data;Data Set;Dietary Fats;Dyslipidemias;Enterocytes;Equilibrium;Esterification;Exhibits;Fasting;Fat-Soluble Vitamin;Fatty acid glycerol esters;Fistula;Foundations;Genes;Golgi Apparatus;Guanine Nucleotide Exchange Factors;Health;High Fat Diet;Homeostasis;Human;In Vitro;Ingestion;Insulin Resistance;Intestinal Absorption;Intestinal Secretions;Intestines;Knowledge;Link;Lipids;Lipolysis;Lipoproteins;Literature;Lymph;Maintenance;Mass Spectrum Analysis;Measurement;Measures;Membrane Fusion;Metabolic;Metabolism;Methods;Mission;Mitochondria;Modeling;Mucous Membrane;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;Obesity;Organism;Particle Size;Pathway interactions;Peripheral;Plasma;Play;Process;Proteins;Publishing;Regulation;Resistance;Risk Factors;Role;Secretory Vesicles;Sucrose;Tissues;Tracer;Transmembrane Transport;Triglycerides;United States National Institutes of Health;Variant;Very low density lipoprotein;Wild Type Mouse;Work;absorption;base;cardiometabolism;cardiovascular disorder risk;cardiovascular risk factor;cell type;crosslink;diet-induced obesity;dietary;exome sequencing;experimental study;gene network;gene regulatory network;improved;insight;intestinal epithelium;lipid metabolism;mouse model;novel;particle;response;single-cell RNA sequencing;trafficking;transcriptome;uptake


application_id: 10498524
project_number: 1R01HL164398-01
project_title: Targeting GLP-1 receptor as a new chronotherapy against nondipping blood pressure in diabetes
administering_ic: NHLBI
award_notice_date: 2022-06-10
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 164398
program_official: OH, YOUNGSUK
project_start_date: 2022-06-15
project_end_date: 2026-05-31
study_section: Integrative Vascular Physiology and Pathology Study Section[IVPP]
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
project_terms:
ARNTL gene;Agonist;Animals;Antidiabetic Drugs;Bilateral;Blood Pressure;Body Weight;Brain;Cardiovascular system;Chronic Disease;Chronotherapy;Circadian Rhythms;Clinical Trials;Data;Diabetes Mellitus;Diabetic mouse;Duodenum;Eating;FDA approved;Fatty acid glycerol esters;Female;Foundations;Future;GLP-I receptor;Genes;Glycosylated hemoglobin A;Goals;High Fat Diet;Hippocampus (Brain);Hypertension;Hypothalamic structure;Knock-out;Knockout Mice;Knowledge;Light;Link;Literature;Mediating;Messenger RNA;Metabolism;Mus;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Phase;Prognosis;Publications;Regimen;Rest;Risk Factors;Role;Scheme;Sympathetic Nervous System;Time;Time-restricted feeding;Type 2 diabetic;Vagotomy;Vagus nerve structure;blood pressure reduction;cardiovascular risk factor;comorbidity;cost;db/db mouse;diabetic;diabetic patient;effective therapy;exenatide;feeding;gut-brain axis;improved;liraglutide;male;novel;pre-clinical;prevent;protective effect;sex;sexual dimorphism;targeted treatment


application_id: 10498396
project_number: 1RF1AG078338-01
project_title: Function of ceramide in extracellular vesicle-mediated neurodegenerative disease
administering_ic: NIA
award_notice_date: 2022-08-25
opportunity_number: PA-20-185
application_type: 1
activity_code: RF1
ic: AG
serial_number: 078338
program_official: DIBATTISTA, AMANDA
project_start_date: 2022-09-01
project_end_date: 2025-08-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
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:
Alzheimers disease (AD) is characterized by the buildup of Amyloid  (A) peptide and hyperphosphorylatedtau both of which drive neurodegeneration and cognitive decline. There is no clarity as to how A and taudamage neurons. A critical knowledge gap and barrier to progress is the lack of a thorough understanding offactors that may enhance neurotoxicity of A and tau. Our previous studies have shown that in response to Aproduced by neurons astrocytes secrete extracellular vesicles (EVs) or astrosomes which are enriched withthe sphingolipid ceramide and bind to A. We discovered that these A-associated astrosomes (AAAs) induceneurodegeneration in AD which can be prevented by inhibition or deficiency of neutral sphingomyelinase 2(nSMase2) an enzyme that generates ceramide by hydrolysis of the membrane lipid sphingomyelin. Thereforewe hypothesize that ceramide is a key factor mediating AAA formation and neurotoxicity and preventing AAAformation and neurotoxicity by inhibiting ceramide generation is a novel strategy for AD therapy.Our studies showed that improvement of AD pathology and cognition by nSMase2 inhibition or deficiency wereonly detected in male mice indicating that additional enzymes in ceramide metabolism contribute to AAAformation and neurotoxicity independently of nSMase2. Our goal is to define enzymes in ceramide metabolismunderlying a sex-specific dimorphism in AAA formation and neurotoxicity and develop novel drug approachesthat are effective in both sexes.In our Specific Aims we will use novel and innovative approaches particularly using new mouse modelsanalytical techniques and drugs to understand the sex-specific AAA formation and target ceramide metabolismto interfere with the formation of AAAs in astrocytes (Specific Aim 1) and their neurotoxicity in neurons (SpecificAim 2) to prevent AD pathology and improve cognition independent of sex (Specific Aim 3).The impact of our study on public health is to generate knowledge that leads to the development of novel ADtherapies. While the primary focus of our study is ceramide and A in AAAs some identified factors may also beapplicable to the neurotoxicity of tau.

project_terms:
Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease therapy;Amyloid beta-42;Amyloid beta-Protein;Astrocytes;Binding;Carrier Proteins;Cell membrane;Cells;Ceramides;Cognition;Development;Drug Targeting;Endosomes;Enzymes;Female;Gene Expression;Generations;Goals;Hydrolysis;Impaired cognition;Impairment;In Vitro;Knowledge;Lipids;Mediating;Membrane Lipids;Metabolism;MicroRNAs;Mitochondria;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Pathway interactions;Patients;Pharmaceutical Preparations;Proteins;Public Health;Sorting - Cell Movement;Sphingolipids;Sphingomyelinase;Sphingomyelins;Techniques;Testing;Tissues;Vesicle;acid sphingomyelinase;analog;dimorphism;exosome;extracellular vesicles;hyperphosphorylated tau;improved;in vivo;inhibitor;innovation;male;microvesicles;mouse model;neuron loss;neurotoxic;neurotoxicity;novel;novel strategies;novel therapeutics;prevent;pro-apoptotic protein;response;sex;targeted treatment;tau Proteins;uptake

public_health_relevance:
Development of novel therapies to treat Alzheimers disease (AD) by preventing neurodegeneration is beinghampered by the lack of knowledge of what mediates or enhances neurotoxicity of proteins such as Amyloid peptide (A). We have pioneered studies showing that binding of A to vesicles that are enriched with a lipidcalled ceramide tremendously enhances A neurotoxicity. Our goal is to inhibit or disrupt this binding bydeveloping novel drugs that antagonize ceramide to delay the onset of or prevent neurodegeneration in AD.


application_id: 10497938
project_number: 2R01CA157429-09A1
project_title: Overcoming Drug Resistance of Castration-Resistant Prostate Cancer
administering_ic: NCI
award_notice_date: 2022-08-23
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: CA
serial_number: 157429
suffix: A1
program_official: FORRY, SUZANNE L
project_start_date: 2011-09-01
project_end_date: 2027-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
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:
Affect;Androgen Receptor;Androgens;Apoptosis;Automobile Driving;Binding;Biochemical;Biological Markers;Cancer Patient;Castration;Catalytic Domain;Cell Nucleus;Cells;Clinic;Clinical Research;Clinical Trials;Complex;Cytoplasm;Data;Development;Disease;Disease Progression;Drug resistance;EZH2 gene;Enhancers;Epigenetic Process;Event;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Health;Homologous Gene;Investigation;Knock-out;Light;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Mission;Mitotic;Mus;Neuroendocrine Prostate Cancer;Oncogenic;Operative Surgical Procedures;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmacology;Phosphorylation;Polycomb;Prostate;Public Health;Receptor Signaling;Research;Resistance;Resources;Role;Signal Pathway;Signal Transduction;Specimen;System;Testing;Therapeutic;Transcriptional Activation;United States National Institutes of Health;Withdrawal;Work;Xenograft Model;abiraterone;androgen sensitive;base;cancer therapy;castration resistant prostate cancer;design;diagnostic biomarker;effective therapy;enzalutamide;gene repression;genetic approach;improved;inhibitor;innovation;mouse model;mutant;novel;novel marker;novel strategies;patient derived xenograft model;programs;prostate cancer cell;prostate cancer model;prostate cancer progression;success;therapeutic target;tumor


application_id: 10495938
project_number: 1P01AG078116-01
project_title: Project 4 - Astrocytic KATP channels in LATE+HS
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6513
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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_terms:
Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Animal Model;Animals;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Binding;Blood Vessels;Blood flow;Brain;Brain Hypoxia;CRSP3 gene;Calcium;Cerebrovascular Circulation;Cerebrum;Clinical;Collaborations;Data;Dementia;Disease;Dose;EEF1A2 gene;Elderly;Electrophysiology (science);Evaluation;Family;Functional disorder;Gene Expression;Genes;Genetic Variation;Genotype;Glutamates;Goals;Human;Image;Immunohistochemistry;Impairment;Ischemic Preconditioning;Knowledge;Link;Magnetic Resonance Imaging;Measures;Memory impairment;Messenger RNA;Metabolic;Methods;Microscopy;Modeling;Morphology;Mus;Neurons;Nicorandil;Oral;Outcome;Outcome Assessment;Pathologic;Pathology;Persons;Pharmaceutical Preparations;Pharmacology;Physiology;Play;Potassium;Preparation;Proteins;Public Health;RNA Splicing;Reporting;Research;Resources;Risk;Role;Sampling;Signal Transduction;Slice;Stress;Testing;Transcript;Up-Regulation;base;biological adaptation to stress;brain metabolism;cell type;cerebrovascular;data management;disorder control;drinking water;follow up assessment;genetic variant;hippocampal cell loss;hippocampal sclerosis;improved;in vivo;limbic-predominant age-related TDP-43 encephalopathy;member;mouse model;multidisciplinary;neurobehavioral;neurobehavioral test;neuropathology;neurovascular;neurovascular coupling;novel;novel therapeutic intervention;prevent;protein TDP-43;sensor;single-cell RNA sequencing;sulfonylurea receptor;transcriptome sequencing;two-photon;uptake


application_id: 10495937
project_number: 1P01AG078116-01
project_title: Project 3 - Astrocytic glutamate dysregulation in AD and VCID
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6512
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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_terms:
Address;Affect;Alzheimer's Disease;Alzheimer's disease related dementia;Amyloid;Amyloid beta-Protein;Animals;Astrocytes;Attention;Autopsy;Biochemical;Biological Markers;Biostatistics Core;Blood Vessels;Blood flow;Brain;Cerebrovascular Circulation;Cerebrovascular Disorders;Collaborations;Consultations;Data;Dementia;Disease model;Electrophysiology (science);Endothelial Cells;Enterobacteria phage P1 Cre recombinase;Enzymes;Functional disorder;Genes;Glucose;Glucose Transporter;Glutamate Transporter;Glutamates;Human;Hyperhomocysteinemia;Image;Impairment;In Situ;Individual;Insulin Receptor;Intervention;Knowledge;Lactate Transporter;MMP9 gene;Magnetic Resonance Imaging;Measures;Metabolic;Metabolic dysfunction;Metabolism;Microelectrodes;Microvascular Dysfunction;Modeling;Mus;Names;Neurons;Pathology;Pathway interactions;Phenotype;Production;Property;Proteins;Receptor Signaling;Rest;Role;Signal Transduction;Slice;Synapses;Synaptic plasticity;Testing;Tissues;Vibrissae;Work;amyloid pathology;awake;barrel cortex;calmodulin-dependent protein kinase II;cerebrovascular;cerebrovascular pathology;comorbidity;data management;excitotoxicity;extracellular;functional outcomes;hippocampal sclerosis;human tissue;knock-down;loss of function;mouse model;network dysfunction;neural network;neuroinflammation;neurotoxicity;neurovascular coupling;neurovascular unit;overexpression;prevent;restoration;synaptic function;treatment strategy;two-photon;vascular cognitive impairment and dementia;vector


application_id: 10495936
project_number: 1P01AG078116-01
project_title: Project 2 - Astrocytic insulin signaling and AD
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6511
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
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_terms:
Address;Age;Aging;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease related dementia;Amyloid;Astrocytes;Attention;Autopsy;Behavior;Bioenergetics;Biological;Blood - brain barrier anatomy;Blood Vessels;Blood flow;Brain;Cells;Classification;Clinic;Clinical;Cognition;Collaborations;Coupled;Coupling;Data;Data Set;Disease;Electroencephalography;Electrophysiology (science);Elements;Environment;Erythrocytes;Female;Frequencies;Future;Gene Expression Regulation;Glial Fibrillary Acidic Protein;Glucose;Glucose Transporter;Goals;Head;Health;Hippocampus (Brain);Human;Image;Impairment;In Situ;Injections;Insulin;Insulin Receptor;Intention;Investigation;Knockout Mice;Knowledge;Lead;Leadership;Learning;Magnetic Resonance Spectroscopy;Measures;Metabolic;Microscopy;Modeling;Mus;Nerve Degeneration;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway interactions;Physiology;Play;Protocols documentation;Radial;Receptor Signaling;Reporting;Resolution;Resource Sharing;Rest;Rodent;Role;Sampling;Series;Signal Transduction;Site;Slice;Somatosensory Cortex;Specimen;Surface;Testing;Time;Translating;Work;adeno-associated viral vector;aged;amyloid pathology;amyloidogenesis;arm;brain dysfunction;brain metabolism;cell type;cellular targeting;cerebrovascular;cognitive function;data management;density;experience;experimental study;glucose sensor;glucose uptake;in vivo;insulin signaling;knock-down;large datasets;lens;male;memory process;mouse model;multi-electrode arrays;neuronal metabolism;neurovascular unit;novel;overexpression;promoter;rhodamine dextran;sex;spatial memory;targeted treatment;tau Proteins;therapeutic target;two-photon;vector;water maze


application_id: 10495935
project_number: 1P01AG078116-01
project_title: Project 1 - Astrocytic end-feet and VCID
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6510
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
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_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Astrocytes;Autopsy;Basement membrane;Biochemical;Biological Markers;Blood Vessels;Brain;Cerebral small vessel disease;Cerebrovascular Disorders;Complex;Data;Dementia;Dissociation;Dystroglycan;Dystrophin;Electrophysiology (science);Euthanasia;Gene Expression;Gene Expression Profile;Glutamate Transporter;Harvest;Histologic;Human;Hyperhomocysteinemia;Image;Impaired cognition;Impairment;Inflammatory;Insulin;Lasers;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinases;Measurement;Measures;Mediating;Metabolic;Microelectrodes;Microscopy;Monocarboxylic Acid Transporters;Mus;Nerve Degeneration;Neuronal Dysfunction;Neurons;Outcome Measure;Pathology;Perfusion;Plasma;Potassium Channel;Proteins;Radial;Regulation;Slice;Testing;Time;Tissue imaging;Water;Wild Type Mouse;Work;aquaporin 4;arm;awake;candidate marker;cerebrovascular;comorbidity;cytokine;digital;foot;human tissue;in vivo;mouse model;multimodality;neurovascular coupling;novel;object recognition;overexpression;protein expression;syntrophin alpha1;two-photon;vascular cognitive impairment and dementia;vascular injury;water channel;water maze


application_id: 10495934
project_number: 1P01AG078116-01
project_title: Core D - Data Management and Statistics Core
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6509
contact_pi_person_id: 12221415
contact_pi: KATSUMATA, YURIKO
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_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Animals;Astrocytes;Binding;Bioinformatics;Biometry;Biostatistical Methods;Biostatistics Core;Complex;Computers;Data;Data Analyses;Data Analytics;Data Collection;Data Security;Data Set;Data Storage and Retrieval;Data Store;Database Management Systems;Deposition;Directories;Discipline;Educational workshop;Electrophysiology (science);Ensure;FAIR principles;Foundations;Goals;Graph;Human;Individual;Interdisciplinary Study;Language;Linux;Location;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Manuscripts;Metadata;Methodology;Methods;Microelectrodes;Mission;Modeling;Perception;Persons;Phase;Play;Practice Management;Procedures;Proteomics;Pythons;Quality Control;Reporting;Reproducibility;Research;Research Activity;Research Personnel;Research Support;Resource Sharing;Resources;Role;Secure;Series;Services;Standardization;Statistical Data Interpretation;Structure;System;Technology;Time;Training;Writing;analysis pipeline;base;biomedical imaging;data format;data harmonization;data integration;data integrity;data management;data quality;data repository;data reuse;data standards;data warehouse;design;experimental study;large scale data;member;metabolomics;multidisciplinary;predictive modeling;statistics;success;synergism;transcriptomics


application_id: 10495933
project_number: 1P01AG078116-01
project_title: Core C - Human Consultation-Biosamples-Biomarkers Core
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6508
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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_terms:
3-Dimensional;ABCC9 gene;Address;Alzheimer's disease related dementia;Amyloid beta-Protein;Anatomy;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Biochemical;Biochemical Pathway;Biochemistry;Biological Assay;Biological Markers;Blood Vessels;Blood capillaries;Brain;Brodmann's area;CD34 gene;CRSP3 gene;Cerebrospinal Fluid;Clinical;Clinical Research;Complement;Complex;Consultations;Data;Data Management Resources;Dementia;Diagnosis;Documentation;Enzyme-Linked Immunosorbent Assay;Fostering;Freezing;Funding;Genotype;Glial Fibrillary Acidic Protein;Hippocampus (Brain);Human;Image;Immunofluorescence Immunologic;Infrastructure;Insulin Receptor;Label;Liquid substance;Longitudinal cohort;MMP9 gene;Magnetic Resonance Imaging;Measurement;Measures;Methods;Molecular;Morphology;Mus;Neocortex;Neurofibrillary Tangles;Neuropsychology;Participant;Phenotype;Plasma;Proteins;Research;Research Design;Resources;Running;Sampling;Senile Plaques;Structure;Syndrome;Testing;Therapeutic Intervention;Tissues;Translating;Translational Research;Translations;Triton X100;United States National Institutes of Health;Urea;Western Blotting;Work;alpha synuclein;arteriole;biobank;blood oxygen level dependent;cerebrovascular;clinical diagnosis;clinical material;clinical outcome measures;clinically relevant;data modeling;data streams;endophenotype;experimental study;frontal lobe;gray matter;human data;human imaging;human subject;in vivo;meetings;mouse model;multimodal data;neuroimaging;neuropathology;pre-clinical;protein TDP-43;risk variant;sarkosyl;specific biomarkers;synergism;tau Proteins;white matter


application_id: 10495932
project_number: 1P01AG078116-01
project_title: Core B - Animal Vascular-Metabolic-Neural Network Core
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6507
contact_pi_person_id: 10287198
contact_pi: SOMPOL, PRADOLDEJ
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_terms:
Acute;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Animals;Astrocytes;Biological Assay;Biological Markers;Biometry;Biostatistics Core;Blood Vessels;Blood flow;Brain;Brain region;Cells;Cephalic;Cerebrovascular Disorders;Cerebrovascular system;Chronic;Consultations;Craniotomy;Data;Data Analyses;Data Collection;Dementia;Electrophysiology (science);Ensure;Faculty;Gene Delivery;Goals;Human;Human Pathology;Human Resources;Image;Imaging Techniques;Impairment;Injections;Kentucky;Laser Speckle Imaging;Magnetic Resonance Imaging;Metabolic;Metabolism;Methods;Microelectrodes;Microscopy;Monitor;Mus;Neurons;Operative Surgical Procedures;Pathology;Phenotype;Physiological;Physiology;Postdoctoral Fellow;Preparation;Procedures;Process;Property;Protocols documentation;Research;Resources;Role;Services;Signal Pathway;Signal Transduction;Slice;Students;Synaptic Transmission;Synaptic plasticity;Techniques;Testing;Thinness;Training;Universities;Vibrissae;Work;brain cell;brain metabolism;cell type;cerebrovascular;cohesion;cranium;data management;experience;experimental study;imaging facilities;implantation;in vivo;in vivo imaging;intravital imaging;knock-down;molecular pathology;mouse model;neural network;neurochemistry;neuroinflammation;novel;patch clamp;preservation;success;two-photon


application_id: 10495931
project_number: 1P01AG078116-01
project_title: Core A - Administrative Core
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
subproject_number: 6506
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Animals;Astrocytes;Behavioral;Breeding;Budgets;Collaborations;Electrophysiology (science);Ensure;Faculty;Feedback;Fostering;Functional disorder;Funding;Future;Genotype;Health;IACUC;Infrastructure;Leadership;Learning;Maintenance;Memory;Neurons;Nutritional Science;Pharmacology;Production;Progress Reports;Protocols documentation;Reagent;Recombinants;Research;Research Personnel;Resources;Role;Route;Science;Services;Signal Transduction;Source;Time;United States National Institutes of Health;Universities;Update;Viral;Work;animal colony;cohesion;data sharing;meetings;mouse model;professor;success;symposium;vascular cognitive impairment and dementia;welfare


application_id: 10495930
project_number: 1P01AG078116-01
project_title: Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias
administering_ic: NIA
award_notice_date: 2022-08-31
opportunity_number: PAR-19-314
application_type: 1
activity_code: P01
ic: AG
serial_number: 078116
program_official: OPANASHUK, LISA A
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-8 (M4)]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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:
ABCC9 gene;Address;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease related dementia;Amyloid beta-Protein;Animals;Area;Astrocytes;Attention;Autopsy;Awareness;Back;Biochemical Pathway;Biological Markers;Biology;Biometry;Blood Vessels;Brain;Brain Pathology;CRSP3 gene;Cells;Cerebral small vessel disease;Cerebrovascular Disorders;Communities;Complex;Consultations;Data;Dementia;Disease;Electrophysiology (science);Functional disorder;Future;Gene Expression Profiling;Glutamate Transporter;Glutamates;Goals;Grant;Human;Imaging Techniques;Impaired cognition;Impairment;Insulin Receptor;Intervention;Kentucky;Leadership;Liquid substance;MMP9 gene;Magnetic Resonance Imaging;Measures;Metabolic;Microelectrodes;Microglia;Modeling;Mus;Neurons;Pathologic;Pathology;Phenotype;Physiological;Property;Receptor Signaling;Recording of previous events;Renaissance;Research;Resources;Role;Signal Transduction;Statistical Data Interpretation;Structure;Techniques;Technology;Testing;Therapeutic;Time;Tissues;United States National Institutes of Health;Universities;base;cerebrovascular;data management;data pipeline;design;disease phenotype;foot;hippocampal sclerosis;human data;human subject;in vivo;insulin signaling;intravital imaging;knock-down;limbic-predominant age-related TDP-43 encephalopathy;magnetic resonance imaging/electroencephalography;mouse model;neural network;neurochemistry;neuroinflammation;novel therapeutic intervention;overexpression;pre-clinical;pre-clinical research;risk variant;two photon microscopy;vascular cognitive impairment and dementia


application_id: 10495712
project_number: 2R24AI138963-05
administering_ic: NIAID
award_notice_date: 2022-08-30
opportunity_number: PAR-20-063
application_type: 2
activity_code: R24
ic: AI
serial_number: 138963
program_official: BREEN, JOSEPH J
project_start_date: 2018-07-23
project_end_date: 2027-08-31
study_section: Special Emphasis Panel[ZAI1 SB-I (M1)]
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: SMITH, MELISSA LAIRD
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
budget_start_date: 2022-09-01
project_terms:
2019-nCoV;Adaptive Immune System;Adult;Antibodies;Antibody Repertoire;Antibody Response;Antibody-mediated protection;Area;Autoimmunity;Award;B-Lymphocytes;Basic Science;Biomedical Research;Brazil;Catalogs;Clinical;Collection;Communities;Complex;Data;Data Set;Databases;Deposition;Development;Disease;Ensure;European;Foundations;Genbank;Gene Expression Regulation;General Practitioners;Genes;Genetic;Genetic Diseases;Genetic Polymorphism;Genetic Recombination;Genetic Variation;Genome;Genomics;Genotype;Genotype-Tissue Expression Project;HIV;Haplotypes;Health;Human;Human Genome;Human Resources;IGL@ gene cluster;Immune;Immunogenetics;Immunogenomics;Immunoglobulin A;Immunoglobulin G;Immunoglobulin Genes;Immunoglobulin M;Immunoglobulins;Immunologic Receptors;Immunology;Individual;Infection;International;Investigation;Knowledge;Lead;Light;Link;Malignant Neoplasms;Methods;Modeling;Nucleotides;Oceania;Outcome;Population;Population Heterogeneity;Positioning Attribute;Quantitative Trait Loci;Research;Resources;Rheumatic Heart Disease;Role;Sampling;Seeds;Single Nucleotide Polymorphism;South African;Summary Reports;Uganda;Underrepresented Populations;Variant;analysis pipeline;cohort;data access;database of Genotypes and Phenotypes;dbSNP;design;ethnic diversity;frontier;genetic association;genome browser;genomic data;high standard;immunoglobulin light chain locus;improved;novel;precision medicine;reference genome;response;tool;vaccine response


application_id: 10495372
project_number: 5R01MD016236-02
project_title: Researching Equitable Sleep Time (REST) in Appalachia
administering_ic: NIMHD
award_notice_date: 2022-07-11
opportunity_number: PAR-20-164
application_type: 5
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_abstract:
Insufficient sleep (habitual sleep duration of 6 hours) is a costly prevalent public health problem associatedwith numerous negative health outcomes. Prior research suggests that insufficient sleep is more prevalentamong health disparity populations (e.g. racial minorities adults of low socioeconomic status) but ourunderstanding of the mechanisms and consequences of sleep disparities in rural populations is limited. Thepresent study Researching Equitable Sleep Time in Kentucky Communities (REST-KY) focuses onAppalachian adults an NIH-designated health disparity population whose serious health inequities includemultiple health morbidities and premature mortality. Six of the counties with the highest concentration ofinsufficient sleep in the nation are in Central Appalachian Kentucky (KY) where 25-58% of adults reportinsufficient sleep 15+ nights/month. These counties are severely economically distressed yet nearby countieswith comparable economic distress rurality and demographic homogeneity are not hotspots of insufficientsleep. Use of a mixed methods longitudinal design will allow us to evaluate mechanisms contributing to bothsleep deficiencies and health in this rural community. Knowledge gaps include 1) Sparse insights into specificindividual- social- and societal-level factors contributing to sleep deficiencies in Appalachian adults.; 2) It is notknown if regional sleep and health disparities share the same underlying mechanisms; and 3) Critical points ofvariance between hotspot and non-hotspot counties have not been examined. We will recruit a cohort of 400adults from 6 insufficient sleep hotspot counties (n=200) in Appalachian KY and 6 similarly rural andeconomically distressed non-hotspot counties. Recruitment will be stratified across hotspot and non-hotspotcounties by key demographic factors linked to sleep deficiencies (e.g. age sex race/ethnicity) to promote countycluster-level comparisons. Specific Aims. 1. Use mixed methods to compare how individual social and societalfactors linked to sleep deficiencies differ between insufficient sleep hotspot and non-hotspot counties. 2.Evaluate mechanisms driving sleep deficiencies and health outcomes over time. Bi-directional models of sleepand health outcomes will be examined. 3. Quantify day-to-day sleep reactivity (i.e. the degree to which daytimedistress impacts sleep) and test if individual differences in sleep reactivity predict worsened health outcomesover time. Differences by sex and county cluster (hotspot vs. non-hotspot) will also be examined in Aims 2-3.Our multiple sophisticated objective and subjective data collection methods made possible by ourinterdisciplinary teams varied expertise will advance scientific knowledge about biological behavioralemotional and social contributions to sleep health. This holistic approach explicitly acknowledges theinseparable overlap between health function and sleep. Our findings will offer unprecedented insight into the bi-directional relationships between sleep and health in an understudied rural health disparity population. Resultswill inform strategies to reduce sleep disparities thus having strong potential for public health impact.

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 Disparities Research;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;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

public_health_relevance:
PROJECT NARRATIVEWe know that rural residents in the Appalachian region of the Southeastern United States have the nationshighest rates of insufficient sleep (habitual sleep duration 6 hours) but the reasons for this are unclear. Thisissue is particularly concerning as these same rural residents also face substantially higher than average ratesof negative health outcomes including heart disease cancer diabetes obesity depression and substance usedisorders. We will follow a group of Appalachian adults over the course of two years to track their sleepphysical and mental well-being and health behavior (e.g. substance use smoking diet exercise) in order tobetter understand the culturally relevant factors that predict difficulties with both sleep and health in this uniqueand underserved rural population.


application_id: 10495216
project_number: 5R21AI166271-02
project_title: Generation of deletion mutants in any chlamydial species: Quick and easy!
administering_ic: NIAID
award_notice_date: 2022-08-17
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 166271
program_official: VINCENT, LEAH REBECCA
project_start_date: 2021-09-24
project_end_date: 2024-08-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 9776107
contact_pi: WOLF, KATERINA
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
project_abstract:
AbstractMembers of the genus Chlamydia are Gram-negative bacteria that cause various acute as wellas chronic diseases in humans. Although chlamydiae share numerous aspects of their typicalbacterial life style such as intracellular developmental cycle and the preference to primarilyinvade epithelial cells these human pathogens employ sophisticated species-specific strategiescontributing to an extraordinary diversity in tissue tropism and disease manifestation. C.trachomatis infects mucosal surfaces of the human urogenital tract or columnar epithelial cellsof the eye. Chlamydia-mediated genital infections represent the leading cause of bacterial STDsin the United States with 1 758668 infections reported to the CDC in 2018. C. trachomatisisolates are divided into 15 major serovariants. The less invasive isolates which causeinfections of mucosal layers include ocular serovars A B Ba C while serovars D through Kcause sexually transmitted diseases. The lymphogranuloma venereum (LGV) serovars L1 L2and L3 transiently infect epithelial cells but then invade the submucosae to infect macrophageswhich facilitates the dissemination of the bacteria to the regional lymph nodes. Geneticmanipulation of C. trachomatis L2 which has been extensively developed in the last decadesignificantly helped to elucidate how these pathogens interact with their hosts and possiblycause diseases. However in order to discover and understand the mechanism(s) for chlamydia-specific host tropism and pathogenesis outcomes with each chlamydial species it is imperativeto expend molecular genetics technologies to all chlamydial species and strains. We proposehere to optimize a unique recently developed approach for generation of null mutants by allelicexchange via homologous recombination using pUC19 shuttle vector that would be applicableto any member of the genus Chlamydia. We intend to utilize this approach in production ofdeletion mutants in pmpI and pmpD in C. trachomatis serovars L2 D and B. Moreover thepmpI and pmpD will be knocked out in C. mudirarum since this rodent chlamydial species istypically employed in studies investigating chlamydial pathogenesis in vivo. Phenotypicalstudies with pmpI and pmpD chlamydiae with their WT counterparts and complementedstrains will be conducted in various human as well as murine cells cultures in order to identifypossible species-specific and host-specific interactions.

project_terms:
Acute;Algorithms;Alleles;Antibiotics;Bacteria;Bacterial Adhesins;Cell Culture Techniques;Cells;Centers for Disease Control and Prevention (U.S.);Chlamydia;Chlamydia Infections;Chlamydia genome;Chlamydia muridarum;Chlamydia trachomatis;Chlamydiaceae;Chronic Disease;Cloning;Columnar Epithelium;Complement;Development;Disease;Environment;Epithelial Cells;Ethyl Methanesulfonate;Excision;Eye;Family;Future;Gene Silencing;Generations;Genes;Genetic;Genital;Genitalia;Genome;Gram-Negative Bacteria;Human;Infection;Invaded;Knock-out;Life Style;Lymphogranuloma Venereum;Mediating;Methods;Molecular Genetics;Mucous Membrane;Mus;Mutagenesis;Nutrient;Open Reading Frames;Organ;Organism;Outcome;Pathogenesis;Phenotype;Plasmids;Play;Production;Replication Origin;Reporting;Rodent;Role;Sexually Transmitted Diseases;Shuttle Vectors;Site;Stains;Surface;System;Tandem Repeat Sequences;Tropism;United States;Untranslated RNA;draining lymph node;genetic manipulation;genetic technology;genital infection;homologous recombination;human pathogen;immunogenic;in vivo;macrophage;member;mutant;novel;pathogen;preference;pressure;promoter;suicide vector;tissue tropism;urogenital tract;vector

public_health_relevance:
PROJECT NARRATIVE (RELEVANCE)Organisms of the family Chlamydiaceae include significant human pathogens. C. trachomatisserovar L2 which is one of the invasive lymphogranuloma venereum strains the noninvasivegenital serovar D and the ocular strain B and C. muridarum will be employed in generation ofpmpI and pmpD null mutants by allelic exchange via homologous recombination utilizing aunique approach with pUC19 shuttle vector to demonstrate that this novel method can beapplied to any chlamydial species. Phenotypical studies with pmpI and/or pmpD are verylikely to reveal a distinctive role(s) these Pmps may play during attachment invasion and/ordevelopment of Chlamydia.


application_id: 10493352
project_number: 5R21AI159194-02
project_title: Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection
administering_ic: NIAID
award_notice_date: 2022-08-04
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 159194
program_official: BAQAR, SHAHIDA
project_start_date: 2021-09-22
project_end_date: 2024-08-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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:
Enterotoxigenic Bacteroides fragilis (ETBF) has been associated with acute diarrhealinflammatory bowel disease and colorectal cancer (CRC). ETBF oncogenesis requires thecoordinated action of its toxin BFT and an inflammatory response to orchestrate the recruitmentof myeloid cells but how ETBF recruits colonic myeloid cells remains poorly understood. S1p actsas bioactive sphingolipid messengers influencing the myeloid cells migration and regulatingcolonic inflammation. However whether ETBF integrates sphingolipid metabolites to determinethe metabolism of colonic myeloid cells needs to be explored. Recent evidence indicates thatremodeling of myeloid cells metabolism is central to the induction of innate immune response.We found ETBF infection alters the activity of sphingosine kinase which is linked to metabolicremodeling histone acetylation and PGE2 production in myeloid cells. Two integrated specificaims are proposed to test: Aim 1 will determine how ETBF infection regulates inflammatorymyeloid cells accumulation in the colon. Aim 2 will determine if ETBF alteration of acetyl-CoAcontributes to metabolic remodeling in myeloid cells via PPAR activation. Deeper understandingof the proper role of sphingolipids and their enzymes in controlling the intestinal immuneproperties and in promoting the pathogenesis and progression of colitis will generate newperspectives in the development of sphingolipid-centered therapeutic strategies that control theonset and perpetuation of the ETBF-induced gut inflammation.

project_terms:
Acetyl Coenzyme A;Acute Diarrhea;Anaerobic Bacteria;ApcMin/+ mice;Bacteroides fragilis;Cell Proliferation;Cell physiology;Cells;Cellular Metabolic Process;Ceramidase;Ceramides;Colitis;Colon;Colonic inflammation;Colorectal Cancer;Data;Development;Diet;Dinoprostone;Disease;Environment;Enzymes;Epithelial;Epithelial Cells;Fatty Acids;General Population;Genes;Histone Acetylation;Human;ITGAM gene;Immune;Infection;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Innate Immune Response;Interleukin-17;Intestines;Lead;Link;Lipids;Liver;Lymphocyte Function;Metabolic;Metabolism;Modeling;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Nuclear;PPAR gamma;PTGS2 gene;Pathogenesis;Pathway interactions;Phosphorylation;Production;Property;Proteins;Reaction;Regulation;Role;Shapes;Signal Transduction;Sphingolipids;Sphingosine;Steroids;Testing;Therapeutic;Toxin;Translating;blood glucose regulation;cell motility;colon tumorigenesis;dietary sphingolipids;extracellular;gene induction;granulocyte;gut bacteria;gut dysbiosis;gut inflammation;histone modification;intestinal epithelium;lipid metabolism;microbial;migration;monocyte;new therapeutic target;polarized cell;promoter;recruit;response;sphingosine 1-phosphate;sphingosine kinase;tumorigenesis

public_health_relevance:
Project NarrativeThis proposal provides the basis for a better understanding of the mechanisms for enterotoxigenic Bacteroidesfragilis-triggered gut inflammation and may lead to the identification of novel therapeutic targets.


application_id: 10493127
project_number: 5R01AG072797-02
project_title: Novel precision medicine approach to treatment of osteoporosis based on bone turnover
administering_ic: NIA
award_notice_date: 2022-08-25
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: AG
serial_number: 072797
program_official: JOSEPH, LYNDON
project_start_date: 2021-09-30
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-S(02)M]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
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_terms:
Achievement;Adult;Affect;Age;Age-Related Bone Loss;Age-Related Osteoporosis;Alendronate;American;Anabolic Agents;Biological Assay;Biopsy;Blood;Bone Density;Bone Resorption;Bone marrow biopsy;Complement;Data;Diagnosis;Disease;Dual-Energy X-Ray Absorptiometry;Effectiveness;Elderly;Enrollment;Estrogens;Familiarity;Female;Forteo;Fracture;Gold;Health;Hematologist;Histology;Hospitalization;Life;Measurement;Measures;Medicare;Menopause;Methods;Myocardial Infarction;Osteocalcin;Osteogenesis;Osteoporosis;Osteoporotic;Outcome;Patients;Pharmaceutical Preparations;Physicians;Population;Quality of life;Randomized;Regimen;Serum;Societies;Stroke;Techniques;Testing;Therapeutic;Training;Treatment Protocols;Validation;Woman;age related;aging population;base;bisphosphonate;bone;bone loss;bone mass;bone turnover;burden of illness;carboxylate;comparison group;design;improved;individualized medicine;malignant breast neoplasm;mortality;normal aging;novel;osteoporosis with pathological fracture;personalized approach;precision medicine;prospective;standard of care;success;tool


application_id: 10492898
project_number: 1U24GM146576-01
project_title: University of Kentucky SuRE Resource Center
administering_ic: NIGMS
award_notice_date: 2022-09-02
opportunity_number: PAR-21-227
application_type: 1
activity_code: U24
ic: GM
serial_number: 146576
program_official: BASKIR, RUBIN SAM
project_start_date: 2022-09-05
project_end_date: 2027-08-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (RC)]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: MURPHY, MICHAEL PAUL
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
project_terms:
Applications Grants;Area;Authorship;Award;Biomedical Research;Communication;Communities;Consultations;Data;Educational workshop;Employment;Ensure;Face;Faculty;Feedback;First Independent Research Support and Transition Awards;Fostering;Funding;Goals;Grant;Growth;Individual;Infrastructure;Institution;Kentucky;Knowledge;Link;Marketing;Measures;Mentors;Methods;Minority-Serving Institution;Modality;National Institute of General Medical Sciences;Outcome;Population;Preparation;Process;Publications;Questionnaires;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Schools;Science;Seeds;Series;Services;Site;Students;Training;United States;United States National Institutes of Health;Universities;Writing;base;career;college;expectation;experience;faculty mentor;faculty support;human disease;meetings;next generation;peer;programs;skills;social media;student conference;student mentoring;success;symposium;webinar


application_id: 10492483
project_number: 5R01HG011598-02
project_title: Utility of Genomic Sequencing in Community Care Contexts
administering_ic: NHGRI
award_notice_date: 2022-07-08
opportunity_number: PAR-20-254
application_type: 5
activity_code: R01
ic: HG
serial_number: 011598
program_official: STERLING, RENE
project_start_date: 2021-09-22
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-SEIR-S(80)S]
contact_pi_person_id: 10692185
contact_pi: BROTHERS, KYLE BERTRAM
other_pis: COOPER, GREGORY MICHAEL
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_abstract:
PROJECT SUMMARY/ABSTRACTEfforts to translate genomic sequencing technologies into clinical care have faced ongoing challenges definingand measuring utility. Evaluation of utility (and disutility) is particularly difficult in the context of efforts totranslate genomic sequencing technologies like exome sequencing (ES) and genome sequencing (GS) to thediagnosis of children with undiagnosed genetic conditions since these conditions are rarely responsive topharmacological interventions and parents often express a wide variety of reasons for wanting a genomicdiagnosis for their child. We hypothesize that previous efforts to identify the effects (positive negative andneutral) of ES and GS have missed important dimensions of utility that fall in the middle ground betweenconventional notions of clinical and personal utility. Most of the care and services that improve functioning andquality of life for children with complex genetic conditions occur outside doctors offices: physical therapy;occupational therapy; speech-language pathology; behavioral intervention and other mental healthcare; andspecial education services. However it is unknown whether receiving a genomic diagnosis currently providesutility or disutility in these community contexts and what evidence might be needed to increase utility andminimize disutility. This project will address this gap through a rigorous study of potential and actual effects thatchildren with undiagnosed genetic conditions might experience in community settings as a result of receiving agenomic diagnosis. The overall aim of this study is to identify (1) community-based utilities currently beingrealized following genomic diagnosis (2) perspectives of community-based professionals regarding thepotential utility of such diagnoses and (3) sources of information (including medical professionals parentsupport groups and social media) that might support utility for rare genetic conditions.

project_terms:
Address;Advisory Committees;Area;Behavior;Behavior Therapy;Caregivers;Caring;Child;Child Care;Childhood;Clinical;Communities;Complex;Diagnosis;Dimensions;Disease;Evaluation;Face;Family;Focus Groups;Future;Genetic;Genetic Diseases;Genomics;Health;Health Personnel;Healthcare;Impairment;Intervention;Interview;Language;Measures;Medical;Mental Health;Mental Health Services;Musculoskeletal;National Human Genome Research Institute;Occupational Therapist;Occupational Therapy;Operative Surgical Procedures;Parents;Pathologist;Pharmacology;Physical therapy;Preventive service;Professional Practice;Quality of life;Research;Resources;Schools;Sensory;Services;Shapes;Site;Source;Special Education;Speech;Speech Therapy;Speech-Language Pathology;Structure;Support Groups;Technology;Testing;Therapeutic;Translating;Underserved Population;base;care systems;clinical application;clinical care;clinical diagnostics;clinical research site;cohort;community based service;community setting;exome sequencing;experience;falls;family support;genetic testing;genome sequencing;improved functioning;physical therapist;policy implication;rural underserved;social implication;social media;teacher

public_health_relevance:
PROJECT NARRATIVEFamilies with children who have identified deficits in speech and/or sensory or musculoskeletal impairmentswithout a known cause may be referred for genetic testing to find out whether there is a genetic cause.However there is little research into how parents and caregivers use this diagnosis to inform decisions abouttherapeutic services access to school services or how a genomic diagnosis informs the practice of thecommunity professionals who provide these services. This project will examine how a genomic diagnosisshapes the care that children receive from community professionals including physical and occupationaltherapists speech-language pathologists special education teachers behavior analysts and mental healthproviders.


application_id: 10492101
project_number: 2P20GM125504-06
administering_ic: NIGMS
award_notice_date: 2023-02-27
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 5336
contact_pi_person_id: 10933857
contact_pi: TENG, YUN
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
budget_start_date: 2023-03-01
project_title:
Edible Plant-derived exosome-like nanoparticles (ELNs) and phage inhibit brain inflammation by targeting microglia and  gut microbiota

project_abstract:
Project Summary/AbstractIncreasing blood-brain barrier (BBB) permeability contributes to the speed of the aging process and theprogression of the development of age-related diseases. Microglia-mediated inflammation is a key element inthe development of BBB permeability which results in brain injury and promotes the progression of many braindiseases. Restoring impaired BBB function by targeting microglial cells without inducing side effects wouldtherefore be a major advance. Compelling evidence shows that healthy edible plants have importantphysiological roles for normal brain function and can prevent neuroinflammatory processes without side-effects.Turmeric root and ginger used in medicines for centuries display a multitude of health benefits includinginhibiting the progression of Alzheimers disease. We have shown that exosome-like nanoparticles (ELNs) fromturmeric root (TELNs) are selectively taken up by microglial cells and their constituent microRNAs inhibit theexpression of aging related inflammatory sensome genes including S100A8 and TLR4 thus enhancing BBBfunction. Additionally S100A8 is induced by metabolites isoamylamine (IAA) and crotonic acid (CA) releasedfrom the bacterial family Ruminococcaceae which is overgrown in aged mice due to a reduction of the Myoviridaefamily phages. ELNs from ginger (GELNs) can inhibit the growth of Ruminococcaceae reduce the levels of IAAand CA thus decreasing sensome inflammation as well as increasing expression tight junction genes Cldn5 andOcln in endothelial cells. In this study we will provide cellular and molecular insight into how ELNs modulatebrain function via the gut-brain axis by targeting microglial cells and the Ruminococcaceae to the benefit of thebrain. Our hypothesis is that impaired brain function in aged mice can be restored by TELNs and GELNsand gut bacterial phages through inhibition of expression of sensome proinflammatory genes andreduction in production of IAA and CA from Ruminococcaceae. We will test our hypothesis through twospecific aims. (1) We will investigate the role of the S100A8/TLR4 pathway targeted by TELN microRNAs inrecovery from cognitive decline in aged mice; (2) We will determine whether oral administration of GELNs andMyoviridae family phages has a beneficial effect on improving cognitive decline through reducing the productionof IAA and CA metabolites from Ruminococcaceae. The Aims will be performed in a mouse model that mimicsthe human aging process. The completion of this study will lead to identification of new therapeutic targets andpotential for the development of ELN based interventions for treating BBB permeability and brain inflammation.In addition the findings will provide a foundation to further study whether oral administration of customized ELNsisolated from different plants will have a synergistic/additive effect with gut beneficial phages in preventing ortreating chronic inflammatory brain related diseases.

project_terms:
Acids;Aging;Alzheimer's Disease;Apoptosis;Bacteriophages;Blood - brain barrier anatomy;Brain;Brain Diseases;Brain Injuries;Chronic;Communication;Data;Development;Disease;Edible Plants;Effectiveness;Elements;Encephalitis;Endothelial Cells;Family;Foundations;Gene Expression;Genes;Ginger;Goals;Growth;Growth Factor;Health Benefit;Human;Impaired cognition;Impairment;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Intervention;Intranasal Administration;Learning;Mediating;Medicine;Memory;MicroRNAs;Microglia;Modeling;Molecular;Mus;Myoviridae;Neurons;Oral;Oral Administration;Pathogenicity;Pathway interactions;Physiological;Plants;Prevention strategy;Process;Production;Publishing;Reporting;Role;Route;S100A8 gene;Shapes;Speed;Surface;Synaptic plasticity;TLR4 gene;Testing;Tight Junctions;Tumeric;age related;aged;blood-brain barrier crossing;blood-brain barrier function;blood-brain barrier permeabilization;brain dysfunction;cell age;cognitive recovery;exosome;gut dysbiosis;gut microbiota;gut-brain axis;improved;in vivo;insight;microbial;microbiome research;mouse model;nanoparticle;nerve stem cell;neuroinflammation;neuronal survival;new therapeutic target;novel;oligodendrocyte precursor;precursor cell;prevent;receptor;side effect


application_id: 10492099
project_number: 2P20GM125504-06
project_title: Regulation of LPS structure and function in Porphyromonas gingivalis
administering_ic: NIGMS
award_notice_date: 2023-02-27
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 5334
contact_pi_person_id: 14927473
contact_pi: MORADALI, FATA
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:
Project Summary/AbstractPeriodontitis is a highly prevalent infectious inflammatory disease of the tissues supporting the teeth that canlead to tissue destruction formation of a deep periodontal pocket alveolar bone resorption and tooth loss.Etiological models suggest that periodontitis is driven by a synergistic community of virulent bacteria that triggerhost inflammatory responses in the gingival tissues resulting in disease progression. Among recognizedpathogens the Gram-negative anaerobe Porphyromonas gingivalis (Pg) has been strongly implicated inperiodontitis. Lipopolysaccharide (LPS) macromolecules produced by Pg strains have been repeatedly shownto stimulate pro-inflammatory innate immune responses. Intriguingly Pg strains can diversify the structure ofLPS in response to biologically relevant stimuli to temporarily disguise themselves evade the immune systemprotect from stresses and promote survival. Accordingly at least four LPS variants have been identified in Pgstrains that may act as agonists or antagonists in the interaction with the innate immune system. Agonistic LPSplays prominent roles in the pathological outcome of infection by being involved in the activation of TLR signalingpathways leading to production of proinflammatory cytokines tissue destruction and bone resorption. Howeverwe do not yet know the mechanisms of the regulation of LPS heterogeneity and its biological importance duringpathogenesis. We discovered that Pg strains possess a c-di-AMP signaling mechanism in which the c-di-AMPsynthase PGN_0523 (dacpg) and the c-di-AMP phosphodiesterase PGN_0521 (pdepg) control the essentialturnover of c-di-AMP and consequently LPS heterogeneity and virulence potential. This study will investigatehow c-di-AMP turnover regulates the heterogeneity and immunomodulatory properties of Pg LPS using in vitroand in vivo models. To this end two independent but related specific aims are proposed: Specific Aim 1: Tounderstand how c-di-AMP-controls heterogeneity of LPS in Pg. Specific Aim 2: To understand the impact of c-di-AMP-dependent variation of LPS on the innate immune response. Upon completion of the proposed studieswe will learn how c-di-AMP signaling controls Pg LPS heterogeneity and determines the innate immuneresponses. Since c-di-AMP signaling does not exist in humans it is a potential novel druggable target. Ourfindings will inform the discovery of potent antagonistic LPS isoforms as a foundation for development of anti-inflammatory therapeutics.

project_terms:
Adenosine;Adenosine Monophosphate;Adult;Agonist;Anaerobic Bacteria;Anti-Inflammatory Agents;Applications Grants;Bacteria;Biological;Bone Resorption;Cell membrane;Cell physiology;Cells;Chemical Structure;Chronic;Communities;Cytoprotection;Data;Detection;Development;Disease;Disease Progression;Equilibrium;Etiology;Foundations;Genes;Gingiva;Heterogeneity;Human;Immune;Immune Evasion;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Innate Immune System;Learning;Lipopolysaccharides;Membrane;Microinjections;Modeling;Molecular;Mus;Outcome;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Periodicity;Periodontal Pocket;Periodontitis;Play;Porphyromonas gingivalis;Production;Property;Protein Isoforms;Regulation;Role;Serum;Signal Pathway;Signal Transduction;Stimulus;Stress;Structure;System;Systemic disease;TLR4 gene;Therapeutic;Tissues;Toll-like receptors;Tooth Loss;Tooth structure;Variant;Virulence;Virulence Factors;Virulent;alveolar bone;antagonist;cytokine;immunoregulation;in vitro testing;in vivo Model;in vivo evaluation;macromolecule;microbiome research;mutant;new therapeutic target;pathogen;pathogenic bacteria;phosphoric diester hydrolase;receptor;response


application_id: 10492098
project_number: 2P20GM125504-06
project_title: Functional Microbiomics Core
administering_ic: NIGMS
award_notice_date: 2023-02-27
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 5333
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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:
Project Summary/AbstractIn this Phase 2 of the Functional Microbiomics Inflammation and Pathogenicity COBRE the primary goal of theFunctional Microbiomics Core (FMC) is unchanged. We will sustain and enhance the well-established integratedservice center that functions as a critical resource for the Research Project Leaders (RPLs) as a priority andsecondarily for all investigators of the Center. Since all new COBRE projects also utilize mouse models to explorethe inter-relationships between inflammation and pathogenesis and the contribution of microbiota to thisprocess our well-established germ-free and gnotobiotic mice facility (GMF) will continue to play a central role inservices provided by the FMC. We will continue to provide anaerobic culturing of mixed and/or mono bacterialstrains to facilitate the specific colonization of the germ-free mice. 16S ribosomal DNA will be profiled with thein-house developed Oxford nanopore sequencing as well as PacBio-long read sequencing tools andbioinformatic support provided. Our most extensively used resource; multiplex-based analysis of inflammatorymediators in biological samples will continue to function using the Bio-Plex 200 (Bio-Rad) multiplex system. Inaddition several recent advances allow us to augment the services provided by the FMC. First the recentlydeveloped highly successful rederivation service of transgenic and KO mouse models as germ-free will greatlyexpand the scope and utility of the GMF. Related to this service is the development of a new area of researchon the role of microbiota in Alzheimers Disease (AD) supported by an administrative supplement to the FMCfrom NIA/NIGMS. The GMF has already rederived several AD mouse models. For this project the FMC alsodeveloped a suite of mouse behavior analysis models including the Morris Water Maze and Novel ObjectRecognition tests. These services will support all future ageing related research at the center including a newproject on the role of edible-plant derived exosomes in restoring the integrity of the Blood Brain Barrier. We alsonow include imaging support in particular Multiphoton Intravital Microscopy for imaging of live tissue and an InVivo Imaging System (IVIS) for live mouse imaging. Besides functioning as a service center another major goalof the FMC is to promote the education and training of researchers primarily the RPLs. The FMC will also interactwith other Core facilities at the University of Louisville such as the Genomics Metabolomics and Bioinformaticscore facilities established with the support of other highly successful COBRE/INBRE programs. In particular thenewly funded Cancer Immunology and Immunotherapy COBRE-operated Functional Immunomics Core (FIC)facility also directed by Dr. Bodduluri has several joint initiatives with the FMC including the establishment of ahistopathology service center. The FMC will work with these and other UofL resources in order to avoidduplication of equipment and to train individual investigators in specific protocols foster innovative protocoldevelopment and integrate analysis of data.

project_terms:
3xTg-AD mouse;Administrative Supplement;Adopted;Aging;Alzheimer's Disease;Area;Award;Behavior;Bioinformatics;Biological;Blood - brain barrier anatomy;Breeding;Centers of Research Excellence;Core Facility;Data Analyses;Dedications;Derivation procedure;Development;Edible Plants;Equipment;Extramural Activities;Fee-for-Service Plans;Fostering;Funding;Future;Genomics;Germ-Free;Gnotobiotic;Goals;Histopathology;Housing;Image;Individual;Inflammation;Inflammation Mediators;Infrastructure;Institution;Joints;Knockout Mice;Laboratories;Mentors;Methodology;Mission;Modeling;Mus;National Institute of General Medical Sciences;Pathogenesis;Pathogenicity;Phase;Play;Process;Protocols documentation;Research;Research Personnel;Research Project Grants;Research Support;Resources;Ribosomal DNA;Role;Sampling;Services;System;Techniques;Testing;Tissues;Training;Training and Education;Transgenic Organisms;Translational Research;Universities;Whole Organism;Work;animal facility;cancer immunotherapy;clinical translation;exosome;experimental study;imaging facilities;in vivo imaging system;innovation;intravital microscopy;metabolomics;microbiome research;microbiota;microscopic imaging;morris water maze;mouse model;multi-photon;nanopore;novel;object recognition;programs;protocol development;success;synthetic polymer Bioplex;tool;tumor immunology


application_id: 10492097
project_number: 2P20GM125504-06
project_title: FMIP COBRE Administrative Core
administering_ic: NIGMS
award_notice_date: 2023-02-27
opportunity_number: PAR-19-312
application_type: 2
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C2)]
subproject_number: 5332
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
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:
Project Summary/AbstractThe University of Louisville (UoL) COBRE in Functional Microbiomics Inflammation and Pathogenicity (FMIP)comprises a multidisciplinary group of investigators addressing thematic aspects that span the humanmicrobiome host inflammatory responses and disease outcomes. The purpose of the Administrative Core is toprovide a formal governance structure for the administrative fiscal and scientific oversight of this Phase 2COBRE. Following on from the success of Phase 1 we are well-positioned to transition to Phase 2 and maintaina coordinated and efficient administrative structure. The departments of Oral Immunology and InfectiousDiseases (OIID) and Microbiology and Immunology (M&I) are the main contributors to the cross-disciplinarynature of the program. These units have established records of federal funding mentoring junior facultygraduate student training and collaborative interactions across campus. We will continue mutually supportivehorizontal interactions with other NIH-funded programs at UoL including the Hepatobiology and ToxicologyCOBRE and the KY-INBRE which will enhance the overall research profile of UoL. The activities of the COBREwill help recruit retain and diversify the faculty. The application is led by well-qualified and well-funded CenterDirectors. Governance and evaluation are supported by an Internal Advisory Committee (IAC) and an ExternalAdvisory Committee (EAC) comprised of five international experts in the thematic area of research. There arethree outstanding Research Project Leaders (RPLs) with senior established funded mentoring teams with atrack record in developing the careers of junior faculty through to independent funding status and further careerdevlopment. We have developed comprehensive mentoring and career development plans with milestones andevaluative metrics. Similarly mentors and the COBRE program are evaluated formatively and summatively. Wehave a strong commitment of support from the UoL which will ensure sustainability beyond the NIH-fundedperiod. The Specific Aims are: to provide the formal governance structure which allows coordination directionand prioritization of all activities including budget issues thus ensuring the quality of all functions and growth ofresearch goals; to administer the process for mentoring and career development of junior faculty and acceleratetheir transition to independence; coordination of the evaluative processes of the COBRE by the IAC and EAC;budget management including budget reconciliation and preparing and submitting RPPRs and FFRs; resolutionof any conflicts as they arise; management of mechanisms to replace RPLs as they become independent andreplacement other key personnel as necessary; administration of the Pilot Program to help maintain a pipelineof investigators; coordination of institutional support; support of clinical translational and commercializationpotential of research projects; provision of biostatistical support; to disseminate pertinent information resultingfrom the COBRE activities; and ensuring compliance with all relevant regulations and guidelines. All projectsand cores will utilize the Administrative Core.

project_terms:
Acceleration;Address;Administrative Efficiency;Advisory Committees;Area;Biometry;Book Chapters;Budgets;Cancer Center;Centers of Research Excellence;Clinical;Collaborations;Communicable Diseases;Credentialing;Development;Development Plans;Disease Outcome;Ensure;Evaluation;Evaluation Research;Faculty;Funding;Goals;Grant;Growth;Guidelines;Human Microbiome;Human Resources;Immunology;Inflammation;Inflammatory;Inflammatory Response;Institution;International;Journals;Leadership;Mentors;Microbiology;Nature;Pathogenicity;Phase;Pilot Projects;Positioning Attribute;Preparation;Process;Qualifying;Records;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Resolution;Services;Structure;Toxicology;United States National Institutes of Health;Universities;Work;Writing;cancer immunotherapy;career;career development;commercialization;data acquisition;expectation;experience;faculty mentor;graduate student;meetings;microbiome research;multidisciplinary;oral immunology;oral infection;programs;recruit;student training;success;symposium;tumor immunology


application_id: 10491743
project_number: 5F32DE031493-02
project_title: Folate-Modulated Virulence of Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2022-08-23
opportunity_number: PA-21-048
application_type: 5
activity_code: F32
ic: DE
serial_number: 031493
program_official: SARE, RACHEL
project_start_date: 2021-09-30
project_end_date: 2024-09-29
study_section: ZDE1-JK(04)
contact_pi_person_id: 15681725
contact_pi: STOCKE, KENDALL
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:
Periodontal disease one of the most common infections of humans is driven by pathogens that influence thecomposition and trajectory of the oral polymicrobial community. These pathogens can take hold in an inhospitableenvironment and pave the way for other organism to colonize and grow. A key factor in allowing a pathogen toestablish itself and colonize despite these odds is successfully regulating the expression of virulence factorswhile acquiring enough essential nutrition for replication and growth. One such essential nutrient is folate whichis classically linked to modulation of virulence in microbes. Although the literature has shown that limiting folateavailability leads to decreased virulence in many microbes however we have found a clear exception to thisrule in the periodontal pathogen P. gingivalis an asaccharolytic organism that uses an amino-acid basedmetabolism. As a model for studying how folate availability regulates virulence in asaccharolytic pathogens weare investigating how restricting the ability of P. gingivalis to produce folate regulates its expression of virulencefactors. The objectives of this study are to: i) define the metabolic phenotype of P. gingivalis induced by folatedeficiency; ii) determine how the metabolic phenotype of P. gingivalis is associated with the expression ofvirulence factors; and iii) characterize the host immune response to folate-deficient P. gingivalis. The completionof this study will provide critical insight into how limiting folate availability does not universally suppress thevirulence of pathogens but has the potential to result in enhanced virulence in asaccharolytic pathogens. Wewill also provide novel information on how the flux of metabolites in the folate and one-carbon metabolic pathwaysare associated with virulence in P. gingivalis and how this could apply to other organisms utilizing non-carbohydrate based metabolisms. Our overall long-term goal is to apply these findings to refine when it isappropriate to use antifolates to treat microbial infections and reduce overall harm caused to patients. Furtherthese findings will help narrow down alternative pathways to target treatments for infections caused byasaccharolytic pathogens.

project_terms:
Abscess;Alveolar Bone Loss;Amino Acids;Antibiotics;Aspergillus fumigatus;Bacteria;Carbon;Communities;Complex;Development;Disease;Environment;Folic Acid;Folic Acid Antagonists;Folic Acid Deficiency;Gene Expression;Goals;Growth;Human;Immune response;Infection;Infection prevention;Innate Immune Response;Link;Literature;Measures;Metabolic;Metabolic Pathway;Metabolism;Microbe;Modeling;Mus;NADH;NADP;Neutrophil Infiltration;Nutrient;Nutritional;Oral;Oral cavity;Organism;Pathogenicity;Pathway interactions;Patients;Peptide Hydrolases;Periodontal Diseases;Porphyromonas gingivalis;Production;Property;Purines;Pyrimidines;Reaction;Reporting;Series;Streptococcus gordonii;Streptococcus pneumoniae;Study models;Sulfonamides;Thromboplastin;Trimethoprim;Virulence;Virulence Factors;Virulent;antimicrobial;bacterial metabolism;base;chemokine;co-infection;cytokine;dihydrofolate;experimental study;folic acid metabolism;gene synthesis;gingipain;insight;metabolic phenotype;metabolomics;microbial;mouse model;mutant;novel;nutrition;pathogen;periodontopathogen;synthetic enzyme;transcriptome sequencing

public_health_relevance:
Periodontal diseases amongst the most common infections suffered by humans are caused by oral bacterialspecies working synergistically to enhance overall pathogenicity. This study aims to understand how thevirulence of an asaccharolytic periodontal pathogen P. gingivalis is modulated by folate availability.Understanding how asaccharolytic pathogens responds to folate deficiency is critical to development of novelantimicrobial tactics to prevent infections by these organisms.


application_id: 10491275
project_number: 5R01AA027990-03
project_title: Estradiol Effects on Behavioral and Reward Sensitivity to Alcohol across the Menstrual Cycle
administering_ic: NIAAA
award_notice_date: 2022-08-20
opportunity_number: PA-19-055
application_type: 5
activity_code: R01
ic: AA
serial_number: 027990
program_official: AKBAR, MOHAMMED
project_start_date: 2020-09-25
project_end_date: 2025-08-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: MARTEL, MICHELLE M
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/ABSTRACTAlcohol use poses significant health problems particularly when characterized by bouts of heavy consumption(i.e. binges). It is now recognized that women demonstrate greater vulnerability to the adverse effects ofalcohol including greater physiological risk of organ damage (e.g. liver cirrhosis) than do men withcomparable histories of alcohol use. Research suggests that ovarian hormones play a role in substance abuse.With regard to alcohol use there is evidence to suggest that women may exhibit distinct patterns of heavydrinking across the menstrual cycle. Indeed our preliminary research shows that surges in follicular estradiol[E2] at ovulation predict increased alcohol use in young women. Yet to date no research has aimed todetermine the specific behavioral mechanisms by which rapid surges in E2 confer increased abuse potential ofalcohol. The proposed study directly examines ovarian hormone flux and acute sensitivity to alcohol to providethe first rigorous and integrative test of the hypothesis that rapid rises in estradiol increase the acute rewardingand disinhibiting effects of alcohol and that this heightened sensitivity increases alcohol use outside thelaboratory. A sample of 100 naturally-cycling women will be examined daily over their menstrual cycle using anintegrative combination of daily ecological assessments of hormone fluctuations and alcohol use along withstrategically-timed laboratory tests of their acute sensitivity to the rewarding and disinhibiting effects of acontrolled dose of alcohol. The findings will advance understanding of the neurobehavioral mechanismslinking E2 to alcohol abuse and inform clinical assessment practice by highlighting the importance of menstrualcycle phase and hormonal profiles when assessing alcohol abuse risk in young women.

project_terms:
Acute;Adverse effects;Affect;Alcohol abuse;Alcohol consumption;Alcohols;Animal Experimentation;Area;Behavior;Behavioral;Behavioral Mechanisms;Clinical assessments;Consumption;Data;Data Reporting;Dose;Estradiol;Estrogens;Exhibits;Female;Grain;Health;Heavy Drinking;Hormonal;Hormones;Impulsivity;Intervention;Investigation;Laboratories;Link;Liver Cirrhosis;Longitudinal Studies;Maintenance;Measures;Menstrual cycle;Neurobiology;Oral Contraceptives;Organ;Ovarian hormone;Ovulation;Ovulation Prediction;Patient Self-Report;Pattern;Periodicity;Phase;Physiological;Placebos;Play;Progesterone;Puberty;Public Health;Recording of previous events;Relapse;Research;Rewards;Risk;Risk-Taking;Role;Saliva;Sampling;Sex Behavior;Sex Differences;Substance abuse problem;Testing;Theoretical model;Visit;Woman;Work;abuse liability;alcohol abuse therapy;alcohol craving;alcohol effect;alcohol sensitivity;alcohol use disorder;binge drinking;craving;disorder later incidence prevention;drinking behavior;men;neurobehavioral;personalized intervention;proliferative phase Menstrual cycle;reproductive;sexual assault;theories;university student;young adult;young woman

public_health_relevance:
The proposed research aims to determine the behavioral mechanisms by which ovulatory surges in estradiolincrease alcohol use in young women by increasing their sensitivity to the rewarding and disinhibiting effects ofalcohol that promote patterns of binge drinking. The research will provide important new information on howcertain hormonal phases such as those linked with estradiol surges can challenge relapse prevention andother alcohol treatment efforts in young women with alcohol use disorders.


application_id: 10491252
project_number: 5R01AA029798-02
project_title: Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
administering_ic: NIAAA
award_notice_date: 2022-07-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AA
serial_number: 029798
program_official: RADAEVA, SVETLANA
project_start_date: 2021-09-22
project_end_date: 2026-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
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_terms:
Affect;Alcoholic Liver Diseases;Alcohols;Animal Model;Apoptosis;Attenuated;Automobile Driving;CYP2E1 gene;Cell model;Cell physiology;Cessation of life;Complex;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cytochrome P450;Data;Development;Disease;Enzymes;Ethanol;FDA approved;Fatty Acids;Fatty Liver;Genes;Goals;H19 gene;HIF1A gene;Heavy Drinking;Hepatic;Hepatitis;Hepatocyte;Hydrolysis;Impairment;In Vitro;Inflammatory;Injury;Knockout Mice;Liver;Liver diseases;MAPK phosphatase;MAPK8 gene;Mediating;Metabolic;Mitogen-Activated Protein Kinases;PDE4B;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Population;Process;Regulation;Role;Second Messenger Systems;Signal Transduction;Specificity;Toxic effect;Transcriptional Regulation;United States;Untranslated RNA;Up-Regulation;Work;alcohol effect;base;cell injury;genetic manipulation;hypoxia inducible factor 1;in vitro Model;in vivo;inhibitor;lipid biosynthesis;lipid metabolism;liver injury;member;mortality;new therapeutic target;novel;oxidation;phosphatase-1 kinase;phosphodiesterase IV;phosphoric diester hydrolase;preclinical study;response;transcription factor


application_id: 10491074
project_number: 5R01AA028447-02
project_title: Impaired Risk Awareness during Intoxication in Recidivist DUI Offenders
administering_ic: NIAAA
award_notice_date: 2022-07-06
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: AA
serial_number: 028447
program_official: BLOSS, GREGORY
project_start_date: 2021-09-20
project_end_date: 2025-06-30
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
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/ABSTRACTAlcohol-related traffic fatality and injury continue to be a major public health problem in the United States.Driving under the influence (DUI) remains one of the most frequently repeated offenses with over one-third ofoffenders being charged with a second DUI offense within five years. Prevention programs involve motivationalinterviewing and education with emphasis on increasing the offenders perceptions of the risks associated withalcohol use (i.e. increasing risk awareness). Our laboratory research has examined acute responses toalcohol in DUI offenders and showed they display heightened impulsivity and reduced perceptions ofimpairment. This suggests a lack of risk awareness in the intoxicated state when critical decisions are madeabout whether or not to drive. This 4-year R01 proposal builds on this evidence by testing the efficacy offeedback-based training to increase DUI offenders perceptions of risk associated with alcohol use. DUIoffenders will undergo experiential feedback-based training in which they are administered controlled doses ofalcohol and receive structured feedback and training to accurately appraise the behavioral impairing effects ofthe dose and accurately estimate their breath alcohol concentration. The research tests the hypothesis that thistraining will increase risk awareness among DUI offenders during intoxication as evident by reduceddisinhibiting and risk-taking effects in response to alcohol. Our evidence for atypical reactions to alcohol amongDUI offenders truly breaks new ground and identifies promising treatment targets for new interventions toreduce recidivism. Testing the efficacy of this experiential-based feedback approach represents a logical nextstep that advances the field by building upon the basic science to date.

project_terms:
Acute;Address;Alcohol consumption;Alcoholic Intoxication;Alcohols;Automobile Driving;Awareness;Basic Science;Behavior;Behavioral;Behavioral Mechanisms;Blood alcohol level measurement;Characteristics;Charge;Coupled;Disinhibition;Dose;Economics;Education;Expectancy;Feedback;Impairment;Impulsivity;Individual;Injury;Intervention;Intoxication;Investigation;Laboratories;Laboratory Research;Laboratory Study;Mindfulness Training;Outcome;Pattern;Perception;Pharmaceutical Preparations;Prevention;Prevention program;Public Health;Publishing;Reaction;Reporting;Research;Resources;Risk;Risk Reduction;Risk-Taking;Role;Self-control as a personality trait;Structure;Testing;Time;Training;United States;alcohol effect;alcohol response;base;behavioral impairment;binge drinking;breath alcohol measurement;drinking;driving behavior;driving under influence;efficacy testing;hazardous drinking;improved;innovation;motivational enhancement therapy;offender;prevent;programs;recidivism;reduced alcohol use;response;risk perception;sobriety;success;trait impulsivity;treatment program

public_health_relevance:
Driving under the influence (DUI) of alcohol remains one of the most frequently repeated offenses with overone-third of offenders being charged with a second DUI offense within five years. Our research suggests thatoffenders awareness of risks associated alcohol use is diminished particularly in the intoxicated state whendecisions are made to drive. The proposed research aims to reduce recidivism in offenders using experientialfeedback and mindfulness-based approaches to enhance their risk awareness during states of intoxication thatpose risk for DUI.


application_id: 10490865
project_number: 5R01AI167297-02
project_title: HDAC6 regulation of myeloid cell responses in sepsis
administering_ic: NIAID
award_notice_date: 2022-08-19
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 167297
program_official: MINNICOZZI, MICHAEL
project_start_date: 2021-09-17
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-IDIA-E(02)M]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
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:
Acetylation;Affect;Apoptosis;Bacteria;Cell Differentiation process;Cell Survival;Cell physiology;Cells;Clinical Trials;Cytoskeleton;Deacetylation;Development;Disease;Endotoxins;Epigenetic Process;Failure;Functional disorder;Future;Generations;Genetic Transcription;HDAC6 gene;Health;Histone Deacetylase;IRF1 gene;Immune;Immune System Diseases;Immune response;Infection;Inflammation;Inflammatory;Interferons;Life;Mediating;Mediator of activation protein;Metabolic;Microtubule Stabilization;Microtubules;Modification;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Pathway interactions;Phenotype;Play;Regulation;Reporting;Role;STAT1 gene;Sepsis;Signal Transduction;Suppressor-Effector T-Lymphocytes;Survival Rate;Testing;Therapeutic;Therapeutic Effect;alpha Tubulin;hematopoietic stem cell expansion;immunoregulation;improved;macrophage;mortality;mouse model;novel;progenitor;response;septic;stem cells;transcriptomics


application_id: 10489895
project_number: 7R21AI143301-03
project_title: Mechanisms of varicella virus dissemination
administering_ic: NIAID
award_notice_date: 2021-12-14
opportunity_number: PA-21-268
application_type: 7
activity_code: R21
ic: AI
serial_number: 143301
program_official: BEISEL, CHRISTOPHER E
project_start_date: 2021-12-01
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-X(02)]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
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
project_abstract:
SUMMARYVaricella zoster virus (VZV) is a highly contagious neurotropic alpha herpes virus that causesvaricella (chickenpox). VZV establishes latency in the sensory ganglia from which it can reactivateto cause herpes zoster (shingles) a painful disease that affects almost 1 million individuals in theUnited States annually. During primary infection VZV is transmitted through the inhalation of viralparticles but the mechanisms by which VZV traffics from the initial site of infection to the gangliaand skin remain unclear. Data from in vitro assays as well as in vivo studies using severe-combined immunodeficient mice implanted with human fetal tissues (SCID-hu) strongly suggestthat T cells are highly susceptible to VZV infection and may play a critical role in VZVdissemination to the skin and ganglia. However the SCID-hu mouse model has two majorlimitations: 1) the lack of an adaptive immune system and 2) the possibility that the strict humanhost specificity of VZV could have altered viral behavior in this murine model. Additionally in vitrostudies of human tonsillar T cells were carried out using the attenuated Oka vaccine strain whichmay not adequately model the outcome of infection with wild type viral strains. In this applicationwe propose to define the mechanisms by which VZV usurps T cells to spread by using a rhesusmacaque model that recapitulates the hallmarks of VZV infection. In this model rhesus macaquesare intra-bronchially infected with Simian varicella virus (SVV) a homolog of VZV. We havedemonstrated that lung-resident T cells are susceptible and permissive to SVV infection.Additionally memory T cells are detected in the ganglia as early as 3 days post-infection at thesame time as viral DNA and before the detection of a viral-specific T cell response. Althoughthese observations establish a significant role for T cells in SVV spread to the ganglia ashas been suggested for VZV the mechanism by which varicella viruses hijack the hostsT cells to disseminate to latency sites remain poorly defined. In this application we willaddress this critical knowledge gap by first identifying transcriptional changes induced by SVVinfection in T cells isolated from the lung during acute infection using high throughput single cellRNA sequencing. Then we will assess alterations in metabolic and migratory function of SVV-infected T cells in vitro. Completion of the studies proposed in this application will yield novelinsight into viral-host interactions at the single cell level and will serve as a model to investigatethe pathogenesis of other T cell tropic viruses.

public_health_relevance:
Project NarrativeVaricella Zoster Virus (VZV) is a highly contagious virus that causes chickenpox during acuteinfection before establishing latency in the sensory ganglia. Data from several studies stronglysuggest a critical role for T cells in trafficking VZV to the ganglia; however the mechanisms bywhich VZV hijacks T cells in order to support its replication and migration to the ganglia are notwell understood. Studies proposed in this application will address this question and enhance ourunderstanding of diseases caused by varicella viruses.


application_id: 10489886
project_number: 7R01AI142841-04
project_title: Maternal obesity and neonatal innate immunity
administering_ic: NIAID
award_notice_date: 2021-11-17
opportunity_number: PA-21-268
application_type: 7
activity_code: R01
ic: AI
serial_number: 142841
program_official: PRABHUDAS, MERCY R
project_start_date: 2021-11-01
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-C(55)R]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
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
project_abstract:
SUMMARYThe developing immune system in the fetus is extremely sensitive to signals from the maternal environment.Maternal pre-pregnancy (pregravid) obesity has recently emerged as one of the most significant negativeregulators of the offsprings immune system development and maturation. Findings from animal models indicatematernal high fat diet-induced obesity is associated with dampened anti-microbial responses and aberrantinflammatory responses. More importantly recent epidemiological studies have reported that neonates born tomothers with high pre-pregnancy BMI are more susceptible to severe infections such as necrotizing enterocolitisand bacterial sepsis requiring admission to the neonatal intensive care unit (NICU). We have recently shownthat cord blood monocytes from babies born to obese mothers generated dampened immune responses tolipopolysaccharide (LPS) indicative of a Toll-like receptor (TLR) signaling defect. These observations provide apotential explanation for the increased susceptibility to severe infections in neonates born to obese mothers.However the mechanisms underlying reduced host defense in offspring of obese mothers remain poorlyunderstood. The goal of this application is to address this knowledge gap. Specically we will define functionalalterations in human neonatal monocytes induced by maternal pre-pregnancy obesity and uncover theirmolecular underpinnings. Moreover we will link data from our experiments with clinical parameters collectedfrom the pregnant mother as well as the child at birth and during the first year of life. The novelty of this applicationlies in the systems biology approach that integrates genomic and functional readouts with clinical metadata.Completion of the proposed experiments will reveal the molecular mechanisms that result in altered neonatalmonocyte function and our findings will form a basis for developing early interventions.

public_health_relevance:
NARRATIVEPre-pregnancy maternal obesity is associated with significant adverse health outcomes for the offspring includingincreased risk of severe neonatal infections and developing chronic diseases such as asthma and cardiovasculardisease which suggests a dysregulated immune system. Recent studies from our laboratory revealed significantchanges in immune cell frequency and/or function in cord blood samples collected from babies born to obesemothers. Since immune cells play a critical role in anti-microbial defense as well as the development of chronicinflammatory diseases this application will carry out an in-depth investigation of maternal pre-pregnancy obesity-driven changes in the functional transcriptional and epigenetic landscape of cord blood immune cells.


application_id: 10489745
project_number: 5R21ES033327-02
project_title: Cr(VI)-Induced DNA Damage Contributes to Brain Aging
administering_ic: NIEHS
award_notice_date: 2022-08-30
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: ES
serial_number: 033327
program_official: HOLLANDER, JONATHAN
project_start_date: 2021-09-17
project_end_date: 2024-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 12632642
contact_pi: WISE, JOHNNY
other_pis: Not Applicable
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_abstract:
PROJECT SUMMARYToday our societies are challenged with the health burdens of environmental pollution and a rapidly agingpopulation. Global lifespan is 30 years longer than it was 100 years ago and 1 in 5 Americans will be geriatricby the year 2030. Given this prolonged aging combined with environmental exposures we urgently need tounderstand how environmental pollution affects an aged body differently from a younger body and howenvironmental pollution contributes to aging phenotypes. Most of our understanding of toxic effects of chemicalscome from human research focused on young to middle aged people or from animal studies using young tomiddle aged rodents. Very few studies have considered toxicity of environmental pollutants in an aged body orpopulation and we simply do not understand the impacts on an aged population. Traditionally the brain wasconsidered composed of mostly post-mitotic neurons and hence genotoxic agents were considered less of athreat. Now we know the opposite is true  most of the brains cells the glia are mitotic and play critical rolesin protecting and supporting neuronal health. Recent studies show these glial cells can exhibit increasedaneuploidy and chromosome instability with aging and early in neurodegenerative diseases. Hence there is acritical need to understand how genotoxic chemicals affect brain health and contribute to premature aging.Hexavalent chromium [Cr(VI)] is a major environmental health concern that can induce aging phenotypes andhas the best defined clastogenic mechanism of metals. Cr(VI) also causes brain damage that may be linked toa variety of neurological symptoms. We propose to investigate the role of Cr(VI) in this aging paradigm usingyoung vs middle-aged vs geriatric rats exposed to Cr(VI) for 90 days via drinking water. We hypothesize agedanimals will be more susceptible to Cr(VI)-induced neurotoxicity and that Cr(VI)-induces brain aging bycausing aneuploidy and chromosome instability resulting in glial senescence. We will test our hypothesiswith two aims. Aim 1 will identify brain regions and cell populations vulnerable to Cr(VI) toxicity across ages. Thisaim will allow us to compare Cr(VI) neurotoxicity across ages and endpoints for premature or advanced aging.Aim 2 will determine the role of aneuploidy and chromosome instability in Cr(VI) neurotoxicity and brain aging.Our study will provide essential detailed insights into Cr(VI) neurotoxicity considering age- sex- region- andcell type-specific effects. Our study will further consider mechanistically how genotoxicity contributes to brainaging with in vivo and in vitro techniques. Outcomes will provide key and novel insights for understanding Cr(VI)srole in the aging process identifying cellular and regional targets in the brain and how an aged brain is affectedby toxicants differently. This study will also characterize a new model system for further study of neurotoxicityand aging for Cr(VI) or other metals and will contribute to improvements in Cr(VI) risk assessment andmanagement that are not currently possible because of limitations due to the absence of these data.

project_terms:
Address;Affect;Age;Aging;American;Aneuploid Cells;Aneuploidy;Animal Model;Animals;Astrocytes;Attention;Biological Aging;Biological Models;Biological Process;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Brain Injuries;Brain region;Cell Aging;Cells;Cerebellum;Cerebrovascular system;Chemicals;Chromosomal Instability;Chronic;Cultured Cells;DNA Damage;DNA Double Strand Break;Data;Dementia;Double Strand Break Repair;Elderly;Endothelial Cells;Environment;Environmental Exposure;Environmental Health;Environmental Pollutants;Environmental Pollution;Etiology;Exhibits;Exposure to;Extravasation;Face;Functional disorder;Health;Heavy Metals;Hemorrhage;High Fat Diet;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Immunohistochemistry;In Vitro;Individual;Inductively Coupled Plasma Mass Spectrometry;Industrialization;Knowledge;Learning;Link;Literature;Longevity;Malignant Neoplasms;Memory impairment;Metabolic Diseases;Metals;Microglia;Mitotic;Motor Neuron Disease;Mutagens;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurologic;Neurologic Symptoms;Neurons;Onset of illness;Outcome;Pericytes;Persons;Phenotype;Play;Poison;Population;Premature aging syndrome;Process;Rattus;Reporting;Research;Risk;Risk Assessment;Risk Management;Rodent;Role;Route;Societies;Techniques;Testing;Tissues;Toxic Environmental Substances;Toxic effect;Toxicology;Vulnerable Populations;White Matter Disease;age group;age related;age related neurodegeneration;aged;aging brain;aging population;brain cell;brain health;cell type;chromium hexavalent ion;drinking water;gene environment interaction;genotoxicity;human disease;improved;in vivo;insight;lifestyle factors;metal poisoning;middle age;neurodegenerative phenotype;neuroinflammation;neuropathology;neurotoxic;neurotoxicity;neurovascular;neurovascular unit;novel;oxidative damage;premature;senescence;sex;toxicant

public_health_relevance:
PROJECT NARRATIVEThis project aims to determine how chronic exposure to hexavalent chromium (Cr[VI]) will induce neurotoxicityand premature brain aging in young middle-aged and geriatric rats. We propose the geriatric rats will be moresusceptible to damaging effects of Cr(VI) and we propose a novel clastogenic mechanism for Cr(VI)-inducedaging. Subsequent studies will further evaluate this proposed mechanism consider Cr(VI) exposure with otherlifestyle factors (e.g. high fat diet) and possible gene-environment interactions contributing to premature aging.


application_id: 10488571
project_number: 5R01AG037868-07
project_title: Chronic Stress Glucocorticoids and Progesterone in Brain Aging
administering_ic: NIA
award_notice_date: 2022-06-16
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: GRAY, ERIN EMILY
project_start_date: 2011-03-01
project_end_date: 2026-05-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
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:
Acceleration;Acute;Address;Age;Age-Months;Aging;Agonist;Astrocytes;Behavioral;Bilateral;Binding;Biological Assay;Biological Markers;Blood;Cells;Chronic;Chronic stress;Clinical;Cognitive;Corticosterone;Data;Dependence;Dimethyl Sulfoxide;Dose;Female;Gene Expression Profile;Genes;Genetic Transcription;Geriatrics;Glucocorticoid Receptor;Glucocorticoids;Gonadal Steroid Hormones;Health;Hippocampus (Brain);Hormone Responsive;Hormones;Hypertrophy;Immunohistochemistry;Intraperitoneal Injections;Knowledge;Label;Measures;Mediating;Mediator of activation protein;Microglia;Microinjections;Mifepristone;Modeling;Myelin;Neurons;Oligodendroglia;Oral;Outcome;Outcome Measure;Pharmacology;Phosphotransferases;Preparation;Process;Progesterone;Rattus;Research Support;Rodent Model;Role;Serum;Sex Differences;Signal Pathway;Signal Transduction;Slice;Stress;Stress Tests;System;Testing;Therapeutic Uses;Tissues;Up-Regulation;Viral;Work;acute stress;age effect;aged;aging brain;animal age group;antagonist;anxiety-related behavior;base;biological adaptation to stress;cell type;cytokine;female sex hormone;glucocorticoid receptor alpha;gray matter;indexing;intervention effect;laser capture microdissection;mRNA Expression;male;morris water maze;nano-string;neuroinflammation;novel;novel strategies;overexpression;receptor;reproductive hormone;response;sex;transcriptome sequencing;treatment group;uptake;white matter


application_id: 10484224
project_number: 1R41AG078096-01
project_title: Using siRNAs against tau circular RNAs as a rational therapy for Alzheimer's disease
administering_ic: NIA
award_notice_date: 2022-05-31
opportunity_number: PAS-19-317
application_type: 1
activity_code: R41
ic: AG
serial_number: 078096
program_official: MARTIN, ZANE
project_start_date: 2022-07-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1 ETTN-H (11)]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 118062812
primary_uei: ZU7XJKHGPKS6
duns_number: 118062812
uei: ZU7XJKHGPKS6
fips: US
organization_id: 10065617
organization_name: CIRCCURE CORPORATION
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405032001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Summary: The formation of neurofibrillary tangles (NFT) formed by aggregation of the microtubule-associatedprotein tau (MAPT) is a hallmark of Alzheimers disease (AD) and the likely cause of neuronal death. Currentlythere are no rational treatments available that directly target NFT formation and thus address the directmolecular cause for AD. Based on our academic research we will develop an siRNA-based product that can bedelivered nasally and prevents NFT formation in early stages of AD. In prior studies we identified human-specific circular RNAs from the MAPT gene that are generatedthrough backsplicing of exon 12 to either exon 7 or exon 10. These tau circRNAs are translated after epigeneticmodifications that change adenosine residues to inosines (A>I editing). The translated proteins correspond tomultimers of the microtubule-binding domain and promote NFT formation. Our company CircCure will develop siRNAs that selectively target tau circRNAs and thus prevent NFTformation; we will test this product in two specific aims: Aim #1: Define the optimal siRNA backbone sequencefor the 12->7 and 12->10 tau circRNA by performing an oligo-walk to identify the backbone sequence with thehighest efficacy toward tau circRNAs and lowest efficacy against linear RNAs. After undergoing standardchemical optimization in Aim #2 we will test the siRNA efficacy (IC50) using intranasal and injection delivery inan in vivo model of human neuroblastoma cells grafted in mouse brains. This product is highly innovative as itwill directly address NFT formation targeting recently discovered circular RNAs. The final product of these Phase I studies will be an siRNA that can be delivered intranasally thatreduces tau circRNAs and NFT formation in human cells embedded in a mouse brain. The product will thusdirectly target the cause of neuronal death in AD which will provide supportive evidence for Phase II studieswhere we will test pharmacology and safety to prepare for an investigational new drug (IND) application.

project_terms:
Address;Adenosine;Adult;Agreement;Alu Elements;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimer's disease therapy;Binding;Biological Assay;Brain;Cause of Death;Cell model;Cells;Chemistry;Clinical;Complex;Data;Ensure;Epigenetic Process;Exons;Genes;Glioblastoma;Human;In Vitro;Incubators;Injections;Inosine;Investigational New Drug Application;Kentucky;Legal;Legal patent;Logistics;MAPT gene;Mediating;Messenger RNA;Methods;Microtubules;Modification;Molecular;Monitor;Mus;Neurofibrillary Tangles;Nose;Oligonucleotides;Pathologic;Pharmaceutical Preparations;Pharmacology;Phase;Primates;Production;Property;Proteins;RNA;RNA Editing;Research;Ribose;Safety;Side;Site;Small Business Technology Transfer Research;Small Interfering RNA;Small RNA;Tauopathies;Testing;Therapeutic;Toxic effect;Translating;Universities;Vertebral column;Walking;Work;base;chemical standard;circular RNA;cost;cross reactivity;design;dosage;human model;in vivo;in vivo Model;innovation;neuroblastoma cell;neurofibrillary tangle formation;neuron loss;phase 1 study;phase 2 study;prevent;protein aggregation;response;siRNA delivery;tau Proteins;tau aggregation;uptake

public_health_relevance:
Narrative:Currently no rational treatment for Alzheimers disease is available. We will develop small RNAs that specificallytarget pathological tau circular RNAs that promote neuronal death by causing protein aggregation and test themin human cell models and in human cells grafted in mouse brains.


application_id: 10483885
project_number: 1R43HL162337-01A1
project_title: Development of novel Aquilo Heat Therapy Device to treat patients with PeripheralArtery Disease
administering_ic: NHLBI
award_notice_date: 2022-04-29
opportunity_number: PA-21-260
application_type: 1
activity_code: R43
ic: HL
serial_number: 162337
suffix: A1
program_official: LIU, SONGTAO
project_start_date: 2022-05-01
project_end_date: 2024-04-30
study_section: Special Emphasis Panel[ZRG1 SBIB-W (12)]
contact_pi_person_id: 78110712
contact_pi: SPENCE, PAUL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 080077503
primary_uei: T9YZMV8SCZ63
duns_number: 080077503
uei: T9YZMV8SCZ63
fips: US
organization_id: 10040692
organization_name: AQUILO SPORTS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40202
organization_country: UNITED STATES
project_abstract:
The objective of this proposal is to develop a novel device to provide leg heat therapy (HT) for patients withsymptomatic peripheral arterial disease (PAD). The current non-interventional standard of care for PAD is a 12week program of supervised exercise therapy (SET). For patients this is often very painful as they are exercisedto the point of claudication and many elderly patients find it difficult or impossible to repeatedly travel to atreatment facility. Thus the majority of these patients remain untreated. Recently HT has been shown to be apromising therapy to treat PAD patients. A recent study demonstrated that an 8 week course of home HT wasboth safe and effective - with improvement in walking performance similar to SET. Home HT was also found tobe comfortable and compliance was the treatment program was very high. Presently there is no systemcommercially available for HT therapy despite the fact that HT may prove to be an optimal therapy for PADpatients since it can be delivered comfortably and at home. The Aquilo multi-disciplinary development team hasthe expertise experience and confidence to achieve our objective of clinical translation and commercializationof a competitive advanced technology to safely and effectively treat PAD which will lead to an improved therapyfor PAD patients.The proprietary Aquilo HT system (U.S. Patent Application No. 63/215129) consists of two principalcomponents. The first component is a wearable lower body garment that has an outer shell that is closed witha zipper and houses 6 pneumatic chambers. Inside the garment is a water circulating pad to provide HT.Temperature thermistors are attached to the water circulating pad in the region of the calf and the thigh of eachleg. The second component is a console. The console houses a heater and two pumps  one to circulate heatedwater and a second that pumps air into the pneumatic chambers to keep the pads in gentle contact with the leg.The console has a touch screen for simple one-touch full treatment operation by elderly PAD patients. Manyimportant safety features are programmed including audible and visual alarms and system shut off if legtemperature is excessive kink detection and a low water level warning. The console will also include a datacollection system. Rigor of prior research was demonstrated by development of prototype devices and proof-of-concept testing to define design specifications evaluate function and performance and identify engineeringchallenges and formulate solutions for new the Aquilo HT system.In this phase I project we will (1) complete fabrication of the Aquilo HT system and confirm achievement of thedesign specifications (Aim 1); (2) demonstrate system safety and function in a small cohort of patients over a12 week treatment period (Aim 2). Successful demonstration of feasibility of the Aquilo HT system will include:(1) achieve design specifications function and performance metrics (Aim 1) and (2) demonstrate safety (noskin injury or skin burn) and device reliability over 12 weeks of therapy in 6 PAD patients (Aim 2). Collectivelyupon successful demonstration of meeting design benchmarks and study metrics (phase I) we will work toachieve a design freeze complete verification and validation (V&V) testing in compliance with GoodManufacturing Practices (GMP) then conduct pre-clinical testing in compliance with Good Laboratory Practices(GLP). Our engineering control documents and pre-clinical test data and analyses will be then used to supportan application for a clinical trial in PAD patients. Our vision is to successfully translate the Aquilo HT system intoclinical practice and improve the outcome of PAD patients.

project_terms:
Achievement;Address;Adopted;Adverse event;Age-Years;Air;Ankle;Atherosclerosis;Benchmarking;Blood flow;Burn injury;Clinical;Clinical Trials;Commuting;Data Analyses;Data Collection;Detection;Development;Devices;Disease;Effectiveness;Elderly;Electronics;Engineering;Ensure;Exercise;Exercise Therapy;Freezing;Goals;Heating;Home;Impairment;Individual;Interruption;Leg;Legal patent;Lower Extremity;Medical Device;Modification;Monitor;Morbidity - disease rate;Outcome;Outcome Study;Pain;Patients;Performance;Peripheral arterial disease;Persons;Phase;Physical Function;Polyurethanes;Preclinical Testing;Pump;Quality of life;Questionnaires;Randomized;Randomized Clinical Trials;Recovery;Regimen;Research;Research Personnel;Safety;Scientist;Skin Temperature;Skin injury;Sports;Supervision;System;Technology;Temperature;Testing;Therapeutic heat application;Thigh structure;Touch sensation;Training Programs;Translating;Travel;United States National Institutes of Health;Validation;Vision;Visual;Walking;Water;Well in self;Work;base;cardiovascular risk factor;claudication;clinical practice;clinical translation;cohort;commercialization;comorbidity;compliance behavior;design;effective therapy;engineering design;exercise training;experience;good laboratory practice;improved;improved outcome;indexing;innovation;meetings;meter;mortality;multidisciplinary;novel;older patient;operation;optimal treatments;phase 1 study;phase 2 study;pressure;prevent;programs;prototype;secondary outcome;skin burn;standard of care;touchscreen;treadmill;treatment duration;treatment program;usability;verification and validation;water testing

public_health_relevance:
Aquilo Sports (Louisville KY) is developing a novel system to provide heat therapy (HT) to the legs of patientswith symptomatic peripheral arterial disease (PAD). Current non-interventional options for these patients arelimited and the most commonly prescribed treatment is supervised exercise therapy (SET). SET is painful forpatients as they are asked to walk to the point of claudication and many patients are not able to travel to atreatment facility for a 12 week course of therapy so most patients remain untreated. Recent evidence hasdemonstrated that home-based HT may be a promising and effective therapy for PAD patients but there is nocommercial device available for treatment. In this Phase 1 study we will develop a prototype HT system for useby elderly patients and demonstrate its safety and efficacy in a small cohort of patients. Our long term goal is todevelop a safe and effective home-based HT system for PAD patients that is both easy to use and comfortable.


application_id: 10482396
project_number: 5R01ES032176-02
administering_ic: NIEHS
award_notice_date: 2022-08-30
opportunity_number: RFA-ES-18-007
application_type: 5
activity_code: R01
ic: ES
serial_number: 032176
program_official: DZIERLENGA, ANIKA LIN
project_start_date: 2021-09-06
project_end_date: 2024-08-31
study_section: ZES1-ARL-D(R0)
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: ANDRES, ALINE ;EVERSON, TODD M
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
budget_start_date: 2022-09-01
project_title:
Growth and metabolic programming from prenatal PFAS exposure: examining the roles of placental functional genomics and protection by maternal exercise

project_abstract:
PROJECT SUMMARY Rates of childhood obesity have more than tripled over the last 40 years with 18.5% of children andadolescents classified as obese. Endocrine-disrupting chemicals particularly environmentally ubiquitousobesogens such as per- and polyfluoroalkyl substances (PFAS) are thought to contribute to the rapid increasesin obesity. Indeed prenatal PFAS exposures have been shown to contribute to gender-specific obesitydevelopment in children. Interestingly PFAS exposures that occur during pregnancy can cross the placentaleading to direct in utero exposure and PFAS have been detected in placental tissues. In addition to supportingfetal growth the placenta is likely involved in longer term persistent effects in the offspring. Howeverinterrelationships between prenatal PFAS impacts on the placenta and postnatal growth and metabolic healthare understudied. Additionally a lifestyle intervention including dietary training physical activity and behavioralmodifications has been shown to attenuate the association between higher PFAS to higher body weight.However similar studies have not been performed in the context of prenatal exposure and childrens healthoutcomes. Thus there are key gaps in our understanding of the impacts and preventive opportunities regardingprenatal PFAS exposure: whether the timing of exposure and/or tissue-specific concentrations are important;whether molecular activities of the placental are disrupted by PFAS; and whether physical activity duringpregnancy may attenuate these effects. For this proposal we have assembled a newly formed collaborativeteam of investigators with unique expertise in childrens growth and metabolic health (mPI Andres Aim 1)environmental health and placental functional genomics (mPI Everson Aim 2) and physical activity interventions(mPI Pearson Aim 3) to address these knowledge gaps. Using an existing longitudinal cohort we aim to quantifyPFAS in maternal serum at each trimester as well as in umbilical cord serum and placental tissues to determinetheir associations with birth weight placental functional genomics as well as pediatric obesity. Additionallybecause PFAS are pervasive and thus exposure avoidance can be difficult we will also explore the role ofmaternal exercise in decreasing maternal PFAS burden during the pregnancy period as part of an ongoingexercise randomized control trial during pregnancy. We hypothesize that 1) prenatal PFAS burden willsignificantly affect birth weight as well as child growth and adiposity accretion; 2) prenatal PFAS exposure willinfluence placental epigenomic regulation with impacts on transcription and metabolic features; and 3) exerciseduring pregnancy will decrease PFAS burden in maternal and umbilical serum. The proposed studies will offerinnovative new insights to understanding the role of PFAS compounds as obesogens during humandevelopment their impact on placental function which could lead to novel targets for intervention or preventionand determine whether exercise mitigates the PFAS exposure risk.

project_terms:
2 year old;Address;Adolescent;Adult;Affect;Attenuated;Behavior Therapy;Birth;Birth Weight;Body Composition;Body Weight;Cell physiology;Chemical Exposure;Child;Child Health;Clinical;Cohort Studies;DNA Methylation;Data;Development;Disease;Endocrine Disruptors;Environmental Health;Environmental Pollution;Epigenetic Process;Exercise;Fatty acid glycerol esters;Fetal Growth;Functional disorder;Gender;Gene Expression;Generations;Genetic Transcription;Genomics;Growth;Health;Human Development;Intervention;Intervention Studies;Knowledge;Lead;Longitudinal cohort;Maternal-Fetal Exchange;Measures;Mesenchymal Stem Cells;Metabolic;Metabolism;MicroRNAs;Molecular;Neonatal;Nutrient;Obesity;Obesity Epidemic;Organ;Outcome;Physical activity;Placenta;Poly-fluoroalkyl substances;Pregnancy;Prevention;Preventive;Randomized Controlled Trials;Regulation;Research;Research Personnel;Research Project Grants;Risk;Role;Sampling;Serum;Testing;Time;Tissues;Training;Translating;Umbilical cord structure;Weight Gain;cohort;cost;dietary;epigenetic regulation;epigenome;epigenomics;exercise intervention;functional genomics;high reward;high risk;improved;innovation;insight;intrauterine environment;lifestyle intervention;lipid biosynthesis;maternal serum;metabolomics;novel;obesity development;obesity in children;obesogen;offspring;postnatal;prenatal;prenatal exposure;prenatal influence;protective effect;response;transcriptomics;wasting

public_health_relevance:
PROJECT NARRATIVEOur ViCTER project will bring together a transdisciplinary group of investigators to perform a novel assessmentof the influences of prenatal per- and polyfluoroalkyl substances (PFAS) exposures on childrens health. Wepropose to measure PFAS concentrations at multiple time points throughout pregnancy and at birth then testfor associations with postnatal growth and adiposity. Additionally we will examine the role of the placenta bystudying placental functional genomics and assess the potential protective effects of maternal exercise duringpregnancy.


application_id: 10482379
project_number: 5R01AA026605-05
project_title: Remote alcohol monitoring to facilitate abstinence reinforcement with an underserved population
administering_ic: NIAAA
award_notice_date: 2022-09-03
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: AA
serial_number: 026605
program_official: ROACH, DEIDRA
project_start_date: 2018-09-20
project_end_date: 2026-08-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 10316536
contact_pi: KOFFARNUS, MIKHAIL NIKOLAAS
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_abstract:
PROJECT SUMMARY/ABSTRACT Lifetime prevalence of DSM-5 alcohol use disorder in the United States is 29% but only 20 to 24% ofpeople with alcohol use disorder ever seek treatment. The most prevalent reasons given for not seekingtreatment relate to an inability or unwillingness (e.g. due to stigmatization) to attend traditional in-persontreatment. For individuals who do receive medical treatment or care for alcohol use disorder their first point ofcontact with the medical community is often for alcohol detoxification. Unfortunately relapse following alcoholdetoxification is common and few people continue utilizing treatment services after being discharged. Thepervasiveness of alcohol use disorder indicates a need for continued development of high-impact treatmentsthat are effective acceptable to the untreated and easily disseminated widely. Contingency management orthe delivery of monetary incentives contingent on verified abstinence is an effective treatment for alcohol usedisorder. However costs and barriers to accurate frequent biochemical verification of alcohol abstinence limitthe widespread use of this technique for alcohol use disorder. In our preliminary data weve successfullydemonstrated the feasibility of remote alcohol monitoring and incentives for the reduction of alcohol use. Weused technologically advanced mobile breathalyzers to verify abstinence remotely cell phones forcommunication and a reloadable debit card to deliver incentives with little delay. Our preliminary study hasshown a high rate of abstinence with this model and participants gave this approach high ratings foreffectiveness and acceptability. Here we will develop this model into two treatment options ready fordissemination: 1) a stand-alone remote treatment directed toward abstinence initiation and maintenance inunderserved individuals and 2) an adjunct to existing treatment services to prevent relapse after hospitaldetoxification. We will also address additional gaps in knowledge in both treatment contexts: 1) what themaximally effective duration and intensity of abstinence incentives is and 2) what the persistence of treatmenteffects are once incentives are discontinued. Through the use of technological advancements combined in anovel way with abstinence incentives the proposed research has the potential to provide a framework forbringing effective evidence-based treatments to a large number of individuals with alcohol use disorder whoare currently underserved by existing treatment options or are unable to maintain abstinence afterdetoxification. Due to the extent of automation and relatively low use of research staff to execute thistreatment model is highly scalable an important feature when addressing the large problem of untreatedalcohol use disorder.

project_terms:
Abstinence;Address;Adult;Alcohol consumption;Alcohols;Area;Automation;Biochemical;Caring;Cellular Phone;Clinical;Clinical Services;Communication;Communities;Control Groups;DSM-V;Data;Development;Drug Metabolic Detoxication;Effectiveness;Evidence based treatment;Goals;Health;Health Personnel;Hospitals;Incentives;Individual;Inpatients;Intervention;Knowledge;Lead;Maintenance;Medical;Modeling;Participant;Persons;Population;Prevalence;Prize;Psychological reinforcement;Randomized;Relapse;Research;Services;Severities;Stigmatization;System;Techniques;Testing;Underserved Population;United States;alcohol abstinence;alcohol monitoring;alcohol services;alcohol use disorder;base;contingency management;cost;disorder later incidence prevention;effective therapy;experimental study;feasibility trial;financial incentive;interest;novel;outpatient programs;prevent;readmission rates;recruit;remote delivery;remote therapy;secondary analysis;treatment as usual;treatment effect;treatment services

public_health_relevance:
PROJECT NARRATIVE Untreated alcohol use disorder among individuals unable or willing to attend existing treatment services aswell as relapse after alcohol detoxification are substantial health concerns. The goals of this project are toevaluate a remote alcohol monitoring and abstinence incentives intervention we have piloted in two contexts:1) the initiation and maintenance of abstinence remotely in underserved adults and 2) the prevention ofrelapse remotely following inpatient clinical detoxification services. Through the use of technologicaladvancements combined in a novel way with abstinence incentives the proposed research has the potential toprovide a framework for bringing effective evidence-based treatments to a large number of individuals withalcohol use disorder.


application_id: 10481871
project_number: 2SB1ES028171-05
project_title: Electrochemical POU Water Purification System
administering_ic: NIEHS
award_notice_date: 2022-05-19
opportunity_number: PAR-20-128
application_type: 2
activity_code: SB1
ic: ES
serial_number: 028171
program_official: HENRY, HEATHER F
project_start_date: 2017-09-15
project_end_date: 2024-04-30
study_section: Special Emphasis Panel[ZRG1 IMST-K (19)]
contact_pi_person_id: 14657253
contact_pi: BOEHME, LINDSAY
other_pis: RASSOOLKHANI, ALAN
congressional_district: 06
department: Unavailable
primary_duns: 079388085
primary_uei: JD9MTUKKNG13
duns_number: 079388085
uei: JD9MTUKKNG13
fips: US
organization_id: 10036767
organization_name: POWERTECH WATER, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40508
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYLead contamination in drinking water is a pervasive health problem across the US.1 Children are especiallyvulnerable to lead poisoning which can have permanent detrimental effects on brain development.23 Despitecorrosion prevention measures taken by public water authorities lead concentrations in drinking water areroutinely elevated nationwide and an estimated 12 million lead services lines are in need of replacement.4 TheEnvironmental Protection Agency (EPA) established The Lead and Copper Rule in 1991 to limit exposure ofthese elements and set the action level to 15 ppb; however there is no safe level of lead consumption andmore stringent regulations are starting to be adopted around the world.5-8 The crisis observed in Flint Michiganin 2014 put lead exposure into the public spotlight increasing consumer awareness. Seven years later leadcontamination of drinking water supplies remains a national issue.Lead filters currently on the market lack specificity with limited device lifetime dictated by the total amount ofwater volume filtered regardless of lead concentration. Incumbent solutions for home water purification arearchaic and outdated. ElectraMetTM from PowerTech Water (PTW) is an electrochemical filter that can targetthe removal of lead. The device uses activated carbon electrodes and a small applied voltage (< 2.0 V) toinduce Faradaic reactions at both the carbon-based anodes and cathodes within the cell. By tuning the deviceconfiguration and operating parameters lead will precipitate out of solution and be permanently removed whileother dissolved minerals are left unaffected.In this CRP project PTW's goal is to design a POU device that meets target end-use product specificationsand certification standards. At the completion of this work we anticipate a consumer-focused device thatexceeds the performance of current off-the-shelf solutions. The device will be reliable and specific for leadhave a multi-year system lifetime and will not be consumed by abundant water constituents. Theseperformance targets will be achieved through the following Specific Aims:1. Product form factor design for a POU solution. Expected outcome: A design that fits under the sink and meets product specifications for the overall device size pressure tolerance price point and lead removalperformance.2. Replication of testing standards to obtain drinking water filtration certifications. Expected Outcome: ElectraMetTM performance to meet NSF/ANSI 53 and 61 certification standards for lead removal and structural integrity.3. Testing of a POU installation to simulate a real-world scenario. Expected Outcomes: Operating parameters required for lead removal under different water usage scenarios and a method to track device lifetime to predict filter replacement.

project_terms:
Adopted;Anodes;Awareness;Brain;Carbon;Cathodes;Cells;Certification;Child;Consumption;Copper;Corrosion;Development;Devices;Drops;Electrodes;Elements;Engineering;Ensure;Excision;Filtration;Foundations;Funding;Goals;Guidelines;Health;Home;Infrastructure;Institution;Knowledge;Lead;Lead Poisoning;Lead levels;Left;Maintenance;Measurement;Metal exposure;Metals;Methods;Michigan;Minerals;Outcome;Performance;Phase;Prevention Measures;Price;Process;Reaction;Regulation;Resources;Sampling;Sanitation;Science;Services;Signal Transduction;Source;Specificity;System;Technology;Testing;Time;Trust;United States;United States Environmental Protection Agency;Update;Water;Water Purification;Water Supply;Work;authority;base;contaminated drinking water;cost;cost effective;design;drinking water;economic evaluation;lead concentration;lead contamination;lead exposure;pressure;response;success;voltage;water treatment

public_health_relevance:
PROJECT NARRATIVELead contamination of drinking water continues to be one of the greatest health threats in theUnited States due to outdated infrastructure and the Environmental Protection Agency (EPA)emphasizes that there is no safe level of lead exposure. PowerTech Water's goal is to design apoint-of-use (POU) drinking water purification device for installation under a sink that is highlyspecific for lead as well as more reliable efficient and longer-lasting than state-of-the-artsolutions. If successful this technology will deliver safe drinking water at the source in a low-cost low-complexity and low-maintenance format.


application_id: 10480950
project_number: 5R01EY033190-02
project_title: Visual mechanisms of intermediate distance space perception during self-motion
administering_ic: NEI
award_notice_date: 2022-08-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: EY
serial_number: 033190
program_official: WIGGS, CHERI
project_start_date: 2021-09-30
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-J(02)M]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: OOI, TENG LENG
congressional_district: 03
department: PSYCHOLOGY
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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryEvery day we rely on our vision to judge the absolute distances of objects around us to plan and guide ouractions such as walking and driving. This wayfinding process of ascertaining ones position and planning forpossible routes of actions cannot be accomplished without reliable perception of visual space in the intermediatedistance range (~2-25m from the observer). Thus the broad long-term objective of this project is to uncover themechanisms underlying intermediate distance space perception that supports distance judgment.Yet less is known about the underlying mechanisms of intermediate distance space perception compared tothose of near space perception (<2m). Moreover extant knowledge is predominantly obtained from testing staticobservers making it difficult to generalize to the more common situation where observers plan and execute self-motion. The latter situation is more complex because self-motion is accompanied by retinal image motion ofstatic objects in the surrounding environment potentially requiring the visual system to simultaneously track thelocations of all objects in the environment. The visual system also requires more processing capacity becauseit has to simultaneously compute the visual space representation explore the environment implement motorcontrols etc. Clearly both challenges  coding complexity and capacity limitation  could pose as potentialthreats to our ability to efficiently judge absolute distances and implement actions. We hypothesize the visualsystem overcomes both challenges by: (a) spatially updating the moving observers position using an allocentricworld-centered spatial coordinate system for representing visual space and (b) use spatial working memory(spatial-image) during spatial updating. We will investigate both hypotheses in three specific aims. Aim 1: Investigate the implementation of the allocentric world-centered spatial coordinate system Aim 2: Investigate the factors affecting the spatial updating of visual space Aim 3: Investigate the role of spatial-image memory in visual space perceptionOur psychophysical experiments will measure human behavioral responses in the real 3D environment. Thisapproach allows us to understand how our natural ecological niche namely the ground surface both constrainsand supports space perception and action in the real world. We will test human observers ability to judge targetlocations in impoverished visual environments under various conditions such as while manipulating theobservers cognitive load (attention and memory) or available visual and idiothetic (vestibular andproprioception) information while they plan and/or execute self-motion (walking). The outcomes of this researchwill advance the space perception literature bridge theoretical knowledge of visual space perception andmemory-directed navigation (cognitive maps) as well as reveal the influence of vestibular and somatosensorysignals. In turn the theoretical advancements provide insights for better understanding of intermediate distancespace perception related to eye and visual impairments and their impacts on mobility in the real 3D environment.

project_terms:
3-Dimensional;Activities of Daily Living;Address;Adopted;Affect;Attention;Automobile Driving;Behavioral;Characteristics;Code;Cognitive;Complex;Cues;Defect;Environment;Eye;Human;Image;Judgment;Knowledge;Literature;Location;Maps;Measures;Memory;Motion;Movement;Neurologic;Outcomes Research;Performance;Positioning Attribute;Poverty;Process;Proprioception;Psychophysics;Research;Resources;Role;Route;Short-Term Memory;Signal Transduction;Space Perception;Surface;System;Testing;Texture;Update;Vision;Visual;Visual Perception;Visual impairment;Visual system structure;Visuospatial;Walking;base;behavioral response;cognitive load;experimental study;insight;motor control;neuromechanism;operation;relating to nervous system;retinal imaging;somatosensory;visual coding;visual information;way finding

public_health_relevance:
Project NarrativeThe ability to judge the locations of various objects from oneself during self-motion in the intermediate distancerange (~2-25m) is crucial for successful performance of activities of daily living such as walking and driving.However little is known about the mechanisms of visual space perception involved in judging distance the focusof this project in the planning and/or execution of self-motion in the natural 3D environment. The theoreticalknowledge to be gained from this project will contribute to the scientific literature and provide insights into howeye and neurological defects could impair visual space perception wayfinding and mobility.


application_id: 10479889
project_number: 5R01DK126777-02
project_title: ABIN1 dysfunction in Lupus Nephritis
administering_ic: NIDDK
award_notice_date: 2022-08-02
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 126777
program_official: CHAN, KEVIN E
project_start_date: 2021-09-01
project_end_date: 2026-06-30
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: CASTER, DAWN
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:
Address;African American;African American population;Alleles;Animal Experiments;Animals;Autoimmunity;B-Lymphocytes;Binding Proteins;Biological Response Modifiers;Blood;Bone Marrow;CXCL10 gene;Cell Maturation;Cell physiology;Cells;Clinical;Complication;Data;Development;Diffuse;Disease;Disease Outcome;Event;Functional disorder;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genotype;Glomerulonephritis;Human;Immune;Immune Complex Glomerulonephritis;Inflammation Mediators;Inflammatory;Interleukin-6;Investigation;Kidney;Kidney Failure;Knowledge;Lupus Nephritis;Mature T-Lymphocyte;Mediating;Molecular;Mus;Mutation;Nature;Outcome;Pathologic;Patients;Peripheral;Physiological;Play;Polyubiquitin;Precision therapeutics;Predisposition;Production;Prognosis;Proteins;Proteinuria;Publishing;Regulation;Reporting;Research Personnel;Risk;Role;Sampling;Scientist;Serum;Severities;Severity of illness;Systemic Lupus Erythematosus;T-Lymphocyte;TNF gene;Target Populations;Transcriptional Regulation;Transgenic Mice;Transgenic Organisms;Transplantation;Validation;Variant;Wild Type Mouse;anti-dsDNA autoantibody;caucasian American;cell type;chemokine;cohort;cytokine;diagnostic biomarker;disorder risk;experimental study;genetic variant;high risk;inhibitor;insight;monocyte;neutrophil;novel diagnostics;personalized diagnostics;podocyte;protein function;racial disparity;risk variant;therapeutic target


application_id: 10479775
project_number: 5R01DK116591-04
project_title: miRNA Mechanism of Acute Kidney Injury in Aging
administering_ic: NIDDK
award_notice_date: 2022-05-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 116591
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2018-07-31
project_end_date: 2024-05-31
study_section: Special Emphasis Panel[ZRG1-VH-C(02)]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
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:
Project SummaryIschemia/reperfusion (I/R)-induced acute kidney injury (AKI) remains a major clinical problem in olderpopulation. Although I/R-induced AKI occurs in a variety of clinical situations such as shock renaltransplantation sepsis and renal artery stenosis the mechanism is multifactorial complex and poorlyunderstood. Under normal physiological conditions kidney produces hydrogen sulfide (H2S) with the aid of fourenzymes: cystathionine -synthase (CBS) cystathionine -lyase (CSE) 3-mercaptopyruvate sulfurtransferase(3MST) and cysteine aminotransferase (CAT). In recent years H2S has been shown to regulate severalphysiological functions and its decrease has been implicated in diseases such as hypertension inflammationatherosclerosis and renal disease progression and failure. MicroRNAs (miRNAs) are small non-coding RNAswhich has the ability to inhibit mRNA transcripts by inducing degradation or blocking protein translation. In I/R-induced AKI several miRNAs have been reported to be differentially expressed. Furthermore in I/R-inducedAKI macrophages play a key role in inflammatory and reparative process. While M1 subset macrophage isinvolved in inflammation subset M2 is involved in repair mechanism. Our preliminary results suggested that inI/R-induced AKI in aging miRNA-21 is upregulated and miRNA-194 is down regulated. The injured kidney alsoshowed decreased expression of CBS and 3MST enzymes leading to diminished H2S production. Theincreased ratio of M1/M2 further suggested prolonged inflammatory phase. In addition expression of matrixmetalloproteinase-9 (MMP-9) and their regulatory molecules EMMPRIN and Meprin-A were also upregulatedin AKI. These changes in concert with endothelial to mesenchymal transition (EndoMT) led us to stronglybelieving a detrimental remodeling in I/R-induced old kidney. Interestingly H2S treatment mitigated remodelingand improved renal function in I/R-induced AKI in old mice. We obtained similar results through miR-21inhibitor treatments. Based on these preliminary findings we hypothesize that H2S is a protective agent againstI/R-induced damage in aging kidney. In further substantiating our concept both male and female old vs youngwild type (WT C57BL/6J) mice will be used to compare severity of I/R-induced kidney injury and dysfunctionand beneficial effects of H2S treatment will be assessed. The gained knowledge will not only help to betterunderstand mechanisms of AKI in aging but will also shed lights on future diagnostic and therapeuticstrategies which will be applicable to older patients suffering from AKI.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Acute Renal Failure with Renal Papillary Necrosis;Aging;Angiography;Animals;Anti-Inflammatory Agents;Antioxidants;Atherosclerosis;Barium;Bilateral;Blood flow;Cardiac Surgery procedures;Clinical;Collagen;Complex;Creatinine;Cystathionine;Cystathionine beta-Synthase;Cysteine;Deposition;Diagnostic;Disease;Disease Progression;Down-Regulation;Endothelium;Enzymes;Equilibrium;Extracellular Matrix;Failure;Female;Fibrosis;Flow Cytometry;Fluorescein-5-isothiocyanate;Functional disorder;Future;Gelatin Zymography;Gelatinase B;Generations;Glomerular Filtration Rate;Goals;Health;Histology;Hydrogen Sulfide;Hypertension;Impairment;Infection;Inflammation;Inflammation Mediators;Inflammatory;Injury to Kidney;Ischemia;Kidney;Kidney Diseases;Kidney Transplantation;Knowledge;Lasers;Lead;Lyase;Matrix Metalloproteinases;Measures;Mediating;Meprin;Mesenchymal;Messenger RNA;Metabolic;Methods;MicroRNAs;Mus;Older Population;Organ Transplantation;Outcome;Peritoneal;Phase;Physiological;Plasma;Play;Population;Prevention strategy;Production;Protective Agents;Proteins;Quality of life;Renal Artery Stenosis;Renal Blood Flow;Renal function;Reperfusion Injury;Reperfusion Therapy;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Sepsis;Severities;Shock;Testing;Therapeutic;Transaminases;Transcript;Translations;Transplantation Surgery;Untranslated RNA;Up-Regulation;Vascular Diseases;Western Blotting;base;density;design;differential expression;experimental study;improved;inhibitor;kidney dysfunction;kidney fibrosis;kidney vascular structure;macrophage;male;older patient;prevent;renal ischemia;repaired;reparative process;treatment strategy;ultrasound

public_health_relevance:
Project NarrativeIschemia-reperfusion (I/R) is the cut off and re-establishment of blood flow and is a commoncause of acute kidney injury (AKI) in a variety of health conditions including shock infectionorgan transplantation and cardiac surgery. Understanding of I/R mechanism is incomplete andtherefore treatment strategies for AKI are insufficient. This proposal is designed to delineate theunderlying mechanism of kidney I/R injury in older population and to effectively counter AKI witha hydrogen sulfide releasing compound GYY4137.


application_id: 10479501
project_number: 3R01AR071398-04S2
project_title: Mechanistic assessment of blood flow restricted training for an ACL injury
administering_ic: NIAMS
award_notice_date: 2021-09-06
opportunity_number: PA-16-160
application_type: 3
activity_code: R01
ic: AR
serial_number: 071398
suffix: S2
program_official: WASHABAUGH, CHARLES H
project_start_date: 2017-07-22
project_end_date: 2022-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
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
project_abstract:
Abstract:Anterior cruciate ligament reconstruction surgery results in protracted quadriceps weakness that is associatedwith altered biomechanics and heightened risk of subsequent injuries. Little progress has been made inimproving quadriceps strength in the past 15-20 years. Alterations in the morphological and cellularcomposition of the vastus lateralis muscle promote muscle weakness following an anterior cruciate ligamentreconstruction. These features are not responsive to traditional physical therapy techniques. A promisingemerging treatment blood flow restriction training (BFRT) has been shown to address these same alterationsin healthy subjects; however it has never been tested in those with an injury. Pilot data in the current proposalshows that BFRT can lead to a significant increase in muscle strength following an anterior cruciate ligamentinjury. This project seeks to mechanistically determine the ability of BFRT to address underlying musclecellular deficits following anterior cruciate ligament reconstruction compared to usual care. Goals in the currentproposal are as follows: aim 1 will determine if BFRT is able to significantly improve knee mechanics andquadriceps strength following an anterior cruciate ligament reconstruction compared to usual care. Aim 2 willuse advanced magnetic resonance imaging techniques to assess improvements in quadriceps morphologyafter training with BFRT. Lastly aim 3 will identify BFRT-mediated improvements in cellular deficits in thequadriceps as the result of BFRT training versus usual care. The expected outcomes will show for the first timethat BFRT is an effective mechanistic treatment for normalizing quadriceps strength within individuals followingan anterior cruciate ligament reconstruction.

project_terms:
3-Dimensional;Address;Anterior Cruciate Ligament;Architecture;Area;Attenuated;Biomechanics;Biopsy;Blood flow;Clinical;Data;Degenerative polyarthritis;Development;Effectiveness;Electric Stimulation;Evidence based intervention;Extensor;Extracellular Matrix;Fatty acid glycerol esters;Fiber;Fibrosis;Frequencies;Generations;Goals;Imaging Techniques;Individual;Infiltration;Injury;Knee;Lead;Limb structure;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mediating;Microscopic;Morphology;Multi-Institutional Clinical Trial;Muscle;Muscle Fibers;Muscle Weakness;Muscle satellite cell;Outcome;Patient Care;Patients;Phenotype;Physical therapy;Physiological;Physiological Adaptation;Population;Positioning Attribute;Procedures;Property;Quality of life;Randomized;Reconstructive Surgical Procedures;Recovery;Rehabilitation therapy;Resistance;Risk;Techniques;Testing;Thigh structure;Time;Training;Work;alternative treatment;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;base;functional outcomes;improved;knee mechanics;muscle strength;novel;novel strategies;premature;prevent;progenitor;quadriceps muscle;reconstruction;rehabilitation strategy;satellite cell;stem;stem cells;strength training;treatment as usual;treatment strategy;vastus lateralis

public_health_relevance:
Project Narrative:Anterior Cruciate Ligament reconstructions are a common procedure which result in significant quadricepsmuscle strength loss. A lack of evidenced-based interventions exist that restore quadriceps strength throughdirect targeting of the underlying morphologic and cellular maladaptations within the muscle. We propose tomechanistically test the ability of blood flow restricted training to improve these underlying physiologicaladaptations and improve knee mechanics and strength following an ACL reconstruction compared to usualcare.


application_id: 10478476
project_number: 1R44DK133065-01
project_title: Developing a new DFU dressing
administering_ic: NIDDK
award_notice_date: 2022-05-17
opportunity_number: PA-21-259
application_type: 1
activity_code: R44
ic: DK
serial_number: 133065
program_official: LI, YAN
project_start_date: 2022-05-17
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 SBIB-K (11)]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Diabetic foot ulcers (DFUs) are the leading cause of nontraumatic lower extremityamputations in the United States and are responsible for more hospitalizations than anyother complication of diabetes. Despite thousands of dressings developed in the pastcentury none have shown any specific effectiveness as DFU treatments. Currentlyeven the best available treatments achieve only a 50% healing rate for thesewoundsand this healing is often temporary with a 66% chance of recurrence. For the first time in history we have found an approach that may change the currentdogma. We have developed a technique for intracellular ATP delivery (ATP-vesicles orVitaSol). When we use VitaSol for wound healing granulation tissue starts toappear within 24 hours. This new tissue keeps growing and fills the wound cavitywithin a few days a phenomenon never seen or reported before by any othertechniques. Control dressings including normal saline free Mg-ATP empty lipidvesicles and the only FDA-approved prescription growth factor Regranex have nosuch effects. The final healing time is much shorter than the controls in long-timediabetic plus ischemic wounds. A preliminary mechanistic study has shown that theextremely rapid tissue regeneration is the result of very early (5 hours after surgery)rapid and massive macrophage accumulation in situ proliferation M2 polarization anddirect collagen production long before traditional fibroblasts come into play. This type ofhealing is totally different from the conventional process known to the wound carecommunity where fibrin platelets and red blood cells are the main components of theearly provisional matrix which is gradually replaced by granulation tissue during theproliferation phase after 36 days of lag time. Although the growth seen with VitaSolis extremely rapid it does not display any unusual growth or hypertrophic scar formationafter 2 years in animals and after more than 9 years in limited human volunteers. If thiscan be duplicated in humans it will be a major breakthrough in medicine. Our central hypothesis is that intracellular ATP delivery provides critical energy atvery early time activates various transcription mechanisms resulting in extremely earlyand rapid tissue regeneration that fills the wound cavity quickly. In this proposal we will perform a preclinical toxicity study aimed at IND applicationand test the effectiveness of VitaSolTM in a new animal model with long-term diabetesischemia and neuropathy. Our product for intracellular energy delivery has consistently been viewed asinnovative. The outcome of this project will be the clinical introduction of a highlyeffective inexpensive and easy-to-use new dressing for DFU treatment. The potentialimpact is very high.

project_terms:
Amputation;Animal Model;Animals;Becaplermin;Blood Platelets;Clinical;Clinical Trials;Collagen;Communities;Complications of Diabetes Mellitus;Cyclic GMP;Diabetes Mellitus;Diabetic Foot Ulcer;Effectiveness;Erythrocytes;FDA approved;Fibrin;Fibroblasts;Genetic Transcription;Granulation Tissue;Growth;Growth Factor;Hospitalization;Hour;Human;Human Volunteers;Hypertrophic Cicatrix;In Situ;Ischemia;Lipids;Lower Extremity;Medicine;Neuropathy;Normal saline;Operative Surgical Procedures;Outcome;Phase;Play;Preparation;Process;Production;Recording of previous events;Recurrence;Reporting;Sterile coverings;Techniques;Testing;Time;Tissues;Toxic effect;United States;Vesicle;Wound models;commercialization;diabetic;effective therapy;effectiveness testing;healing;innovation;macrophage;phenome;preclinical toxicity;success;tissue regeneration;wound;wound care;wound healing

public_health_relevance:
NARRATIVE Diabetic foot ulcers (DFUs) are the leading cause of nontraumatic lower extremityamputations but effective treatment is still lacking. In this proposal we will use ournewly developed intracellular ATP delivery for wound care in a newly developed long-term diabetes plus ischemia and neuropathy and to test its toxicity in preparation forFDA approval. The success of the project will have a major contribution to medicine.


application_id: 10478126
project_number: 5U44AA026126-04
administering_ic: NIAAA
award_notice_date: 2022-08-20
opportunity_number: PAR-15-154
application_type: 5
activity_code: U44
ic: AA
serial_number: 026126
program_official: SHIRLEY, MARIELA
project_start_date: 2017-08-25
project_end_date: 2024-08-31
study_section: ZAA1-DD(44)
contact_pi_person_id: 79171237
contact_pi: BURKLOW, CINDY ANN
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
budget_start_date: 2022-09-01
project_title:
Development of JR-220 (4-Chlorobenzylidenamino-guanidine hydrochloride) as a medication for alcohol dependence

project_abstract:
AbstractAlcohol dependence affects at least 4% of the US population with a financial cost in excess of $100Bn.Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target butcurrent treatments are ineffective and there is an urgent need for new medications. Major factors in causingrelapse include the protracted symptoms of withdrawal from alcohol which are relieved by returning todrinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence.There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcoholwithdrawal and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapsepharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2Bsubunit as a specific target in alcohol withdrawal and molecular screening identified several lead compounds.JR220 was the most active novel compound from an aryliminoguanidine series and its cellular effects onneuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety ofrodent screens relevant to alcohol dependence withdrawal and neurotoxicity including several screens inother laboratories. The drug was highly active in all of these screens with a potency 5-200x that ofacamprosate which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higherdoses but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the ratshowed dose dependent elevations of concentrations in plasma after intraperitoneal subcutaneous and oraladministration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasmasuggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 daysJR220 did not accumulate in plasma or brain and no overt toxicity was observed. The only concern is that theplasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. Thiscan be addressed by formulation as an oral extended release formulation or by a transdermal patch (whichwould also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as atreatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered byprovisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate asan anti-relapse medication and the current proposal is to develop the drug further for this use. The aim is nowto complete the studies required prior to submission of the drug to the FDA for consideration as aninvestigational new drug (IND). Thus in the proposed studies we will complete investigation of metabolism andmetabolite identification in vitro and Absorption Distribution Metabolism and Excretion in vivo. The studieswill also include a screen for off target actions and studies on safety and toxicology in two species (rats andnon-human primates). These studies will include escalating acute dose studies and sub-chronic studies (toreflect the maintenance of patients on anti-relapse medication). The best formulation and dosing schedule willthen be tested in a translational model of alcohol dependence in non-human primates. JR220 will be producedunder GMP conditions and production scaled up to meet requirements for future human trials. If an INDdesignation is obtained the objective will then be to partner with a major pharmaceutical company in testingthe drug in a human safety trial and then in clinical trials in alcohol dependent volunteers. The objective is todevelop JR220 for relapse prevention and neuroprotection to provide a pharmacotherapy that is more effectivefor these therapeutic targets than others currently available.

project_terms:
Acute;Address;Affect;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcohols;Autopsy;Binding;Biological Availability;Blood - brain barrier anatomy;Brain;Canis familiaris;Cardiovascular system;Chemicals;Chronic;Clinical;Clinical Trials;Complex;Data;Dependence;Development;Dose;Drug Kinetics;Enzymes;Equilibrium;Evaluation;Excretory function;FDA approved;Financial Hardship;Financial cost;Formulation;Future;Gastritis;Glutamates;Guanidines;Half-Life;Hepatic;Hepatocyte;Human;In Vitro;Intellectual Property;Investigation;Investigational Drugs;Kilogram;Label;Laboratories;Lead;Liver Microsomes;Lung;Macaca fascicularis;Maintenance;Maximum Tolerated Dose;Medical;Metabolism;Methods;Modeling;Molecular;Molecular Target;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Nerve Degeneration;Neurons;Oral;Oral Administration;Pathologic;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Physiological;Plasma;Plasma Proteins;Play;Polyamines;Population;Production;Rattus;Receptor Inhibition;Recovery;Relapse;Research;Rodent;Role;Route;Safety;Schedule;Sedation procedure;Series;Site;Symptoms;System;Testing;Therapeutic Uses;Toxic effect;Toxicokinetics;Toxicology;Up-Regulation;Validation;Withdrawal;Withdrawal Symptom;absorption;acamprosate;alcohol abuse therapy;alcohol exposure;alcohol use disorder;aminoguanidine;chemical synthesis;design;disorder later incidence prevention;drinking;drug testing;genotoxicity;high throughput screening;human subject;in vivo;ineffective therapies;intraperitoneal;meetings;neuroprotection;neurotoxicity;nonhuman primate;novel;novel therapeutics;phase 1 study;preclinical development;preclinical study;receptor;receptor function;reduce symptoms;scale up;screening;side effect;subcutaneous;therapeutic target;therapeutically effective;translational model;uptake;volunteer

public_health_relevance:
Project NarrativeDependence on alcohol is a very serious problem in the US with a huge medical and financial burden. Currenttreatments are unsatisfactory and new medications are required. The applicants have synthesized a novel drugthat has shown great promise in preclinical development and this proposal is to obtain the data necessarybefore investigation of the drug in the human.


application_id: 10477519
project_number: 1R56DK126935-01A1
administering_ic: NIDDK
award_notice_date: 2021-09-22
opportunity_number: PA-20-183
application_type: 1
activity_code: R56
ic: DK
serial_number: 126935
suffix: A1
program_official: HAMILTON, FRANK A
project_start_date: 2021-09-23
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-DNPD-A(01)]
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: O'GRADY, GREG
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_title:
Definitive Evaluation of Gastric Dysrhythmia as a Disease Mechanism by a Novel Body Surface Gastric Mapping Technique

project_abstract:
Functional dyspepsia and chronic nausea and vomiting syndromes affect >10% of the population inducing avast burden of ill-health and economic harm. Yet despite their enormous impact these diseases remain poorlyunderstood with few objective diagnostic tests available to subtype patients and direct therapies. There is apressing need for new mechanistic insights and diagnostic solutions that can better characterize thesecommon and burdensome disorders. In this proposal we translate and apply a new diagnostic approach withoutstanding potential to define mechanims of gastric dysfunction - Body Surface Gastric Mapping (BSGM).BSGM has been pioneered by our team and represents the first accurate non-invasive tool for detecting andmapping spatial patterns of gastric electrical activity. In this project we will apply BSGM to definitively resolvewhether gastric dysrhythmias are an important mechanism of gastric dysfunction. Although this hypothesis islongstanding it has never been adequately investigated because past clinical methods (electrogastrography;EGG) were inaccurate due to their technical limitations and their focus on frequency. Our preliminary BSGMdata is revealing new sensitive and specific spatial biomarkers of gastric dysfunction which correlate well withsymptoms and which were not addressable using previous EGG metrics such as frequency.Several innovations have converged to now enable the translation of BSGM in large clinical studies: flexiblearrays of 8x8 cutaneous electrodes a custom-built multichannel data-logger a symptom-tracking App coupledto the data-logger by Bluetooth and a sophisticated analysis pipeline to accurately map the retrieved signals.These BSGM innovations will be applied to definitively evaluate the clinical significance of gastric dysrhythmiaswith reference to an expert consensus guideline: Plausibility Criteria for Putative Mechanisms of GI FunctionalDisorders. This guideline identifies 5 specific criteria that must be met to validate new functional disordermechanisms and these criteria therefore also define our 5 Specific Aims: 1. Defining the presence of gastricdysrhythmia in a subset of patients with symptoms of gastric dysfunction; ii) Defining a temporal associationbetween gastric dysrhythmia and symptoms; iii) Correlation with symptom severity; iv) Induction of gastricdysrhythmia with symptom onset in healthy controls; and v) A congruent natural history. These aims will beaddressed by building and applying BSGM devices in non-invasive studies of 400 patients and 200 controls.The studies will be performed at two leading US motility centers of excellence backed by an interdisciplinaryteam of clinicians and bioengineers who share an outstanding track record for innovation and translation.This project is anticipated to yield 3 high-impact outcomes each of which would be a breakthrough advance inthe GI motility field: i) A definitive answer to the longstanding question of whether gastric dysrhythmias areclinically important; ii) Presenting BSGM as a new clinical diagnostic tool for gastric dysfunction; and iii)Validation of novel biomarkers and therapeutic targets through BSGM to guide future interventions.

project_terms:
Address;Adhesives;Adult;Affect;Antral;Anxiety;Back;Biological Markers;Biomedical Engineering;Bluetooth;Body Surface;Chronic;Clinical;Clinical Research;Clinical Trials;Consensus;Coupled;Custom;Cutaneous;Data;Devices;Diagnosis;Diagnostic;Diagnostic tests;Disease;Dyspepsia;Economic Burden;Electrodes;Electronics;Electrophysiology (science);Evaluation;Event;Frequencies;Functional Gastrointestinal Disorders;Functional disorder;Future;Gastric Emptying;Gastroesophageal reflux disease;Gastroparesis;Guidelines;Impairment;Intervention;Journals;Link;Maps;Mental Depression;Methods;Natural History;Nausea and Vomiting;Outcome;Patients;Pattern;Phenotype;Physiology;Population;Prevalence;Publishing;Quality of life;Radionuclide Imaging;Reflux;Research Personnel;Role;Rome;Series;Severities;Signal Transduction;Skin;Stomach;Stretching;Subgroup;Symptoms;Syndrome;Techniques;Technology;Testing;Translating;Translations;Validation;analysis pipeline;bioelectricity;cell motility;clinical care;clinical diagnostics;clinically significant;cohort;diagnostic platform;disease phenotype;electric impedance;flexibility;gut-brain axis;health economics;innovation;insight;new therapeutic target;noninvasive diagnosis;novel;novel diagnostics;novel marker;patient subsets;preclinical development;programs;response;response biomarker;therapeutic target;tool;translational study

public_health_relevance:
Disorders of gastric function impact >10% of the US population but remain poorly understoodwith a pressing need for new diagnostic tests to better define these diseases. We will translate anew clinical tool for non-invasively assessing gastric dysfunction called Body Surface GastricMapping which applies flexible skin electrodes to spatially map underlying patterns of gastricelectrical activity. We will apply this promising new diagnostic tool in large clinical studies todefine how gastric electrical abnormalities impact disease and to validate this new diagnosticapproach.


application_id: 10476401
project_number: 5R01MH119119-04
project_title: Estrogen Effects on ADHD and Cognition
administering_ic: NIMH
award_notice_date: 2022-08-31
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: MH
serial_number: 119119
program_official: PACHECO, JENNIFER LYNN
project_start_date: 2019-09-10
project_end_date: 2025-08-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 8204810
contact_pi: MARTEL, MICHELLE M
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:
Females with Attention-Deficit/Hyperactivity Disorder (ADHD) remain dramatically understudied even thoughthey exhibit increased impairment beginning around puberty. Estrogen rises rapidly at puberty and exertsimportant effects on dopamine and cognition in both humans and animals. Both animal and human worksuggest that cognition and ADHD symptoms may be sensitive to hormonal effects particularly in highlyimpulsive females. Yet the effect of estrogen on ADHD symptoms in young adult women remains virtuallyunstudied. Our pilot data in 33 naturally-cycling young women suggest that among women with greater ADHDsymptoms within-person declines in estrogen particularly in the context of rising levels of progesterone justpost-ovulation are associated with clinically significant increases in ADHD symptoms. Yet no publishedempirical work has directly examined the role of circulating estrogen in relation to ADHD symptoms andcognitive mechanisms in women with ADHD. The current study would pioneer a new stage of work by beingthe first to utilize a rigorous quasi-experimental design that involves intensive longitudinal measurement acrossthe menstrual cycle in order to examine within-person estrogen effects on ADHD and cognitive mechanisms inyoung women with ADHD. A sample of 120 young women ages 18 to 25 with inattention overactivity orimpulsivity problems will be recruited from the university health center and local ADHD clinic psychologydepartment and through social media. Participants will be comprehensively assessed for ADHD and exclusioncriteria (e.g. use of hormone-based medication or hormonal conditions). Female participants will completewell-established assessment measures of ADHD and other psychopathological symptoms and diagnoses andcognition and provide saliva samples of hormones in the laboratory during a baseline laboratory visit within thefirst few days of the start of their menstrual cycle (i.e. during the mid-follicular phase characterized by stablelow estrogen). Then they will provide daily saliva samples for hormone assay each morning and completeshort daily assessments of ADHD and cognition every evening for up to 2 full menstrual cycles. They will alsocomplete laboratory cognitive testing of inhibition and working memory targeted to key cycle phasescharacterized by declining estrogen (post-ovulatory perimenstrual) and a cycle phase characterized by stablehigh estrogen levels (midluteal) based on menses onset and ovulation test results. Multi-level modeling willevaluate the clinical significance of within-person estrogen associations with ADHD and cognition withconsideration of progesterone as an interactive factor. Effects of comorbid disorders and affect will also beexplored. Study results have the potential to shift our understanding of ADHD in women by consideration ofdynamic hormone influences. In addition results will change clinical practice by indicating the need to accountfor cycle phase in ADHD evaluations in women as well as suggest personalized approaches to treatmenttargeted to cycle phase or hormone levels.

project_terms:
Adolescence;Adult;Affect;Age;Animals;Attention;Attention deficit hyperactivity disorder;Back;Basic Science;Biological;Biological Assay;Childhood;Clinic;Clinical;Cognition;Cognitive;Communities;Data;Deltastab;Diagnosis;Disease;Dopamine;Estradiol;Estrogens;Evaluation;Exclusion Criteria;Exhibits;Feasibility Studies;Female;Goals;Gonadal Steroid Hormones;Health;Hormonal;Hormone use;Hormones;Human;Impairment;Impulsivity;Laboratories;Link;Longitudinal Studies;Measurement;Measures;Menstrual cycle;Menstruation;Neurocognitive;Ovarian hormone;Ovulation;Participant;Persons;Pharmaceutical Preparations;Phase;Prevalence;Progesterone;Psychology;Puberty;Publishing;Quasi-experiment;Rattus;Research Design;Risk;Risk Factors;Role;Sampling;Short-Term Memory;Symptoms;Test Result;Testing;Thinking;Translating;Universities;Visit;Withdrawal;Woman;Work;animal data;base;clinical practice;clinical predictors;clinically significant;cognitive function;cognitive performance;cognitive testing;comorbidity;design;falls;hypothalamic pituitary gonadal axis;improved;inattention;innovation;male;multilevel analysis;perimenstrual;personalized approach;proliferative phase Menstrual cycle;recruit;response;saliva sample;sex;social media;treatment response;virtual;young adult;young woman

public_health_relevance:
The current project will evaluate how changes in hormones across the menstrual cycle influence Attention-Deficit/Hyperactivity Disorder (ADHD) and thinking in young adult women. Results will change the way ADHDis understood by suggesting hormonal influences on ADHD symptom expression in women changing clinicalpractice by requiring consideration of sex pubertal status menstrual cycle phase or even hormone profiles in assessment and treatment of ADHD in women.


application_id: 10475845
project_number: 5R37CA229337-05
project_title: Adoption of Smoke-free Laws and Voluntary Policies in Rural Communities in Southern States
administering_ic: NCI
award_notice_date: 2022-08-02
opportunity_number: PAR-17-217
application_type: 5
activity_code: R37
ic: CA
serial_number: 229337
program_official: REYES-GUZMAN, CAROLYN
project_start_date: 2018-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-RPHB-N(56)R]
contact_pi_person_id: 11363954
contact_pi: FALLIN-BENNETT, AMANDA
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
project_abstract:
AbstractSmoking remains high in Americas rural southern population despite rapid declines in other regions of the U.S.in recent decades. While 58.3% of U.S. citizens are covered by comprehensive smoke-free (SF) laws only16.7% of citizens living in the East South Central or the South Atlantic regions are protected. Current bestpractices for SF law advocacy have not been effective in closing the gaps in coverage for rural southernresidents. Meanwhile adoption of voluntary policies (e.g tobacco-free schools public housing outdoorspaces) have accelerated nationwide. The presence of voluntary policies may increase readiness for SF policyadoption or they may derail SF law adoption in rural municipalities in southern states. Our study is innovativebecause we will incorporate a political theory Kingdons Multiple Streams framework to guide SF law adoptionresearch in a region with tobacco use disparities. The Specific Aims are to: 1) determine the differencesbetween rural municipalities with and without SF laws in regard to community readiness problem indicators(e.g. smoking prevalence) focusing events and feedback; politics (e.g. consensus building); policy factors(e.g. anticipated constraints); and policy entrepreneurs (e.g. strength of tobacco control) controlling forpopulation size and other demographic factors; 1a) compare the number and type of voluntary smoke- andtobacco-free policies (e.g % tobacco-free schools public housing outdoor spaces) in rural municipalities withand without SF laws; and 2) describe facilitators and barriers in the sociopolitical environment that impactadvocacy strategies the policy window (e.g. the tipping point for policy adoption) and enactment of SF laws inrural municipalities with and without SF laws. We will use a mixed methods case-control design to conducttelephone and online surveys to assess policy adoption factors with local advocates (N = 150-250) and electedofficials (N = 150) from 50 municipalities (cities towns or villages) (25 cases; 25 controls) nested within fourstates: Alabama Kentucky Mississippi and South Carolina. Case municipalities will have enacted a SF lawwithin the past 3 years; controls will be matched with cases in each state based on community population sizeand rurality. Using qualitative methods we also will conduct in-depth interviews with community leaders citizenactivists and policymakers in case municipalities with the most recent SF law and their matched controls fromeach state (two communities per state; 10-15 key informants per community). Participants will be asked todescribe factors affecting SF policy adoption and asked to comment on key events that may have contributedto or inhibited policy adoption. A Community Advisory Board consisting of 8 leaders in tobacco control and SFlaw adoption in rural areas and representing the four southern states will guide all aspects of the study. Thisstudy will shift the current research paradigm to a new way of understanding SF law adoption in rural southernmunicipalities. Tobacco-related health disparities will continue to lead to poor health outcomes and enormoussocietal costs in rural southern municipalities until we can advance the science of SF policy adoption.

project_terms:
Address;Adopted;Adoption;Advocacy;Advocate;Affect;Alabama;Area;Cities;Communities;Complex;Consensus;Demographic Factors;Environment;Event;Feedback;Fostering;Future;Goals;Government;Health;Intervention;Interview;Kentucky;Laws;Lead;Methods;Mississippi;Modeling;Municipalities;Outcome;Participant;Policies;Policy Developments;Politics;Population;Population Sizes;Psychosocial Factor;Public Health;Public Housing;Published Comment;Qualitative Methods;Readiness;Research;Rural;Rural Community;Schools;Science;Smoke;Smoking;Social Change;Social Justice;South Carolina;Stream;Surveys;Telephone;Tobacco;Tobacco smoke;Tobacco use;Urban Community;Work;Workplace;base;case control;community engaged research;design;evidence base;experience;health disparity;improved;informant;innovation;reduce tobacco use;rural America;rural area;rurality;self reliance;smoke-free policy;smoking prevalence;social norm;societal costs;success;theories;tobacco control;tobacco-free;treatment group

public_health_relevance:
NarrativeSmoking rates remain high in rural southern areas in part because of regional disparities in smoke-free laws.Current best practices have not been effective in closing gaps in coverage. This study will shift the currentresearch paradigm to a new way of understanding smoke-free policy adoption in rural southern communities.


application_id: 10475257
project_number: 5R25CA221765-05
project_title: Appalachian Career Training in Oncology (ACTION) Program
administering_ic: NCI
award_notice_date: 2022-08-08
opportunity_number: PAR-17-059
application_type: 5
activity_code: R25
ic: CA
serial_number: 221765
program_official: GHOSH, SANGEETA AHUJA
project_start_date: 2018-09-18
project_end_date: 2023-08-31
study_section: ZCA1-RPRB-Z(O2)
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
other_pis: EVERS, BERNARD MARK;FRAZIER, DONALD T
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:
PROJECT SUMMARY/ABSTRACTAppalachian Kentucky has significant challenges associated with health socioeconomic and educationdisparities. This predominantly rural region not only has the highest cancer incidence and mortality rates in theUnited States it is also one of the most economically disadvantaged medically underserved and poorlyeducated regions of the country in which less than 1% of residents earn doctoral degrees. These disparities formthe basis for the need to create targeted educational and scientific workforce preparedness and health literacyintervention strategies for this population. As such the research educational and outreach strengths of theUniversity of Kentucky's Markey Cancer Center will be leveraged to develop the Appalachian Career TrainingIn ONcology (ACTION) Program as a Youth Enjoy Science education intervention. The ACTION Program willimmerse underrepresented and underserved high school and undergraduate students from AppalachianKentucky in cross-disciplinary mentored research projects cancer care observational experiences and cancereducation and career development activities as well as provide hands-on community and school outreachopportunities. The overarching goal of the program is to enhance cancer-focused biomedical workforce diversityin a high-risk rural population and to increase the community's cancer-related literacy. Expected impacts of theprogram include: 1) increasing our students' matriculation into post-secondary professional and/or graduatescience degree programs; 2) instilling in our students lifelong commitments to research education/outreach orhealth care careers focused on the cancer burden and unique challenges in Appalachian Kentucky and beyond;and 3) enhancing the Appalachian Kentucky community's understanding of cancer research and clinical carelinking these facets to the benefits of science education. The overarching goal and the program impacts will beaccomplished through four Specific Aims including: 1) developing participants' cancer research knowledge andskills through cross-disciplinary faculty-mentored research training experiences; 2) enhancing students' cancer-focused career preparation by providing didactic cancer education and career development mentoring throughfaculty-led courses workshops seminars and career coaching and mentoring; 3) conducting outreach activitiesin participant communities to increase the understanding of the research and clinical aspects of cancer and theimportance of science education among universities; primary and secondary school groups; civic organizations;health care providers; and the families and communities of our student participants; and 4) evaluating programprogress and impacts focusing on longitudinal participant data (including tracking progression of participantsthrough their academic and professional careers) and outreach activity efficacy. Ultimately the program willestablish a new paradigm for enhancing cancer-focused educational preparation among rural low-socioeconomic students and increasing citizens' understanding of cancer and the importance of scienceeducation in rural low-socioeconomic and low-education-attainment areas.

project_terms:
Academic achievement;Achievement;Address;Appalachian Region;Area;Award;Cancer Burden;Cancer Center;Cancer Research Project;Clinical;Communities;Country;County;Data;Degree Completion;Degree program;Doctor's Degree;Early Intervention;Economically Deprived Population;Education;Education and Outreach;Educational Intervention;Educational workshop;Faculty;Family;Fostering;Funding;Goals;Health;Health Personnel;Healthcare;Home;Incidence;Income;Intervention;Kentucky;Knowledge;Link;Literature;Localized Malignant Neoplasm;Malignant Neoplasms;Mentors;Mentorship;Participant;Population;Poverty;Poverty Areas;Preparation;Primary Schools;Readiness;Research;Research Project Grants;Research Training;Rest;Rural;Rural Population;Schools;Science;Secondary Schools;Socioeconomic Status;Students;Training;Training and Education;Underrepresented Students;Underserved Population;United States;Universities;Youth;anticancer research;cancer care;cancer education;cancer health disparity;cancer site;career;career development;career preparation;clinical care;economic indicator;education research;experience;faculty mentor;health literacy;high risk;high school;higher education;literacy;matriculation;medically underserved;mortality;oncology program;outreach;peer;peer learning;peer networks;programs;rural area;science education;skills;socioeconomic disparity;socioeconomics;student training;undergraduate student;underserved community;underserved students

public_health_relevance:
PROJECT NARRATIVEKentucky has the highest all-site cancer incidence and mortality rates in the United States with the highest burdenof cancer localized to the Appalachian region of the state. Residents of Appalachian Kentucky also experiencehigh rates of poverty and below-average education attainment. To address these issues we will create theAppalachian Career Training In ONcology (ACTION) Program which proposes a new paradigm to foster cancer-focused education and training for students from rural low-socioeconomic and low-education-attainmentcommunities and to develop a better understanding of cancer and the benefits of cancer education within suchunderserved communities.


application_id: 10475253
project_number: 5UG1OD024954-05
project_title: The Kentucky ECHO Pediatric IDeA Research Center (KE-PIRC)
administering_ic: OD
award_notice_date: 2022-08-12
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_abstract:
PROJECT SUMMARY/ABSTRACT As a predominantly rural state Kentucky leads the nation in many pediatric and adult chronic andenvironmentally-related diseases and ranks nationally in low educational achievement. These adverse factorscombine to make Kentuckians especially unhealthy residents with a high prevalence of obesity diabetessmoking alcohol use heart disease stroke lung cancer etc. Many of these diseases are environmentallyrelated to poor nutrition obesity smoking drug abuse and work-place exposures. Kentucky also leads thenation in the percentage of pediatric populations with special health care needs. Prior work has shown thatmost adult diseases have their origin in childhood and some begin during fetal development making childhoodthe ideal time for intervention with the goal of improving health outcomes into adulthood. Improving healthcare outcomes and wellness in children is contingent on expanding and sustaining highquality clinical research that includes diverse populations. Pediatricians at the University of Louisville (UofL)with our Healthcare Partners serve a highly diverse patient population that includes the rural and urban poor aunique Appalachian community refugees and numerous ethnic minorities. To better serve this population wepropose to build upon our current programs expand our bidirectional community engagement effortscollaborate with other institutions on pediatric clinical trials through the ECHO IDeA Pediatric Clinical TrialsNetwork and collaborate with ECHO cohort INBRE and CTSA sites to advance healthcare for children.Education and training of local and regional faculty and staff is critical to sustain this initiative. The Kentucky ECHO-Pediatric IDeA Research Center (KE-PIRC) as part of the IDeA States Pediatric ClinicalTrials Network will make it possible for 1) rural and underserved infants children and adolescents toparticipate in clinical research; 2) junior investigators to be trained in clinical research and communityengagement improve the health of both children and adults in Kentucky through this research and developtheir academic career; and 3) the development of a regional network of partners to sustain this clinicalresearch initiative. The five primary focus areas are 1) pre- peri- and postnatal outcomes; 2)neurodevelopmental; 3) upper and lower airway disease; 4) obesity; and 5) positive health. These primaryfocus areas are highly prevalent in Kentucky; therefore KE-PIRC will enable strengthening currentcollaborations and accelerate the development of new networks within the state through bidirectionalcommunity engagement and feedback to support pediatric clinical research. Through these efforts we aim toimprove the health outcomes of Kentucky children and adults and establish a local and national sustainablepediatric clinical research workforce.

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;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

public_health_relevance:
PROJECT NARRATIVEThe Kentucky ECHO-Pediatric IDeA Research Center (KE-PIRC) as part of the ECHO IDeA States PediatricClinical Trials Network will continue to make it possible for 1) rural and underserved infants children andadolescents to participate in clinical research; 2) junior investigators to be trained in clinical research andcommunity engagement improve the health of both children and adults in Kentucky through this research anddevelop their academic career; and 3) the development of a regional network of partners to sustain this clinicalresearch initiative. The five primary focus areas are 1) pre- peri- and postnatal outcomes; 2)neurodevelopmental; 3) upper and lower airway disease; 4) obesity; and 5) positive health. These primaryfocus areas are highly prevalent in Kentucky therefore the efforts of the KE-PIRC in collaboration with ourcommunity partners will improve the health outcomes of Kentucky children and adults.


application_id: 10475242
project_number: 5R25GM125680-05
project_title: Interactive Mentoring to Enhance Research Skills (IMERS)
administering_ic: NIGMS
award_notice_date: 2022-09-02
opportunity_number: PAR-17-070
application_type: 5
activity_code: R25
ic: GM
serial_number: 125680
program_official: STOKES, KALYNDA K
project_start_date: 2018-09-01
project_end_date: 2025-08-31
study_section: ZGM1-TWD-7(IP)
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: FRAZIER, DONALD T
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:
PROJECT SUMMARY/ABSTRACTIn an era of increasingly competitive biomedical funding as well as recognized needs for bolder efforts tofacilitate inclusion of disparate perspectives in 21st century discoveries that impact human health theimportance of successful grant-seeking skills and behaviors is clear. Recent findings of underrepresentation ofminority scientists in award of biomedical research grants underscore the importance of this skill set for facultyat institutions with significant enrollments of underrepresented students. Similarly the role of research projectfunding as a pipeline for student development as next-generation researchers places even greater importanceon the need for skills training in research mentoring. To address these two integrated needs the University ofKentucky (UK) proposes Interactive Mentoring to Enhance Research Skills (IMERS) as a workshop series toprovide interactive grant-writing training for faculty cohorts from minority-serving institutions (MSIs) across theUnited States. The IMERS training in NIH-focused grantsmanship will be coupled with professionaldevelopment on research education mentoring for participating faculty. The program based on a well-established long-running conference grant program directly addresses issues of diversity in biomedicalresearch. The proposed expansion to a research education program reflects two new priorities: a newprofessional development intervention to train participants in skills and strategies to effectively mentor studentsin research and direct engagement of a research-active program faculty to serve in mentor and outreach roles.IMERS will continue a grantsmanship training model that incorporates guided writing participatory training andactive learning. The core event is a three-day grant-writing workshop to be held on the UK campus for twodifferent faculty cohorts (25 participants per event) each year. Off-site regional or institution-specific eventsprovide opportunities for complementary outreach and a continuum of mentored support. Specific aims are to:1) engage participants in hands-on active-learning style grant-writing training for selected faculty poised tosubmit NIH proposals ranging from developmental/exploratory to R01s; 2) to provide targeted training ineffective laboratory-based research training and mentorship strategies; and 3) to provide mentored post-workshop proposal development support from a broad community of funded research mentors and researchdevelopment professionals. The proposed PI-centered IPERT provides an integrated model of skillsdevelopment mentoring and outreach that collectively feature guided proposal development support usingparticipants' own developing research narratives. In addition the mentoring components span initial hands-onmentoring during group workshop sessions proposal-specific one-on-one consultations with mentors andsubsequent post-workshop support. Expected outcomes are to facilitate individual faculty skills development inresearch and research education for faculty from MSIs with limited research development resources.

project_terms:
Active Learning;Address;Award;BRAIN initiative;Behavior;Biomedical Research;Communities;Consultations;Coupled;Development;Discipline;Diverse Workforce;Educational workshop;Enrollment;Event;Extramural Activities;Faculty;Foundations;Funding;Future;Goals;Grant;Health;Human;Individual;Institution;Kentucky;Laboratories;Malignant Neoplasms;Mentors;Mentorship;Minority;Minority-Serving Institution;Mission;Modeling;Motivation;Outcome;Participant;Personal Satisfaction;Productivity;Research;Research Personnel;Research Project Grants;Research Support;Research Training;Resource Development;Role;Running;Science;Scientific Advances and Accomplishments;Series;Site;Statistical Data Interpretation;Students;Teacher Professional Development;Time;Training;Training and Education;Underrepresented Minority;Underrepresented Students;United States;United States National Institutes of Health;Universities;Writing;base;career;cohort;community based participatory research;data management;demographics;design;education research;experience;extended reality;faculty research;innovation;interest;minority scientist;minority undergraduate;next generation;outreach;post-doctoral training;precision medicine;programs;research and development;skill acquisition;skills;skills training;student mentoring;student training;success;symposium;therapy development;training opportunity

public_health_relevance:
PROJECT NARRATIVEDiversity in the biomedical workforce is essential to the ability to enlist the power of divergent perspectives togenerate discovery-driven innovations in biomedical research. The proposed program is designed to facilitatethe success of researchers at minority-serving institutions in competing for extramural funding and inimplementing effective mentored research education activities for their students thereby exerting a substantialimpact on the health and well-being of our citizens.


application_id: 10475211
project_number: 5U01HL152392-04
project_title: Kentucky Network for Innovation & Commercialization (KYNETIC)
administering_ic: NHLBI
award_notice_date: 2022-08-18
opportunity_number: RFA-OD-19-014
application_type: 5
activity_code: U01
ic: HL
serial_number: 152392
program_official: BERZHANSKAYA, JULIA
project_start_date: 2019-09-23
project_end_date: 2025-08-31
study_section: ZHL1-CSR-O(S1)
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: MERTEN, KEVYN E
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:
ABSTRACTKnowledge generated by academic research is a major source of health-related innovations. Transforminginnovative discoveries into commercialized products that improve human health is a difficult process. Howeverall stakeholders (universities funding bodies pharmaceutical and medical device industries federal and stategovernments and the public) have a vested interest in identifying scalable approaches that accelerate thetranslation of academic innovations into biomedical products. The goal of the Kentucky Network for Innovationand Commercialization (KYNETIC) is to build a Research Evaluation and Commercialization Hub (REACH)network of commercialization resources accessible across the entire Commonwealth of Kentucky to acceleratetranslation of academic innovations into biomedical products. To reach this goal the following aims will beconducted: 1) establish KYNETICs organizational and collaborative structure; 2) Find fund and manage productdefinition/development projects; 3) Provide mentoring skills development experiential education and networkingopportunities with industry experts entrepreneurs and investors; and 4) Devise and implement a plan totransition to a self-sustaining entity. KYNETIC will build on lessons learned from developing a regional IDeAtechnology transfer accelerator (at UK) and a current REACH hub (at UL). KYNETIC will be led by the Universityof Kentucky (UK) in partnership with the University of Louisville (UL) and the Commonwealth CommercializationCenter (C3) a private 501(c)3 non-profit commercialization organization. Also KYNETIC will include all ofKentuckys public regional universities and community and technical college system (KCTCS). KYNETICsmission is to nurture innovations and academic innovators by providing funding mentoring education and anetwork of relevant expertise. Required matching funds for KYNETIC have been committed in full by KentuckyCommonwealth Economic Development (CED) and the state R1 universities. KYNETIC will be directed by aleadership team consisting of 2 academic innovators 2 technology transfer professionals (from UK and UL) and2 representatives from partnering entities (C3 and CED). A steering committee including the leadership teamand representatives from each participating institution an External Review Board and the NIH will review andevaluate KYNETIC projects and fund up to 13 projects/yr using an innovative quick kill management strategy.Our services will be available to as many individuals as possible. Diverse role models including innovators andentrepreneurs from underrepresented groups will be sought. The proposed Kentucky-wide REACH program willleverage our collective wealth of resources ecosystems and extensive experience to apply and expand bestpractices for innovator education and mentoring. The overall impact of KYNETIC will be unprecedentedopportunities for collaboration and synergy well-prepared innovators a statewide pro-entrepreneurial cultureand delivery of de-risked technologies to benefit health and overcome the states health disparities.

project_terms:
Address;Area;Back;Biomedical Research;Businesses;Clinic;Collaborations;Complement 3a;Development;Devices;Diagnostic tests;Economic Development;Economics;Ecosystem;Education;Entrepreneurship;Evaluation Research;Federal Government;Fund Raising;Funding;Goals;Grant;Health;Health Benefit;Human;Individual;Industry;Institution;Kentucky;Knowledge;Laboratories;Leadership;Licensing;Medical Device;Mentors;Mission;Modeling;Paper;Pharmacologic Substance;Principal Investigator;Private Sector;Privatization;Process;Publishing;Research;Resources;Risk;Services;Site;Source;State Government;Structure;System;Technology;Technology Transfer;Text;Translational Research;Translations;Underrepresented Populations;United States;United States National Institutes of Health;Universities;Work;biomedical resource;college;commercialization;community college;experience;health disparity;improved;industry partner;innovation;interest;member;novel therapeutics;programs;public-private partnership;role model;skill acquisition;synergism;technical college;tool

public_health_relevance:
NARRATIVEThe goal of the Kentucky Network for Innovation and Commercialization (KYNETIC) is to build a ResearchEvaluation and Commercialization Hub (REACH) network of commercialization resources accessible across theentire Commonwealth of Kentucky to accelerate translation of academic innovations into biomedical products.KYNETIC will nurture innovations and academic innovators by providing funding mentoring education and anetwork of relevant expertise. The overall impact of KYNETIC will be unprecedented opportunities forcollaboration and synergy well-prepared innovators a statewide pro-entrepreneurial culture and delivery of de-risked technologies to benefit health and overcome the states health disparities.


application_id: 10475204
project_number: 5K01CA251487-03
project_title: Promoting Cervical Cancer Screening among African American and Sub-Saharan African Immigrant women
administering_ic: NCI
award_notice_date: 2022-08-29
opportunity_number: PAR-18-365
application_type: 5
activity_code: K01
ic: CA
serial_number: 251487
program_official: VAHEDI, SHAHROOZ
project_start_date: 2020-09-02
project_end_date: 2025-08-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 14387971
contact_pi: ADEGBOYEGA, ADEBOLA O
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
project_abstract:
PROJECT SUMMARY/ABSTRACTThe highest incidence rates of cervical cancer (CC) are in sub-Saharan Africa South Central Asia and SouthAmerica. In the United States (U.S.) CC ranks 14th in frequency. However in certain populations and geographicareas of the U.S. CC incidence and death rates are significantly higher due in part to racial and ethnic disparitiesin access utilization and quality of care all of which contribute to worse health outcomes. Black womenexperience a disparate burden of CC incidence and mortality having a higher risk of being diagnosed with anddying from CC than non-Hispanic White women. Appropriate and timely CC screening is a key factor inprevention. Leveraging the positive benefits of CC screening may reduce the CC disparate burden amongBlacks. Research studies typically treat Blacks as a homogeneous group despite differences within thispopulation. To begin to address a gap in the literature within the scope of a career development award thisstudy focuses specifically on two subgroups of Black women - African Americans (AA) and Sub-Saharan Africanimmigrants (SAI) given that there is paucity of research with SAI despite known cancer related disparities amongSAI women. To promote screening for these underserved minority women we will conduct research to betterunderstand factors that influence engagement in cancer screening practices and willingness to conduct HPVself-sampling in which women self-collect samples for HPV testing using a swab brush or lavage. Guided by thefindings we will develop and pilot test an innovative tailored intervention incorporating HPV self-sampling withpeer-delivered education. The specific aims are to (1) examine general awareness and cultural factors relatedto cancer control and prevention among AA and SAIs; (2) examine the socioecological barriers and facilitators toCC screening with HPV self-sampling to tailor an evidenced based cervical health promotion program in theseunderserved subgroups; and (3) assess feasibility acceptability and preliminary efficacy of the intervention. Theintervention entitled Health is Wealth: A Cervical Health Program will be pilot tested with 30 AA and 30 SAIwomen aged 30 to 65 years using a quasi-experimental design. These aims will also support the candidatescareer goal of developing an independent and extramurally funded program of research to promote cancercontrol and prevention for minority women. To further support this goal a mentored career development planconsisting of training in mixed methods adaptation and development of behavioral interventions randomizedclinical trial design and research team management is proposed. The rich research environment at theUniversity of Kentucky and the expertise of the mentoring team will provide the supplemental resources andsupport needed for the candidate to successfully complete the proposed research and training plans. As suchthis K01 award will provide the training mentoring and research experiences needed for the candidate tosuccessfully compete for a R01-level CC screening intervention study and expedite her career development.

project_terms:
Address;Africa South of the Sahara;African;African American;African American population;Awareness;Behavior Therapy;Belief;Black Populations;Cancer Control;Cancer Etiology;Central Asia;Cervical;Cervical Cancer Screening;Cessation of life;Clinic Visits;Clinical Trials Design;Collection;Consent;Cross-Sectional Studies;Data;Death Rate;Developing Countries;Development;Development Plans;Diagnosis;Education;Emotional;Environment;Evidence based intervention;Extramural Activities;Frequencies;Fright;Funding;Future;Geographic Locations;Goals;Health;Health Promotion;Health behavior;Health education;Healthcare Systems;Human Papillomavirus;Human papilloma virus infection;Immigrant;Incidence;Individual;Intervention;Intervention Studies;Irrigation;K-Series Research Career Programs;Kentucky;Knowledge;Lesion;Literature;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentored Research Scientist Development Award;Mentors;Methods;Minority;Minority Women;Modality;Modeling;Not Hispanic or Latino;Outcome;Outcome Measure;Pattern;Physicians;Population;Population Heterogeneity;Population Study;Preventative vaccination;Prevention;Privatization;Quality of Care;Quasi-experiment;Race;Randomized Clinical Trials;Research;Research Personnel;Research Training;Resources;Role;Sampling;Screening for cancer;Screening procedure;Self Efficacy;Sensitivity and Specificity;South America;Structure;Subgroup;Swab;Testing;Time;Training;Treatment Efficacy;Underserved Population;United States;Universities;Visit;Vulnerable Populations;Woman;aged;anticancer research;behavior change;behavior influence;black men;black subgroup;black women;cancer health disparity;cancer prevention;career;career development;cervical cancer prevention;cost;evidence base;experience;health belief;health care availability;health knowledge;high risk;high risk population;innovation;intervention effect;mortality;peer;pilot test;prevent;programs;racial and ethnic disparities;recruit;research study;satisfaction;screening;screening participation;skills;social;social cognitive theory;underserved minority;willingness

public_health_relevance:
PROJECT NARRATIVEDespite the availability of screening tools that can prevent cervical cancer Black women are burdened by highcervical cancer incidence and mortality. This project seeks to enhance cervical cancer screening among Blackwomen African Americans and sub-Saharan African immigrants by tailoring and pilot testing an evidence-basedintervention incorporating HPV self-sampling and peer-delivered education to promote cervical cancerscreening.


application_id: 10474405
project_number: 5R01DA046526-04
project_title: Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
administering_ic: NIDA
award_notice_date: 2022-08-16
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_abstract:
PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a significant burden to public health. Nicotine an active alkaloid intobacco is responsible for addiction to tobacco-containing products such as cigars cigarettes and vaporizedliquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surgein popularity of nicotine-containing e-cigarettes there is a great need for innovative research on theneurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brainregions associated with drug reward especially within the nucleus accumbens core (NAcore). NAcoreglutamatergic mechanisms are involved in nicotine relapse including rapid transient potentiation of synapticstrength (t-SP; measured as increased AMPA to NMDA ratios) and accompanying glutamate receptor changes.Due to the cue dependency of smoking behavior exposure to nicotine-associated cues is a risk factor for relapse.We and others recently found that N-acetylcysteine (NAC) an antioxidant and anti-inflammatory currently underinvestigation as an addiction therapeutic appears to inhibit nicotine cue-associated t-SP and restore glialglutamate transport (GLT-1). As well preliminary data collected during an R00 award period indicate that NAcoreGLT-1 restoration is necessary for NAC to reduce nicotine seeking and NAC inhibits expression of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) within the NAcore. TNF activates nuclear factor-kappa B (NF-B) signaling and regulates learning memory and synaptic plasticity. Thus in Aim 1 we proposeto characterize the role of NF-B signaling in nicotine self-administration and cued nicotine seeking. As well thisaim will determine if TNF signaling impacts t-SP during cued nicotine relapse and if a monoclonal antibodyagainst TNF can inhibit these aberrant processes. Importantly TNF monoclonal antibodies are used clinicallyfor autoimmune disorders and are known to inhibit TNF from binding to its receptor. Aim 2 will then determinethe role of microglia in t-SP and nicotine seeking using chemogenetics. Interestingly we have found that GLT-1expression rapidly increases along with t-SP during cued nicotine seeking. It is unclear however if this isregulated by neuroinflammation and accompanied by astrocyte and microglial migration to the synapse duringnicotine seeking. Therefore in Aim 3 we propose to bi-directionally control microglia using chemogenetics todetermine their ability to gate NAcore astrocyte-synaptic contact during nicotine seeking. In conclusion findingsfrom these investigations will uncover an active dynamic role of neuroinflammatory signaling in nicotine self-administration and cue-driven nicotine relapse-associated synaptic plasticity and broaden the scope of ourcurrent understanding of neurobiological mechanisms underlying nicotine addiction.

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;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

public_health_relevance:
PROJECT NARRATIVENicotine addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability evenafter extended drug abstinence. The proposed research has the potential to reveal novel neuroimmunologicalmechanisms of nicotine addiction which could contribute to the development of novel therapeutic options aimedat reversing nicotine-induced alterations in the brain and promoting nicotine use cessation.


application_id: 10473896
project_number: 5F99CA264165-02
project_title: Aberrant Glycogen Modulates Metabolism in Ewings Sarcoma
administering_ic: NCI
award_notice_date: 2022-08-30
opportunity_number: RFA-CA-20-048
application_type: 5
activity_code: F99
ic: CA
serial_number: 264165
program_official: ELJANNE, MARIAM
project_start_date: 2021-09-01
project_end_date: 2023-01-03
study_section: ZCA1-SRB-H(M1)
contact_pi_person_id: 16250663
contact_pi: YOUNG, LYNDSAY E A
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:
Project Summary Ewing's sarcoma (ES) is the second most common pediatric bone malignancy affecting ~10000 childrenadolescents and young adults worldwide each year. Approximately half of all patients with Ewing's sarcomawill develop either recurrent or metastatic disease with less than 20% of such patients surviving long-term. Thestandard of care for ES patients includes multi-agent chemotherapy to treat documented or potential metastaticdisease coupled with surgery and/or irradiation to treat the primary tumor. Although some incrementaladvances have been made in the last three decades through intensification of conventional chemotherapyagents more significant improvements will likely depend on the identification of novel treatment strategies.Two hallmark clinical features of ES are: 1) the accumulation of intracellular glycogen deposits that arePeriodic acid-Schiff positive (PAS+) during pathological analysis and 2) the EWS-FLI1 fusion oncogene.Contribution of EWS-FLI1 to tumorigenesis and epigenetics is well defined but little is known about the biologyand pathology of ES glycogen accumulation nor has ES glycogen metabolism been explored as an anti-EStarget. The aims presented in this proposal are designed to interrogate the role of glycogen metabolism inpromoting tumorigenesis in ES and extend my career in cancer metabolism. My preliminary data demonstrateglycogen in ES models has aberrant architecture with long chains increased branching pattern and highphosphate content. Thus this glycogen is more similar to pathogenic polyglucosan bodies (i.e. ES-PGBs) anddisrupts normal cellular processes. Excitingly I have demonstrated that targeting ES-PGBs using a glycogensynthase inhibitor reduces in vivo tumor growth. I will expand on these findings in Aim 1 by demonstrating ES-PGBs alter cellular energy homeostasis utilizing high-throughput metabolomics profiling and innovativebiochemical assays in vitro and in vivo. These results will advance our understanding of glycogen metabolismin ES and have broad implications for designing new therapeutic options for ES patients. In Aim 2 I plan toextend my predoctoral training in cellular metabolism of a rare cancer to my postdoctoral training in theemerging field of cancer metabolism's role in epigenetic regulation. I have received excellent training in thefield of glycogen metabolism in cancer and I believe this foundation will help answer key outstanding questionsin the utilization of key metabolites to control gene expression and protein function. Cumulatively this proposalprovides time in both my predoctoral and postdoctoral training to learn skills necessary to achieve my goal ofan independent investigator in cancer metabolism.

project_terms:
5'-AMP-activated protein kinase;Adolescent;Adolescent and Young Adult;Affect;Age;Aggressive behavior;Architecture;Biochemical;Biological;Biology;Bone Tissue;CRISPR/Cas technology;Cell physiology;Cellular Metabolic Process;Child;Childhood;Clinical;Comprehension;Coupled;Cyclic AMP-Dependent Protein Kinases;Cytoplasmic Granules;Data;Deposition;Diagnosis;Disease;EWS-FLI1 fusion protein;Enzymes;Epigenetic Process;Event;Ewings sarcoma;Foundations;Gene Expression;Gene Proteins;Genetic;Glucose;Glycogen;Glycogen (Starch) Synthase;Goals;Histones;Homeostasis;In Vitro;Incidence;Knock-out;Learning Skill;Malignant Childhood Neoplasm;Malignant Neoplasms;Metabolic;Metabolism;Metastatic Ewing's Sarcoma;Modeling;Modification;Nude Mice;Oncogenes;Operative Surgical Procedures;Pathogenicity;Pathologic;Pathology;Patients;Pattern;Periodic acid Schiff stain method;Phosphorylation;Positioning Attribute;Primary Neoplasm;Proliferating;Protein Kinase;Proteins;Recurrence;Research;Research Personnel;Resolution;Role;Sampling;Survival Rate;Techniques;Therapeutic;Time;Training;Translating;Work;Xenograft Model;base;bone;cancer cell;career;chemotherapy;design;epigenetic regulation;glucose metabolism;glycogen metabolism;histone modification;in vitro Assay;in vivo;inhibitor;innovation;inorganic phosphate;insight;irradiation;lipid metabolism;macrophage;metabolomics;multidisciplinary;novel;novel therapeutic intervention;novel therapeutics;personalized medicine;polyglucosan;post-doctoral training;pre-doctoral;protein function;rare cancer;soft tissue;stable isotope;standard of care;therapeutic target;treatment strategy;tumor;tumor growth;tumor metabolism;tumorigenesis

public_health_relevance:
Project Narrative The focus of my work is to determine the role of glycogen in Ewing's sarcoma tumorigenesis andidentify these accumulations as a novel therapeutic intervention. This proposal is built on our pastdiscoveries understanding aberrant glycogen in disease through profiling cell metabolismproliferation and tumorigenesis. Completion of this work will yield a better comprehension betweenglycogen and these events and will allow us to translate our insights into disease mechanismsdiagnoses and treatments.


application_id: 10473814
project_number: 5F31AA028423-03
project_title: sEH Inhibition in Alcoholic Liver Disease: A Novel Therapeutic Strategy
administering_ic: NIAAA
award_notice_date: 2022-07-22
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: AA
serial_number: 028423
program_official: RADAEVA, SVETLANA
project_start_date: 2020-09-01
project_end_date: 2023-04-30
study_section: ZAA1-GG(32)
contact_pi_person_id: 15958059
contact_pi: WARNER, JEFFREY B
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:
Project SummaryAlcoholic liver disease (ALD) is the most common liver disease and is responsible for nearly half of all deathsfrom diseases affecting this organ. Despite this there remain no FDA-approved treatments for any stage of thedisease highlighting the need for the discovery of new therapies. As an aspiring scientist whose goal is to pursuea career in alcohol-related multi-organ pathology investigating new therapies for ALD treatment would not onlyhelp fill this medical need but also serve as an excellent platform from which to learn how to become a successfulscientist. With the help and supervision of my co-mentors Dr. Kirpich (an expert in basic research on ALD) andDr. McClain (an expert on clinical aspects of the disease) as well as several knowledgeable collaborators I willinvestigate soluble epoxide hydrolase (sEH) inhibition as a novel therapeutic strategy for the treatment of ALDusing pre-clinical mouse models. This approach has been applied to other inflammatory diseases but not toALD a disease shown by previous work in our group to be characterized by a loss of anti-inflammatoryepoxygenated lipids (epoxides) in part due to their rapid degradation by sEH. I have generated substantialpreliminary data with an orally-administered sEH inhibitor in a chronic-binge mouse model of ALD thatrecapitulates human ALD. Through two related but independent specific aims proposed in this application I willfurther assess the efficacy of sEH inhibition and explore its mechanisms of action. Aim 1 will use pharmacologicaland genetic ablation of sEH to further characterize the effects of sEH inhibition in mouse models of ALD. Aim 2will describe the mechanistic effects of individual anti-inflammatory epoxides on changes in hepatocyte andimmune cell health and function to explain changes seen in vivo. To complete this research I will follow a detailedtraining plan laid out for me by my co-mentors and pursue the career goals that I have set for myself. Theseinclude among others continuing my didactic training in areas relevant to my research gaining experience innew laboratory techniques developing effective written and oral communication skills and building aprofessional network of scientists. For example to assess liver injury and changes in cellular function I will learnto read histological liver slides use enzymatic assays set up ELISAs isolate and culture primary hepatocytesand macrophages and learn flow cytometry. The research environment at the University of Louisvilles state-of-the-art Clinical and Translational Research Building is highly productive and staffed with expert faculty andresearch personnel willing to help me learn these techniques and advise me as I pursue my training and careergoals. My academic department the Department of Pharmacology & Toxicology is equally positioned to supportmy training in the classroom and provide many resources (e.g. travel funds career development seminars andnew courses) to ensure my success. Collectively the training and research proposed here will not only fill asignificant 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:
ANXA5 gene;Ablation;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animals;Anti-Inflammatory Agents;Area;Attenuated;Basic Science;Biological;Biological Assay;CXCL1 gene;Cell Death;Cell Line;Cell physiology;Cells;Cellular biology;Cessation of life;Chronic;Clinical;Clinical Research;Data;Development;Disease;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epoxide hydrolase;Epoxy Compounds;Ethanol;FDA approved;Fatty Acids;Flow Cytometry;Fostering;Funding;Genetic;Goals;Health;HepG2;Hepatic;Hepatocyte;Histologic;Human;IL6 gene;Immune;Individual;Inflammation;Inflammatory;Interleukin-1 beta;Knock-out;Knockout Mice;Kupffer Cells;Laboratories;Learning;Lipids;Liver;Liver diseases;Medical;Mentors;Modeling;Mus;Neutrophil Infiltration;Oral;Organ;Palmitic Acids;Pathogenesis;Pathology;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology and Toxicology;Phenotype;Physiological;Polyunsaturated Fatty Acids;Positioning Attribute;Predisposition;Prevention;Production;Propidium Diiodide;Research;Research Personnel;Resolution;Resources;Role;Scientist;Slide;Stains;Supervision;TNF gene;Techniques;Testing;Therapeutic;Training;Translational Research;Translations;Travel;Universities;Work;alcohol exposure;bench to bedside;career;career development;career networking;chronic liver disease;cytokine;efficacy evaluation;experience;experimental study;faculty research;feeding;improved;in vivo;inhibitor;lipid mediator;lipidome;lipidomics;liver inflammation;liver injury;macrophage;mouse model;novel therapeutic intervention;novel therapeutics;oral communication;pre-clinical;prevent;recruit;skills;success;translational therapeutics;treatment strategy

public_health_relevance:
Project NarrativeAlcoholic liver disease (ALD) is responsible for nearly half of liver disease deaths yet there are no FDA-approvedtherapies available for the treatment of any stage of its progression. Discovery of unique changes in the hepaticlipidome reveal soluble epoxide hydrolase (sEH) inhibition as a therapeutic strategy with high potential to lessenliver damage associated with ALD. Full assessment of the efficacy of sEH inhibition through this proposedresearch will allow us to better understand its uses and mechanisms of action and contribute to the translationof this approach from bench to bedside.


application_id: 10473603
project_number: 5F31HL154663-03
project_title: Metabolic regulation of exercise-induced adaptation in striated muscle
administering_ic: NHLBI
award_notice_date: 2022-07-15
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: HL
serial_number: 154663
program_official: HUANG, LI-SHIN
project_start_date: 2020-08-10
project_end_date: 2022-12-31
study_section: Special Emphasis Panel[ZRG1-F10A-K(20)L]
contact_pi_person_id: 15945691
contact_pi: FULGHUM, KYLE
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:
AbstractAerobic exercise promotes beneficial adaptations in the heart. Previous studies demonstrate that transientreductions in cardiac glucose catabolism at the level of phosphofructokinase are important for exercise-inducedcardiac growth. Although this finding links changes in metabolism with initiation of growth the mechanisms bywhich glucose metabolism changes during exercise and how metabolism coordinates cardiac growth remainunclear. Metabolic changes could promote exercise-induced muscle growth in two ways. First changes in thelevels of glycolytic intermediates during exercise could regulate carbon availability for building block biosynthesiswhich constitutes a material cause for cardiomyocyte hypertrophy. Second metabolic changes that occur duringexercise could regulate the exercise gene program which is important for exercise-induced tissue remodeling.Nevertheless it has been difficult to disentangle the contribution of these two causes to the adaptations broughtforth by exercise. Addressing these problems requires understanding how metabolism changes both during andafter exercise and then identifying the metabolic components that modulate cardiomyocyte growth. In thisproject I will test the general hypothesis that high levels of competing substrates such as lactate and fatty acidsprompt ancillary biosynthetic pathway activity in the heart and drive gene programs for cardiac growth. Tounderstand how glucose metabolism changes in response to exercise or in the presence of competingsubstrates I have standardized deep network tracing methods to measure glucose-derived carbon fate in vivousing dietary delivery of a 13C6-glucose-containing diet. Specifically the aims are (1) to define changes in cardiacglucose metabolism in response to exercise training and (2) to determine how circulating substrates influencecardiac hypertrophic signaling and gene programs. This research plan will provide training in areas critical to mygrowth as a scientist and prepare me for a career in the exercise sciences. The project will provide freshperspectives about how metabolism regulates cardiac muscle growth and could identify innovative metabolicapproaches to control tissue remodeling or optimize the cardiovascular benefits of exercise. Importantly thesestudies will integrate our current understanding of striated muscle catabolism with new knowledge of howanabolism is regulated within muscle tissue.

project_terms:
Address;Adipose tissue;Aerobic Exercise;Affect;Anabolism;Area;Blood capillaries;Carbohydrates;Carbon;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Catabolism;Data;Diet;Enzyme Activation;Enzymes;Exercise;FRAP1 gene;Fatty Acids;Genes;Genetic;Glucose;Glucosephosphate Dehydrogenase;Glucosephosphate Isomerase;Glycolysis;Growth;Heart;Hypertrophy;In Vitro;Insulin-Like Growth Factor I;Ketones;Knowledge;Link;Liquid substance;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular;Mus;Muscle;Myocardial;Myocardium;Nucleotides;Pathway interactions;Pharmacology;Phospholipids;Phosphotransferases;Production;Regulation;Research;Role;Science;Scientist;Signal Pathway;Signal Transduction;Standardization;Stimulus;Striated Muscles;Study Subject;Testing;Tissues;Training;aminoacid biosynthesis;carbohydrate metabolism;career;density;dietary;effective intervention;energy balance;exercise training;glucose metabolism;heart function;in vivo;innovation;interest;macromolecule;novel;prevent;programs;pyruvate dehydrogenase;respiratory;response

public_health_relevance:
PROJECT NARRATIVEExercise is an effective intervention to treat and prevent cardiovascular diseases; however the mechanismscontrolling exercise-induced adaptations in cardiovascular tissues are poorly understood. In this project we willexamine how exercise regulates carbohydrate metabolism in the heart and how changes in carbohydrateutilization affect tissue responses to exercise.


application_id: 10472670
project_number: 5DP5OD028155-05
project_title: Histamine in homes: Exposure risks and health effects
administering_ic: OD
award_notice_date: 2022-08-29
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;Persons;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: 10472657
project_number: 5R01AI141889-05
project_title: Influenza D Virus Entry and Tissue Tropism
administering_ic: NIAID
award_notice_date: 2022-08-18
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: 2025-08-31
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;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;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;vaccine strategy;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: 10472508
project_number: 5R35GM131807-04
project_title: Hedgehog Signaling in Development and Metabolism
administering_ic: NIGMS
award_notice_date: 2022-08-19
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 131807
program_official: CHOW, CHI-WING
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;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;diagnostic tool;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

public_health_relevance:
PUBLIC HEALTH RELEVANCEHedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation anddifferentiation during embryogenesis. Mutations in Smoothened (Smo) a critical protein in the signal receptionsystem results in human diseases such as basal cell carcinoma and medulloblastoma. Investigation of how Hhand Smo signaling regulates lipid metabolism and how Smo is regulated by cholesterol will provide insights intodevelopmental problems and create novel concepts of Hh signaling in cancer obesity and metabolic diseases.


application_id: 10472097
project_number: 261201800013I-0-759102100001-1
administering_ic: NCI
project_start_date: 2021-04-05
project_end_date: 2022-04-04
contact_pi_person_id: 78121794
contact_pi: DURBIN, ERIC
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
funding_mechanism: R and D Contracts
project_title:
NCI PATTERNS OF CARE (POC)/QUALITY OF CARE STUDY: DIAGNOSIS YEAR 2019 (URINARY BLADDER CANCER AND KIDNEY CANCER)

project_abstract:
The primary objectives of the Fiscal Year 2021 NCI POC Study are to: 1) describe the use of recommended biomarker tests which shall be verified with the treating physician/physician office staff or with a unified medical record (record with all inpatient and outpatient records in a single file) and 2) describe the use of targeted therapy which shall be verified with the treating physician/physician office staff or with a unified medical record (record with all inpatient and outpatient records in a single file). Other objectives are to: 3) describe the use of adjuvant therapy which shall be verified with the treating physician/physician office staff or with a unified medical record (record with all inpatient and outpatient records in a single file); 4) characterize the practice patterns in different communities; 5) compare the patterns of treatment (surgery radiation therapy systemic therapy (chemotherapy immunotherapy hormonal therapy targeted therapy) and other adjuvant therapy) over time and by age sex race/ethnicity and insurance status; 6) describe comorbidities and the effect of co-morbid conditions on treatment; 7) describe treatment by hospital characteristics (i.e. for profit vs. not for profit teaching vs. non-teaching bed size etc.); 8) describe the use of diagnostic tests and compare their use by demographic variables and geographic region; 9) describe the medical record documentation of multidisciplinary care and patient navigation; 10) assess the incidence of cancer recurrence; and 11) collect information on changes in cancer treatment patterns due to medication shortages.

project_terms:
Adjuvant Therapy;Age;Beds;Biological Markers;Caring;Characteristics;Communities;Diagnosis;Diagnostic tests;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Hospitals;Immunoglobulin Variable Region;Immunotherapy;Incidence;Inpatients;Insurance Coverage;Malignant neoplasm of urinary bladder;Medical Records;Operative Surgical Procedures;Outpatients;Patients;Pattern;Patterns of Care;Pharmaceutical Preparations;Physicians;Physicians' Offices;Quality of Care;Race;Radiation therapy;Records;Renal carcinoma;Systemic Therapy;Testing;Time;cancer recurrence;cancer therapy;chemotherapy;comorbidity;hormone therapy;multidisciplinary;sex;targeted treatment


