# projects

application_id: 10693558
project_number: 1R21ES035320-01
project_title: Impact of Landfill Mitigation Efforts to Reduce Air Toxics in Bristol Tennessee and Virginia
administering_ic: NIEHS
award_notice_date: 2023-05-23
opportunity_number: RFA-ES-19-011
application_type: 1
activity_code: R21
ic: ES
serial_number: 035320
program_official: O'FALLON, LIAM
project_start_date: 2023-05-23
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZES1 LWJ-W (R2)]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractFor over a year residents of Bristol Tennessee (TN) and Virginia (VA) have experienced significant exposureto landfill emissions including volatile organic compounds (VOCs) such as benzene toluene and hydrogensulfide. Ambient levels of these air toxics have been measured by the EPA and the Virginia Department ofEnvironmental Quality. Based on the concentrations found during these sampling events a Plan of Action wasreleased on July 6 2022 to begin incremental steps towards mitigating the air toxics emanating from thelandfill. This Plan of Action presents a critical opportunity to measure the impact of this environmental policy toimprove air quality and reduce odors. Since October 2021 Haynes (PI) has been developing a community-academic research partnership with Bristol residents to identify research strategies to identify their indoor andoutdoor exposures and potential health impacts. The residents have reported their experiences as an endlessnightmare with non-stop odor that stays in the house and its hard to breathe. Given our partnership withthe City Manager and community residents we are poised to evaluate the impacts of an environmentalpolicy to reduce air toxics and odors and evaluate the potential long-term health consequences related to theseexposures. We propose these highly time-sensitive specific aims: Aim 1: Characterize indoor and outdoorconcentrations of VOCs including benzene and hydrogen sulfide in and around homes of Bristol VA/TNresidents prior to the implementation of the mitigation action plan. Aim 2: Characterize indoor and outdoorconcentrations of VOCs and hydrogen sulfide in and around homes of Bristol VA/TN residents after eachstage of the mitigation action plan in order to determine the impact of the various strategies to mitigateexposures. Aim 3: Evaluate the impact of the landfill and the mitigation plan on odor detection quality of lifeand stress of residents. This time-sensitive research is critical to inform future landfill mitigation efforts asnumerous communities across the country face challenges associated with municipal solid waste facilities.

project_terms:
Acrolein;Affect;Air;Air Pollutants;Benzene;Breathing;Censuses;Chemicals;Cities;Collaborations;Collection;Communities;Country;Detection;Development;Ecological momentary assessment;Effectiveness;Engineering;Ensure;Environmental Health;Environmental Impact;Environmental Policy;Event;Exposure to;Face;Faculty;Future;Health;Health Hazards;High temperature of physical object;Home;Hour;Household;Hydrogen Sulfide;Industry;Investigation;Liquid substance;Location;Low Income Population;Measurement;Measures;Municipalities;Neighborhoods;Nightmare;Odors;Personal Communication;Pharyngeal structure;Poverty;Quality of life;Recommendation;Reporting;Research;Sampling;Solid;Stress;Symptoms;Tennessee;Time;Toluene;Toxicology;United States;Universities;Virginia;air monitoring;air sampling;community partnership;experience;falls;follow-up;improved;landfill;meetings;operation;pollutant;recruit;response;sample collection;sensor;student training;toxicant;volatile organic compound;wasting

public_health_relevance:
Project NarrativeA community-academic team will quantify the impact of a mitigation action plan to reduce air toxics and odorsat a landfill in Bristol Virginia.


application_id: 10693395
project_number: 5R24AI138963-06
administering_ic: NIAID
award_notice_date: 2023-08-17
opportunity_number: PAR-20-063
application_type: 5
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: 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: 2023-09-01
project_title:
An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

project_abstract:
PROJECT SUMMARYThere is a fundamental gap in our understanding of how germline variation in the immunoglobulin (IG) heavy(IGH) and light chain (kappa IGK; lambda IGL) loci in the human population impacts the development of thefunctional antibody (Ab) response in health and disease. However there is growing appreciation for the fact thatIG polymorphism contributes to variability in the Ab repertoire indicating that the integration of IG genetic datain basic and biomedical research can inform our understanding of how IG gene regulation as well as Abrepertoire dynamics function in various clinical contexts. A critical barrier to progress has been that existinggenomic resources for the IG loci are incomplete and poorly represent diversity across human populationsparticularly those from non-European ancestries. Evidence continues to accumulate in support of the notion thatthe IG regions are among the most structurally complex and polymorphic regions of the human genome enrichedfor large structural variants (SVs) and single nucleotide variants (SNVs) resulting in extreme interindividualhaplotype variation. These complexities have long made the IG loci difficult to study using standard high-throughput methods with direct negative impacts on genetic disease association studies and more recently theanalysis of adaptive immune receptor repertoire sequencing (AIRR-seq) data. As a result knowledge of humanIG germline diversity particularly in populations underrepresented in genomics databases and its contributionto disease lags far behind that of other well-studied immune loci. This highlights a direct need for publiclyavailable well-characterized IG haplotype references and accurate variant catalogues from diverse ethnicbackgrounds to facilitate the design and integration of more accurate genotyping tools analysis pipelines andtheir interpretation. To meet these needs we have developed this renewal proposal which will build the mostcomprehensive IG genomic dataset to date with transformative potential impact for the fields of B cellimmunology and immunogenetics. The resource generated will: (i) shed light on the extent of IG diversityworldwide; (ii) establish a framework for linking genetic data to expressed antibody repertoire variation to informour understanding of V(D)J recombination and seed models of antibody repertoire dynamics; and (iii)substantially augment key databases and research initiatives pushing the frontiers of genomics and immunologyresearch. This renewal project will seamlessly build and expand upon the foundational IG genomics datagenerated in our initial proposal and continue to establish desperately needed genomic resources for the humanIG loci particularly in underrepresented populations and cohorts of immediate biomedical relevance which willserve the immunology and larger genomics communities for years to come.

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;Collaborations;Collection;Communities;Complex;Data;Data Set;Databases;Deposition;Development;Disease;Ensure;European;Genbank;Gene Expression Regulation;General Practitioners;Genes;Genetic;Genetic Diseases;Genetic Polymorphism;Genetic Variation;Genome;Genomics;Genotype;Genotype-Tissue Expression Project;Germ-Line Mutation;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;Light;Link;Malignant Neoplasms;Methods;Modeling;Nucleotides;Oceania;Outcome;Population;Population Heterogeneity;Positioning Attribute;Quantitative Trait Loci;Research;Resources;Rheumatic Heart Disease;Role;Sampling;Single Nucleotide Polymorphism;South African;Summary Reports;Uganda;Underrepresented Populations;V(D)J Recombination;Variant;analysis pipeline;cohort;data access;database of Genotypes and Phenotypes;dbSNP;design;ethnic diversity;frontier;genetic association;genome browser;genome resource;genomic data;high standard;immunoglobulin light chain locus;improved;novel;precision medicine;reference genome;response;tool;vaccine response

public_health_relevance:
PROJECT NARRATIVEGenomic resources for the human immunoglobulin loci poorly represent diversity among human populationslimiting our ability to resolve the role of antibody genetic variation in health and disease. This renewal project willbuild the most comprehensive immunoglobulin genomic dataset to date with transformative impact on the fieldsof B cell immunology and immunogenetics. The data generated will (i) shed light on the extent of immunoglobulindiversity worldwide; (ii) establish a framework for linking genetic data to expressed antibody repertoire variationto inform our understanding of V(D)J recombination and seed models of antibody repertoire dynamics in disease;(iii) and substantially augment key databases and research initiatives pushing the frontier of disease genomicsand immunology research.


application_id: 10693261
project_number: 5R01ES032176-03
administering_ic: NIEHS
award_notice_date: 2023-08-02
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: 2025-08-31
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: 2023-09-01
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;Classification;Clinical;Cohort Studies;DNA Methylation;Data;Development;Disease;Endocrine Disruptors;Environment;Environmental Health;Environmental Pollutants;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;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;Umbilicus;Weight Gain;bioaccumulation;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: 10693099
project_number: 5DP5OD028155-06
project_title: Histamine in homes: Exposure risks and health effects
administering_ic: OD
award_notice_date: 2023-08-29
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: 2025-08-31
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;Dust;Educational process of instructing;Eligibility Determination;Entomology;Environmental Health;Environmental Pollutants;Environmental Risk Factor;Epidemiology;Exposure to;Extrinsic asthma;Faculty;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;Shapes;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;neighborhood disadvantage;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: 10692764
project_number: 5R21AA029201-02
administering_ic: NIAAA
award_notice_date: 2023-08-03
opportunity_number: PA-20-194
application_type: 5
activity_code: R21
ic: AA
serial_number: 029201
program_official: HAGMAN, BRETT THOMAS
project_start_date: 2022-09-01
project_end_date: 2023-08-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: MOLONEY, MAIREAD
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
budget_start_date: 2023-08-01
project_title:
Testing an Online Insomnia Intervention to Reduce Alcohol Use via Improved Sleep Among Heavy Drinkers

project_abstract:
ABSTRACTAlcohol use disorder (AUD) inflicts enormous physical emotional and financial burdens on the individual andsociety at large. Insomnia a public health crisis in its own right is highly prevalent among individuals withAUD. Both AUD and insomnia are particularly problematic in women as women have a 40% higher insomniarisk than men and incidence of AUD is increasing among women at alarming rates. AUD and insomnia have abidirectional and feed-forward relationship such that excessive alcohol consumption negatively impacts sleepand disrupted sleep contributes substantially to alcohol-related problems. Moreover our preliminary datasuggests that this association may be particularly pronounced in women. Importantly insomnia often precedesproblematic drinking in both adolescents and adults. As such insomnia serves as a potential interventiontarget for hazardous drinking. The recommended first-line insomnia treatment - cognitive behavioral therapy forinsomnia (CBT-I) - holds promise as a therapy that may reduce alcohol use via improved sleep. CBT-I trainedpractitioners however are rare and the multiple required visits may not be covered by insurance. One solutionto these obstacles is the implementation of efficacious accessible electronic cognitive behavioral therapy forinsomnia (e-CBT-I). For this project we will utilize Sleep Healthy Using the Internet (SHUTi) the most widelyused and well-validated version of e-CBT-I in a sample of heavy drinking community dwelling adults withinsomnia. We have exciting preliminary data showing that SHUTi improves sleep and reduces alcoholconsumption in this population. Here we will extend these findings by conducting a well-powered randomizedcontrolled trial. We will utilize a two-arm single blinded randomized control mixed methods design. For theactive treatment condition (n=50) participants will have 9 weeks to complete the 6-week SHUTi program. In thecontrol condition (n=50) participants will have access to a web-based sleep education program for the sametime period. Both programs will be accessed through the Internet and will contain information about sleep andsleep hygiene; only the SHUTi group will receive feedback and targeted recommendations based on sleepdiary data. Alcohol use insomnia severity and sleep quality will be quantitatively assessed via online surveyand sleep and alcohol use diaries at baseline and three time points: T1 (at the end of the 9-week interventionperiod) T2 (3-months post-intervention) and T3 (6 months post-intervention). All participants will additionallytake part in semi-structured qualitative interviews at T1. Our central hypothesis is that SHUTi will reducealcohol use via improved sleep in this population and that effects will be more pronounced in women. Thisproject will be the first to test SHUTi in community dwelling heavy drinking adults with insomnia. If successfulour intervention will provide an easily-accessible cost effective intervention for a high-risk population andholds potential for positive public health impact especially for women.

project_terms:
Adolescent;Adult;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic beverage heavy drinker;Appalachian Region;Asthma;Behavior Therapy;Cancer Survivor;Cellular Phone;Cognitive Therapy;Communities;Data;Diagnosis;Education;Effectiveness;Electronics;Emotional;Feedback;Female;Financial Hardship;Goals;Heavy Drinking;Incidence;Individual;Insurance;Internet;Intervention;Interview;Learning Module;Mediating;Methods;Office Visits;Online Systems;Participant;Personal Computers;Persons;Play;Population;Prevention;Public Health;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research;Risk;Role;Sampling;Self Administration;Severities;Sex Differences;Single-Blind Study;Sleep;Sleep disturbances;Sleeplessness;Societies;Structure;Surveys;Tablets;Technology;Telephone Interviews;Testing;Time;Training;United States;Visit;Woman;active method;aged;alcohol related problem;alcohol use disorder;arm;binge drinking;comorbidity;cost;cost effective intervention;design;diaries;drinking;effectiveness evaluation;hazardous drinking;high risk;high risk population;improvement on sleep;innovation;male;men;novel;post intervention;prevent;programs;recruit;reduced alcohol use;sleep health;sleep quality;stem;symptomatology

public_health_relevance:
Alcohol use disorder (AUD) is an urgent and escalating public health problem estimated to cost the UnitedStates $249 billion per year. Insomnia a public health crisis in its own right often precedes problematicdrinking thus treating insomnia may serve as a novel prevention target for AUD. Our innovative mixedmethods project will be among the first to test a technologically-facilitated non-pharmaceutical insomniaintervention to reduce alcohol consumption in heavy-drinking community dwelling adults with insomnia.


application_id: 10692624
project_number: 5K01CA251487-04
project_title: Promoting Cervical Cancer Screening among African American and Sub-Saharan African Immigrant women
administering_ic: NCI
award_notice_date: 2023-08-21
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;Disparate;Disparity;Education;Emotional;Environment;Evidence based intervention;Extramural Activities;Frequencies;Fright;Funding;Future;Geographic Locations;Goals;Gynecologic;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 Measure;Pattern;Physicians;Population;Population Heterogeneity;Population Study;Preventative vaccination;Prevention;Privatization;Quality of Care;Quasi-experiment;Research;Research Personnel;Resources;Role;Sampling;Screening for cancer;Screening procedure;Self Efficacy;Sensitivity and Specificity;South America;Structure;Subgroup;Swab;Testing;Training;Treatment Efficacy;Underserved Population;United States;Universities;Visit;Vulnerable Populations;Woman;access disparities;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;detection method;ethnic disparity;evidence base;experience;health belief;health care availability;health knowledge;high risk;high risk population;innovation;intervention effect;mortality;peer;pilot test;poor health outcome;prevent;programs;racial disparity;racial population;randomized clinical trials;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: 10692561
project_number: 5U01DK074007-17
administering_ic: NIDDK
award_notice_date: 2023-08-29
opportunity_number: RFA-DK-20-504
application_type: 5
activity_code: U01
ic: DK
serial_number: 074007
program_official: SERRANO, JOSE
project_start_date: 2006-04-15
project_end_date: 2027-07-31
study_section: ZDK1-GRB-9(M2)S
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-01
project_title:
U of L Clinical Center to Investigate the Pathogenesis Etiology and Treatment of Gastroparesis through the NIDDK Gastroparesis Consortium

project_abstract:
Gastroparesis is a disorder of gastric function characterized by delay in gastric emptying frequently associatedwith chronic nausea and vomiting early satiety postprandial fullness abdominal pain and malnutrition thatmay require nutritional support. Gastroparesis has a devastating impact on quality of life and predominantlyaffects younger women. In the past 5 years the Gastroparesis Clinical Research Consortium (GpCRC) hasmade a series of important contributions (see below) to improve our understanding of this disorder andadvancing the goals of patients physicians and the NIH for management of gastroparesis. Yet much remainsto be learned about its etiology natural history treatment strategies and clinical course whichis the rationale behind our response to the Continuation of the Gastroparesis Consortium. The biggest barrierto effective therapeutic approaches to gastroparesis is our lack of knowledge about either its pathogenesis orits pathophysiology. Further the correlation between the major symptoms such as nausea vomiting pain andcurrent methods to measure change in gastric function (electrical motor activity meal emptying times) is poorat best. Finally we do not understand the long-term outcomes of these patients and whether outcomes differon the basis of etiology symptom severity and degree of emptying abnormalities. Consequently our approachto these patients is erratic and treatment has been empirical and only partially effective if at all in relieving themajor symptoms. The mission of the GpCRC is completely aligned with the recommendations of the NationalCommission on Digestive Diseases: specifically Research Goal 2.6 relates to gastroparesis and states:"Understand the noxious visceral signaling causing nausea and vomiting related to gastric neuro-electricaland/or motor dysfunction and the bi-directional brain-gut interactions. Gastroparesis provides an archetypaldisease for investigative inquiry. Chronic vomiting a debilitating and socially isolating digestive symptomcreates potentially life-threatening disruptions in fluid and electrolyte homeostasis and compromises nutritionalstatus. Chronic nausea remains a significant hidden disability. Nausea and vomiting usually occur in tandemand overlay with other Gl symptoms as well as presenting in numerous digestive diseases. More effectivetreatments for nausea and vomiting would improve quality of life and physical functioning in a vast array ofillnesses. A paucity of research exists for defining peripheral noxious signaling of nausea and vomiting relatedto primary Gl motor/sensory disturbances." The Specific Aims of this proposal are to: 1. Complete the currentGpCRC registry (Registry Three); 2. Extend the GpCRC core lab responsible for anatomic and related studieson tissue samples of patients with Gp syndromes; 3. Perform pharmacologic studies on patients with Gpsyndromes.; 4. Perform a new device/pyloric intervention study protocol for patients with the Gp syndromes;and 5. Utilize several novel approaches to some of the unmet needs in patients with gastroparesis symptomswhich could be incorporated in new studies of the Consortium.

project_terms:
Abdominal Pain;Affect;Age;Anatomy;Autoimmune;Botulinum Toxins;Caring;Characteristics;Chronic;Clinical;Clinical Research;Databases;Devices;Digestive System Disorders;Disease;Electric Stimulation;Electrolytes;Enrollment;Esophagus;Ethnic Origin;Etiology;Feces;Functional disorder;Gastric Emptying;Gastrointestinal Diseases;Gastroparesis;Gender;Genomics;Goals;Health;Health Services Accessibility;Homeostasis;Hormonal;Inflammatory;Intervention Studies;Knowledge;Learning;Life;Liquid substance;Malnutrition;Maps;Measures;Methods;Microanatomy;Mission;Motor;Motor Activity;National Institute of Diabetes and Digestive and Kidney Diseases;Natural History;Nausea;Nausea and Vomiting;Nortriptyline;Nutritional Requirements;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmacology Study;Physical Function;Physicians;Physiological;Physiology;Protocols documentation;Psychological Impact;Publishing;Quality of life;Questionnaires;Race;Randomized;Recommendation;Registries;Research;Resolution;Sensory;Series;Severities;Signal Transduction;Social isolation;Stomach;Symptoms;Syndrome;Therapeutic;Tissue Sample;United States National Institutes of Health;Visceral;Vomiting;Weight;Work;clinical center;disability;early satiety;effective therapy;evidence base;frailty;gastrointestinal function;gut-brain axis;improved;metabolomics;motor disorder;neuromuscular;novel;novel strategies;nutrition;persistent symptom;psychologic;recruit;response;therapeutically effective;treatment strategy;young woman

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


application_id: 10691630
project_number: 75N93022C00038-0-9999-1
project_title: Increasing Availability of Emulsion Adjuvants via Synthetic Biology
administering_ic: NIAID
project_start_date: 2022-08-30
project_end_date: 2025-08-29
contact_pi_person_id: 78833994
contact_pi: KEMPINSKI, CHASE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 080540683
primary_uei: P3KJFJJR58R4
duns_number: 080540683
uei: P3KJFJJR58R4
fips: US
organization_id: 10045877
organization_name: ENEPRET, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405032006
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
Squalene-based oil-in-water emulsions such as MF59 have been shown to demonstrate adjuvant activity in a variety of vaccine settings including seasonal influenza vaccine. The awardee seeks to develop a mimic of MF59 using squalene that has been sustainably synthesized by yeast cultures. This adjuvant will be tested in preclinical studies and advanced toward large production capacity.

project_terms:
Adjuvant;Animals;Blood;COVID-19 vaccine;Cyclic GMP;Emulsions;Immunology procedure;In Vitro;Influenza A virus;MF59;Marketing;Oils;Pharmacology and Toxicology;Process;Production;Property;Squalene;Testing;Tissues;Vaccines;Water;Yeasts;base;influenza virus vaccine;novel;preclinical study;seasonal influenza;synthetic biology;vaccine evaluation;vaccine immunogenicity


application_id: 10691435
project_number: 5K23AG075262-02
administering_ic: NIA
award_notice_date: 2023-07-31
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: AG
serial_number: 075262
program_official: RIDDLE, MELISSA
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
budget_start_date: 2023-07-01
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;Career Mobility;Caregiver Burden;Caregivers;Caring;Client satisfaction;Clinic;Clinical;Clinical Trials Design;Clinical assessments;Communities;Country;Cues;Data;Dementia;Development;Development Plans;Diagnosis;Dimensions;Elderly;Environment;Extramural Activities;Faculty;Fellowship;Fostering;Foundations;Funding;Future;Goals;Grant;Health Services Accessibility;Home;Home environment;Individual;Institution;Institutionalization;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;Postdoctoral Fellow;Protocols documentation;Proxy;Psychiatrist;Psychophysiology;Quality of life;Randomized Controlled Trials;Reporting;Research;Research Activity;Research Personnel;Residencies;Rural;Rural Appalachia;Rural Community;Safety;Scholarship;Science;Scientist;Single-Blind Study;Sleep Disorders;Stimulus;Surveys;Teacher Professional Development;Testing;Training;Underrepresented Populations;United States National Institutes of Health;Universities;Work;aging in place;arm;behavior change;behavioral response;career;career development;caregiver education;college;community based research;dementia care;empowerment;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;research and development;response;rural area;satisfaction;skills;social;standard of care;supportive environment;symptom management;telehealth;tenure track;therapy development;tool


application_id: 10690664
project_number: 5R01AG072797-03
project_title: Novel precision medicine approach to treatment of osteoporosis based on bone turnover
administering_ic: NIA
award_notice_date: 2023-08-22
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: AG
serial_number: 072797
program_official: NELLISSERY, MAGGIE JACOB
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_abstract:
1. Project Summary/AbstractOsteoporosis is a health problem of major proportions. It affects more than 40 million Americans and results inmore than 2 million fractures annually among Medicare patients alone. Hospital admissions for osteoporoticfractures exceed those of heart attacks strokes and breast cancer combined. Osteoporosis is commonlyconsidered a disease associated with menopause. This estrogen deficiency related bone loss is characterizedby high bone turnover with increased resorption without commensurate changes in bone formation. It is incontrast to age-related bone loss which starts as early as in the fourth decade of life and continues withincreasing age. Age-related bone loss is usually associated with lower bone turnover and decreased boneformation is the main abnormality. Current therapies do not address age-related bone loss and the special needsof the age-related osteoporosis population is currently ignored. This is to a great degree due to difficultiesassociated with the bone biopsy necessary for determination of bone turnover status. Thus the current standardof care relies on starting with an antiresorber which is less effective in age-related osteoporosis and in factimpedes the effectiveness in this population of the appropriate anabolic medication.Our study seeks to achieve two specific aims: Aim 1) to establish a novel precision medicine approach totreatment of age-related osteoporosis based on recognition of low bone turnover and initial treatment withanabolics and Aim 2) to find a non-invasive method for diagnosing low bone turnover in osteoporotic patientsby measurements of serum carboxylated osteocalcin (1-43/49) with validation via the gold standard bonebiopsy and histomorphometry.Our approach will be to enroll female patients who have been diagnosed with osteoporosis in a prospectiveproof of concept study. Patients will undergo bone biopsy and blood draws at baseline. Bone turnover status willbe assessed employing histomorphometry. In addition blood levels of carboxylated osteocalcin (1-43/49) will bemeasured in order to determine their validity - alone or in combination with other bone markers - for diagnosinglow bone turnover prevailing in age-related bone loss.Patients will be grouped according to turnover status. Low-turnover patients will be randomized (1:1) either totreatment with the anabolic teriparatide (Group 1) or with the standard of care antiresorber alendronate (Group2) for one year. In order to provide the necessary comparison group for the non-invasive assessment of turnovernormal-high turnover patients (Group 3) will be treated with standard of care alendronate for one year. At baselineand at one-year bone mineral density measurements will be performed by DXA and 1-year changes in BMD willbe compared between groups. Our central hypothesis is that low turnover age-related osteoporosis needs to bediagnosed and treated differently from estrogen deficiency related osteoporosis. The results will provide aparadigm shift in the treatment of osteoporosis.

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;Estrogen deficiency;Familiarity;Female;Forteo;Fracture;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;bisphosphonate;bone;bone loss;bone mass;bone turnover;burden of illness;carboxylate;carboxylation;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

public_health_relevance:
8. Project NarrativeOsteoporosis affects 24.5% of women over 65 and results in fracture-related hospital admissions exceedingthose of heart attacks strokes and breast cancer combined. Current treatment options do not account fordifferences between age-related and estrogen deficiency related osteoporosis because of the need for bonebiopsies for determination. This study will establish a paradigm-shifting individualized treatment protocol for age-related osteoporosis and a non-invasive method for its determination thereby reducing the major healthproblems and enormous burden on society and the elderly related to this disease.


application_id: 10690636
project_number: 5R35ES028373-07
project_title: Environmental Liver Disease
administering_ic: NIEHS
award_notice_date: 2023-08-22
opportunity_number: RFA-ES-16-008
application_type: 5
activity_code: R35
ic: ES
serial_number: 028373
program_official: SCHUG, THADDEUS
project_start_date: 2017-09-15
project_end_date: 2025-08-31
study_section: ZES1-LWJ-K(R)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Liver disease is a major global health problem. Fatty liver disease or excess accumulation of lipids inhepatocytes affects more than 25% of the worldwide adult population but children and adolescents may alsobe affected. Chronic liver disease may progress to cirrhosis and liver cancer resulting in liver-related death ortransplantation. Liver disease also impacts the development of diabetes and cardiovascular disease. Liverdiseases may be caused or influenced by exposures to environmental chemicals but this is an understudiedarea. To address these problems this project establishes a major integrative and collaborative researchprogram the Environmental Liver Disease Revolutionizing Innovative Visionary Environmental Health ResearchProgram (ELD-RIVER). ELD-RIVER will have a transformative impact in the field. The project investigates two broad scientificthemes: (i) the impact of endocrine and metabolism disrupting chemicals (EDCs/MDCs) in fatty liver diseaseand (ii) other liver diseases (such as liver cancer) associated with chemical exposures. The ELD-RIVER takes abroad integrative scientific approach by investigating relevant chemicals; nutrient:chemical interactions; bothanimal models and human subjects; and both sexes through state-of-the-art methods including multi-omics.EDC/MDC exposures may also impact liver disease through their effects on obesity and diabetes. Thus obesityand diabetes endpoints will also be evaluated. While the specific projects are expected to evolve over time the initial work focusses on exposures topolychlorinated biphenyls and vinyl chloride. Both of these chemicals currently rank in the top five in the Agencyfor Toxic Substances and Disease Registry (ATSDR) Substance Priority List. ELD-RIVER strictly adheres to theprinciples of scientific rigor and reproducibility and data transparency and availability. ELD-RIVER leveragesexisting collaborations between multiple organizations including academia government agencies industry andscientific/medical societies. The vision is for ELD-RIVER to become the global hub for environmental liverdisease research. To accomplish its translational mission the program integrates the work of basic scientistsepidemiologists and physicians. The project will also develop diagnostic biomarkers new treatments practiceguidelines and it has the potential to impact policy change. Along the way unique institutional education/trainingresources will be utilized so that ELD-RIVER will help produce the next generation of environmental healthscientists. The work proposed is relevant to Strategic Plan of the National Institute of Environmental HealthSciences (Themes 1 2 and 5 and Goals 1 4 7 and 8).

project_terms:
Academia;Address;Adolescent;Adult;Affect;Animal Model;Area;Cardiovascular Diseases;Cessation of life;Chemical Exposure;Chemicals;Child;Cirrhosis;Collaborations;Data;Development;Diabetes Mellitus;Endocrine;Environment;Environmental Health;Epidemiologist;Exposure to;Goals;Government Agencies;Health;Hepatocyte;Industry;Institution;Lipids;Liver;Liver diseases;Malignant neoplasm of liver;Medical Societies;Metabolism;Methods;National Institute of Environmental Health Sciences;Nutrient;Obesity;Physicians;Poison;Policies;Polychlorinated Biphenyls;Population;Practice Guidelines;Reproducibility;Research;Resources;Scientist;Strategic Planning;Time;Training and Education;Transplantation;Vinyl Chloride;Vision;Work;chronic liver disease;diagnostic biomarker;disease registry;environmental chemical;fatty liver disease;global health;human subject;innovation;next generation;programs;sex;translational goal

public_health_relevance:
Liver disease is an important health problem which may be caused or influenced by exposures to chemicals inthe environment. To study this problem this project establishes an integrative and collaborative researchprogram the Environmental Liver Disease Revolutionizing Innovative Visionary Environmental Health ResearchProgram (ELD-RIVER).


application_id: 10689770
project_number: 5F32DE031493-03
project_title: Folate-Modulated Virulence of Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2023-08-25
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 Deletion;Gene Expression;Goals;Growth;Human;Immune response;Infection;Infection prevention;Inflammatory;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;Trimethoprim;Virulence;Virulence Factors;Virulent;antimicrobial;bacterial metabolism;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: 10689361
project_number: 3P30AG072946-02S1
project_title: Core C: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2022-08-24
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: AG
serial_number: 072946
suffix: S1
program_official: ELLIOTT, CERISE
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1
subproject_number: 6368
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
project_abstract:
Project Summary/Abstract: Data Management and Statistics CoreThe Data Management and Statistics (DMS) Core can be conceptualized as the lynchpin for integration of theADRC Cores and is vital to the success of the UK-ADRC. Its critical roles include managing a large centralizeddatabase consulting with ADRC-affiliated researchers and working to develop and apply innovative statisticalmethodology for data analysis. Data management efforts focus on collecting storing and sharing high qualitydata using a web-based platform. This focus begins with the leadership and vision and attention to detailprovided by the DMS Core. This core has an enviable track record of timely and accurate reporting of a highvolume of data to NACC. Further weekly Core meetings are popular with UK-ADRC investigators who find thatthe expert advice provided by our seasoned investigators improves their success in pilot studies grantapplications and publications. The Core also participates as a full partner to the research mission of the UK-ADRC emphasizing transitions in late life from normal to multiple etiology dementia. A key element of thisCore is the well-established track record of developing novel methodology to analyze data collected at the UK-ADRC and from other cohorts with a focus on elderly subjects transitions to MCI and eventually dementia. TheCore also provides training for students enrolled in the graduate programs in Gerontology Public HealthEpidemiology and Biostatistics Psychology and Statistics. It is committed to developing younger faculty tobecome productive ADRC investigators. In keeping with the mission of the UK-ADRC faculty in this Core alsocontribute to the dementia research community at large through service on external advisory committeesstudy sections manuscript reviews and data safety monitoring boards. The DMS Core will continue thesecritical responsibilities through the following specific aims.Aim 1: Maintain and expand an integrated data warehouse and suite of web-based data collection applicationsand reporting platforms for ADRC Cores and projects.Aim 2: Provide expertise on experimental design and statistical analysis.Aim 3: Support the clinical biomarker neuropathological educational and outreach missions of the ADRC.Aim 4: Contribute to the activities of the dementia community at large through service and research.

project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Attention;Bioinformatics;Biological Markers;Biometry;COVID-19 pandemic;Clinical;Clinical Data;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Computer software;Consult;Data;Data Analyses;Data Collection;Dementia;Development;Elderly;Elements;Enrollment;Environment;Epidemiology;Etiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Generations;Genetic;Gerontology;Information Systems;Interruption;Kentucky;Leadership;Life;Literature;Manuscripts;Methodology;Mission;Neuroepidemiology;Observational Study;Online Systems;Participant;Pathology;Pilot Projects;Procedures;Psychology;Public Health;Publications;Reporting;Research;Research Design;Research Methodology;Research Personnel;Resources;Risk Factors;Role;Sampling;Seasons;Services;Software Engineering;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Universities;Ursidae Family;Vision;base;central database;clinical biomarkers;cohort;dashboard;data dictionary;data management;data warehouse;direct application;doctoral student;education research;electronic data capture system;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;portability;programs;recruit;statistics;student training;success;user-friendly;web app;web site


application_id: 10689252
project_number: 5R01DE024509-10
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2023-07-21
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 024509
program_official: MCNEALY, TAMARA L
project_start_date: 2014-07-01
project_end_date: 2025-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
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:
AbstractPeriodontitis is one of the six most common chronic inflammatory diseases affecting ~ 50% of the adults in theUSA. The etiology of periodontitis is strongly associated with changes in both the microbial composition anddensity of an indigenous symbiotic community to a more diverse dysbiotic microbial community. High-throughputsequencing techniques applied to characterize the composition of the periodontal microbiota obtained fromdisease sites revealed the presence of high number of newly appreciated oral pathogens. Among these is theGram-positive anaerobic rod Filifactor alocis present in high numbers in the oral biofilm of periodontal diseasesites compared to healthy sites. The challenge now is to determine the potential pathogenicity virulencemechanisms and possible immune subversion arsenal of F. alocis. The response that the host mounts to thebacterial challenge plays a major role in disease progression. Neutrophils are the primary leukocyte recruited tothe subgingival crevice and their interaction with the microbial community is a key determinant of oral healthstatus. Understanding how the host responds to the different microbial challenges will increase our knowledgeof the disease process. The current proposal will test the hypothesis that F. alocis undermines neutrophil effectorfunctions to promote its survival. We will test our hypothesis by the following specific aims: Aim 1: To define F.alocis regulation of neutrophil vesicular trafficking to evade killing and promote bacteria colonization and boneloss. The goal of this aim will be to test the hypothesis that F. alocis manipulates neutrophil signaling pathwaysto uncouple the bactericidal activity from the inflammatory response to successfully evade killing. Aim 2: Tocharacterize F. alocis ability to modulate apoptosis in human neutrophils. The goal of this aim will be to test thehypothesis that F. alocis modulates neutrophils apoptotic program as a virulence strategy to preserve anintracellular niche within the neutrophil phagosome. The current project is a collaborative effort from aninvestigator who is an expert in the field of neutrophil biology and inflammation and its interactions with emergingoral pathogens (Dr. Uriarte) and an expert in the field of oral pathogens and host cell responses using in vivomodels of periodontitis (Dr. Lamont). The proposed collaborative efforts offer an innovative and strong frameworkto characterize the pathogenic potential of F. alocis. In addition the data generated from this application will filla significant gap in our knowledge and lay the foundation for development of new therapeutic approaches tocombat periodontitis.

project_terms:
Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Apoptosis;Apoptotic;Bacteria;Biology;Bone Marrow;Cells;Chemotaxis;Communities;Complex;Cytoplasmic Granules;Data;Development;Disease;Disease Progression;Etiology;Exocytosis;Experimental Models;Focal Infection;Foundations;Fusobacterium nucleatum;Gene Expression;Generations;Gingiva;Goals;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;In Vitro;Indigenous;Infection;Inflammation;Inflammatory;Inflammatory Response;Intention;Knowledge;Laboratories;Leukocytes;Longevity;Mediating;Molecular;Mus;NF-kappa B;Oral;Oral health;Organism;Pathogenesis;Pathogenicity;Pathology;Periodontal Diseases;Periodontal Pocket;Periodontitis;Phagocytes;Phagosomes;Play;Porphyromonas gingivalis;Process;Proteins;Publishing;Reactive Oxygen Species;Regulation;Research;Research Personnel;Rod;Role;Secure;Signal Pathway;Signal Transduction;Site;Stimulus;TLR2 gene;Techniques;Testing;Tissues;United States;Virulence;Work;antimicrobial;bactericide;bone loss;chronic inflammatory disease;combat;cytokine;defined contribution;density;dysbiosis;extracellular;host-microbe interactions;in vivo;in vivo Model;information gathering;innovation;microbial;microbial community;microbial composition;microbicide;microbiota;neutrophil;novel therapeutic intervention;oral bacteria;oral biofilm;oral pathogen;pathogenic bacteria;periodontopathogen;preservation;prevent;programs;recruit;response;trafficking;transcriptome;transcriptome sequencing

public_health_relevance:
Project NarrativePeriodontitis is a chronic inflammatory disease induced by oral pathogenic bacteria that affects ~50% of theadults in the United States. Oral health status is maintained by the presence of white blood cells which areinvolved in killing the oral bacteria that cause periodontitis. In the current study we propose to define how anewly appreciated bacterium manages to avoid being killed by the white blood cells; with the intention of filling asignificant gap in the understanding of which factors contribute to periodontal disease.


application_id: 10689102
project_number: 5R01CA157429-10
project_title: Overcoming Drug Resistance of Castration-Resistant Prostate Cancer
administering_ic: NCI
award_notice_date: 2023-06-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 157429
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
arra_indicator: N
project_abstract:
Title: Overcoming drug resistance of castration-resistant prostate cancerAbstractBecause androgen receptor (AR) signaling is essential for development of prostate cancer (PCa) includingcastration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) are becoming the first linetreatment for CRPC. However the limited success of ASIs makes it urgent to develop approaches to treatASI-resistant CRPC. EZH2 (enhancer of zeste homolog 2) the catalytic subunit of the Polycomb RepressiveComplex (PRC2) responsible for H3K27me3 and gene repression has been identified as a promising targetin PCa. However it was also discovered that oncogenic function of EZH2 in CRPC is PRC2-independent.Thus identifying regulators that control EZH2 function is of significance as it may provide an avenue toenhance the efficacy of EZH2 inhibitors (EZH2i) in CRPC. The long-term goals of this study are to identifydruggable signaling pathways that offer effective treatment options for patients with ASI-resistant CRPC.The objective is to define the role of polo-like kinase 1 (Plk1) in regulating EZH2 to exploit this pathway asa therapeutic target for ASI-resistant CRPC patients and to examine whether Plk1-dependentphosphorylation of EZH2 is a novel biomarker for CRPC. The central hypothesis is that Plk1 phosphorylationof EZH2 leads to a functional switch from PRC2-dependent gene repression to PRC2-independent but AR-dependent transcription activation eventually contributing to disease progression into CRPC stage. Ourdata show that Plk1 inhibition leads to an increased level of H3K27me3 and that Plk1 directly phosphorylatesEZH2 at T144. We also show that Plk1 phosphorylation of EZH2 results in decreased levels of H3K27me3destabilization of the PRC2 complex and increased association between EZH2 and AR. Our hypothesis willbe tested by pursuing three Aims - (1) to dissect how Plk1 phosphorylation of EZH2 regulates the PRC2complex; (2) to test whether expression of unphosphorylatable EZH2 antagonizes PCa progression andenhances the efficacy of EZH2i in genetically engineered mouse (GEM) models; and (3) to determinewhether Plk1 inhibitor (Plk1i) plus EZH2i is a novel approach to treat ASI-resistant CRPC and whetherpT144-EZH2 is a novel biomarker for CRPC. These complementary aims will be accomplished usingbiochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mousemodels culture systems and patient-derived xenograft (PDX) methodologies. The rationale for the researchis that it will probe the importance of Plk1 to PRC2 complex examine whether a combination of Plk1i withEZH2i is a novel approach to treat ASI-resistant CRPC and ask whether pT144-EZH2 is a new biomarkerto predict PCa progression. This contribution is significant because if positive the results of the proposedstudy will support an immediate clinical trial for Plk1i plus EZH2i to treat ASI-resistant CRPC. The researchis innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditionalview that Plk1 functions solely to regulate mitotic events.

project_terms:
Affect;Androgen Receptor;Androgens;Apoptosis;Automobile Driving;Binding;Biochemical;Biological Markers;Breeding;Cancer Patient;Castration;Catalytic Domain;Cell Nucleus;Cells;Clinic;Clinical Research;Clinical Trials;Complex;Creativeness;Cytokine-Inducible Kinase;Cytoplasmic Receptors;Data;Development;Disease;Disease Progression;Drug resistance;Enhancers;Epigenetic Process;Event;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Health;Homologous Gene;Investigation;Knock-out;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Methylation;Mission;Mitotic;Mus;Neuroendocrine Prostate Cancer;Oncogenic;Operative Surgical Procedures;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;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;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;pharmacologic;programs;prostate cancer cell;prostate cancer model;prostate cancer progression;success;therapeutic target;tumor


application_id: 10688137
project_number: 5R01EY033190-03
project_title: Visual mechanisms of intermediate distance space perception during self-motion
administering_ic: NEI
award_notice_date: 2023-07-21
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;Darkness;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 System;Visual impairment;Visuospatial;Walking;behavioral response;cognitive load;experimental study;insight;motor control;neural;neuromechanism;operation;phenomenological models;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: 10687845
project_number: 5U44AA026126-05
administering_ic: NIAAA
award_notice_date: 2023-08-29
opportunity_number: PAR-15-154
application_type: 5
activity_code: U44
ic: AA
serial_number: 026126
program_official: SENEVIRATNE, CHAMINDI
project_start_date: 2017-08-25
project_end_date: 2025-08-31
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: 2023-09-01
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;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;Incubated;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;Pharmacotherapy;Phase;Physiological;Plasma;Plasma Proteins;Play;Polyamines;Population;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;drinking;drug testing;genotoxicity;high throughput screening;human subject;in vivo;ineffective therapies;intraperitoneal;manufacturing scale-up;neuroprotection;neurotoxicity;nonhuman primate;novel;novel therapeutics;pharmacologic;phase 1 study;pre-Investigational New Drug meeting;preclinical development;preclinical study;receptor;receptor function;reduce symptoms;relapse prevention;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: 10687820
project_number: 5R01AA027990-04
project_title: Estradiol Effects on Behavioral and Reward Sensitivity to Alcohol across the Menstrual Cycle
administering_ic: NIAAA
award_notice_date: 2023-08-31
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;Disinhibition;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;Progesterone;Puberty;Public Health;Recording of previous events;Relapse;Research;Rewards;Risk;Risk Taking;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;drinking behavior;men;neurobehavioral;personalized intervention;proliferative phase Menstrual cycle;relapse prevention;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: 10687269
project_number: 5R35GM131807-05
project_title: Hedgehog Signaling in Development and Metabolism
administering_ic: NIGMS
award_notice_date: 2023-07-19
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 131807
program_official: XU, JIANHUA
project_start_date: 2019-09-01
project_end_date: 2025-01-31
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;Cell membrane;Cell surface;Cholesterol;Circulation;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;Proliferating;Protein Family;Proteins;Publishing;Regulation;Research;Role;SMO gene;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;transmission process

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: 10687226
project_number: 5R01AI167297-03
project_title: HDAC6 regulation of myeloid cell responses in sepsis
administering_ic: NIAID
award_notice_date: 2023-07-31
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_abstract:
Project SummarySepsis is a life-threatening disease caused by dysregulated host responses to infection. Sepsisremains a major health problem worldwide with high mortality. Myeloid cell responses such asendotoxin tolerance epigenetic modification metabolic failure and apoptosis are profoundlyaffected in sepsis which leads to systemic dysfunction of immune cells and progenitor cells. Theregulation of myeloid cell responses in sepsis remains largely unknown. The histone deacetylaseHDAC6 regulates a variety of cellular responses. However HDAC6 regulation of myeloid cellresponses in sepsis has not been investigated. Our preliminary studies indicate that HDAC6 is akey mediator of cell signaling in myeloid cells. Myeloid-specific HDAC6 deletion reduces themortality in septic mice. Furthermore selective HDAC6 inhibition can modulate myeloid cellresponses in the mouse models of sepsis. In the proposed studies we will test the hypothesisthat HDAC6 activation mediates myeloid cell dysfunction in sepsis and HDAC6 inhibition couldimprove myeloid cell function and survival rate in sepsis.

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;Macrophage;Mediating;Mediator;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;mortality;mouse model;novel;progenitor;response;septic;stem cells;transcriptomics

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of HDAC6 in the regulationof myeloid cell immune responses in sepsis. The studies will validate the therapeutic potential ofHDAC6 inhibition to improve myeloid cell function in sepsis. The proposed studies will provideimportant information for future clinical trials.


application_id: 10686352
project_number: 5R01NS102920-05
project_title: Transformation of Paraplegic Paralysis to Overground Stepping in Humans
administering_ic: NINDS
award_notice_date: 2023-09-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 102920
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2019-09-30
project_end_date: 2025-08-31
study_section: Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section[BNVT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryIt is becoming increasingly evident that the spinal circuitries below a paralyzing injury have a functional potentialthat far exceeds what has been thought to be possible. From recent studies in mice and rats with motor completeparalysis we know that the lumbosacral spinal cord can be neuromodulated electrically (eEmc) andpharmacologically (fEmc) to enable motor control including full weight-bearing stepping. The main goal of theproject is the development of noninvasive multiple neuromodulatory strategies to facilitate full weight bearingoverground stepping in paralyzed subjects. Recently we demonstrated that four chronic completely paralyzedindividuals regained the ability to stand independently and the ability to voluntarily flex the hip knee and anklewhen being stimulated epidurally. We propose to accomplish similar outcomes using a novel noninvasivemulti-site spinal cord stimulation strategy in concert with pharmacological modulation with stand and steptraining to neuromodulate the lumbosacral circuitry so that completely paralyzed individuals can regain somelocomotor function as well as voluntary movements. We propose to develop these strategies further bycombining these interventions with an exoskeleton technology so that individuals with complete paralysiscan regain significant levels of community mobility. We will determine the effectiveness of noninvasive spinalstimulation and administration of buspirone (a monoaminergic agonist) treatment for facilitating of locomotoractivity in the gravity-neutral apparatus body weight supported stepping on a treadmill and stepping in the EKSOrobotic device to achieve full weight bearing stepping in paralyzed subjects in rolling walker. It is anticipated thatthe early stages of development of this technology could be available within the clinic to improve motor functionwithin a matter of a few years. These interventions have the potential to improve health and can impact thequality of life and in many cases can likely to lead to reduced health costs and a lower burden not only to theparalyzed individuals but also to their families and caregivers.

project_terms:
Agonist;Ankle;Awareness;Body Weight;Buspirone;Caregivers;Chronic;Clinic;Communities;Cutaneous;Development;Devices;Diagnosis;Dimensions;Electrodes;Family;Force of Gravity;Generations;Goals;Health;Health Care Costs;Hip region structure;Human;Individual;Injury;Intervention;Knee;Lesion;Locomotion;Lower Extremity;Mediating;Motion;Motor;Motor Activity;Movement;Mus;Musculoskeletal Equilibrium;Neurostimulation procedures of spinal cord tissue;Outcome;Painless;Paralysed;Paraplegia;Performance;Probability;Property;Quality of life;Rattus;Recovery;Recovery of Function;Sensory;Series;Site;Speed;Spinal;Spinal Cord;Spinal Injuries;Spinal cord injury;Spinal cord injury patients;Step training;Technology;Training;Vertebral column;Weight-Bearing state;connectome;cost;effectiveness evaluation;exoskeleton;exoskeleton device;experience;experimental study;improved;insight;limb movement;motor control;motor function improvement;motor function recovery;neuroregulation;novel;pharmacologic;relative effectiveness;robot assistance;robotic device;technology development;tool;treadmill;walker

public_health_relevance:
Project NarrativeWe have demonstrated that the human lumbosacral spinal cord can be neuromodulated with epiduralstimulation to enable recovery of standing and volitional control of the lower limbs after complete motorparalysis. We now propose to develop several novel noninvasive and complementary neuromodulatorytechnologies using exoskeleton device to recovery of motor functions including overground weightbearingmobility and their volitional control of movement after severe (motor complete and incomplete paralysis).


application_id: 10685796
project_number: 1DP2MH136495-01
administering_ic: NIMH
award_notice_date: 2023-08-25
opportunity_number: RFA-RM-22-019
application_type: 1
activity_code: DP2
ic: MH
serial_number: 136495
program_official: BURSTEIN, MARCY ELLEN
project_start_date: 2023-09-01
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 RCCS-L (70)]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
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
budget_start_date: 2023-09-01
project_title:
Innovations in Personalizing Treatment for Eating Disorders Using Idiographic Methods and the Impact of Personalization on Psychological Physical and Sociodemographic Outcomes

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are serious mental illness: someone dies of an ED every 52 minutes.EDs are highly related to a host of negative outcomes including public health and individualdisease burden medical and psychological comorbidities and social determinants of health(SDOH). Treatment response for EDs are suboptimal; there are no evidence-based treatmentfor adults with anorexia nervosa (AN) or Other Specified Feeding or Eating Disorder (OSFED)and only 50% of adults respond to current evidence based treatments. There are no precisiontreatments nor any treatments that consider social context in existence. Personalizedtreatments for EDs that consider social contexts are urgently needed to improve treatmentresponse and minimize the suffering associated with these illnesses. Our overall goal extendingupon our past work is to create a treatment personalized based on idiographic (or one person)models (termed Transdiagnostic Network Informed Personalized Treatment for EDs; T-NIPT-ED). We will carry out a two-phase study to systematically characterize individual mechanismsof treatment (Phase I: N=900) and then test the efficacy of each treatment module (Phase II:N=240 drawn from Phase I) compared to the current gold-standard treatment (CognitiveBehavioral Therapy Enhanced: CBT-E). Our study goals are to (1) characterize the prevalenceof T-NIPT-ED precision treatment mechanisms and medical and psychological comorbidities(e.g. obesity; depression) individual disease burden (e.g. disability) SDOH (e.g. foodinsecurity) and public health outcomes (e.g. service utilization) specific to these mechanisms(2) identify if personalized target mechanisms improve when matched to evidence-basedtreatment modules of T-NIPT-ED and (3) test if change in T-NIPT-ED is associated withimproved outcomes (vs CBT-E) including ED outcomes comorbidities disease burden andpublic health outcomes and if these outcomes are moderated by SDOH. These goals willultimately lead to the very first precision treatment for ED and can be extended to additionalpsychiatric illnesses. The proposed research uses highly innovative methods; intensivelongitudinal data collected with mobile technology is combined with state-of-the art idiographicmodeling methods to deliver a virtual personalized treatment. This proposal integratesassessment of broad (e.g. SDOH; public health burden) and specific (e.g. ED symptoms)outcomes to ensure that social context can be integrated into personalization. The proposedresearch has high clinical impact. Ultimately this proposal will lead directly to the creation anddissemination of an evidence-based individually-personalized treatment for EDs as well as willserve as an exemplar for precision treatment development across the entire field of psychiatry.

project_terms:
Adult;Anorexia Nervosa;Clinical;Cognitive Therapy;Data;Diagnostic;Eating Disorders;Evidence based treatment;Goals;Individual;Lead;Medical;Mental Depression;Mental disorders;Methods;Modeling;Obesity;Outcome;Persons;Phase;Precision therapeutics;Prevalence;Psychiatry;Public Health;Research;Social Environment;Specific qualifier value;Symptoms;Testing;United States National Institutes of Health;Work;burden of illness;comorbidity;disability;efficacy testing;evidence base;feeding;food insecurity;improved;improved outcome;innovation;mobile computing;personalized medicine;psychologic;public health relevance;service utilization;severe mental illness;social health determinants;sociodemographics;standard care;therapy development;treatment response;virtual

public_health_relevance:
PROJECT NARRATIVEThis project will build a new precision treatment for eating disorders and identify how individualtreatment mechanisms relate to public health outcomes individual disease burden medicalcomorbidities and social determinants of health. The proposed research has significant publichealth relevance as it will directly lead to a highly accessible and deployable personalizedtreatment that can improve treatment response rates and be applied to all psychiatric illnesses.The proposed research is relevant to NIHs strategic aim 3.3b as it will lead to the creation of apersonalized treatment consistent with NIHs precision treatment initiative.


application_id: 10685301
project_number: 5R01CA258421-03
project_title: Gold-derived therapeutic compounds for disease application
administering_ic: NCI
award_notice_date: 2023-07-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 258421
program_official: FU, YALI
project_start_date: 2021-08-04
project_end_date: 2026-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 11956743
contact_pi: AWUAH, SAMUEL GORMAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
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/ABSTRACT. Gold-derived anticancer compounds are promising therapeutic agents fordisease applications including cancer. Triple negative breast cancer (TNBC) is an aggressive clinical subtypeof breast cancer that lacks effective therapy. Approximately 66% of all breast cancer deaths are TNBC-relatedhence pragmatic treatment options are sorely needed. Our research program seeks to harness the unique spatialproperties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for new targetedtherapeutic regimen to eliminate TNBC. We have developed gold compound libraries with different scaffolds anddistinct mode of action in TNBC cells including modulating mitochondrial biogenesis and morphology. Thecompounds display high potency in the nanomolar range with >30-fold selectivity to cancer cells over normalcells. Comparative profiling using the NCI-60 screen confirmed toxicity of a lead compound AuPhos against apanel of breast cancer including TNBC. Preliminary maximum tolerated dose studies in BALB/c mice suggestthat different classes of gold compounds can be well tolerated in animals. Additionally AuPhos exerts profoundantitumor effect and prevents liver metastasis in the metastatic 4T1 TNBC mouse model. Mechanism of actionstudies suggest that the gold compounds target different mitochondrial processes including mitochondrialbiogenesis or morphology. We hypothesize that synthetic modification of the gold scaffold will enable thedevelopment of a suite of gold-based drugs that are targeted to different mitochondrial locales and biologicaltargets to eliminate TNBC. We will test the hypothesis in this project via the following aims: Aim 1) optimizechemically and functionally diverse gold anticancer agents; Aim 2) Delineate the mechanism of gold-basedmodulation of mitochondrial function; and Aim 3) Determine the therapeutic index of optimized gold compoundsin TNBC mouse models. The outcomes of this project will 1) provide novel gold-based compounds with specificityfor mitochondrial function to eliminate TNBC; 2) delineate the mechanism of TNBC inhibition by the developedgold-based compounds; and 3) establish in vivo efficacy and pharmacodynamics of gold anticancer agents.Critically the compounds generated will provide impetus for targeted therapies for TNBC which is an unmetneed.

project_terms:
4T1;Adopted;Animals;Antineoplastic Agents;Apoptosis;Autophagocytosis;Biogenesis;Bioinformatics;Biological;Biology;Biometry;Breast Cancer Cell;Cancer Biology;Cancer Model;Cessation of life;Chemicals;Complex;Data;Development;Disease;Drug Kinetics;Drug Targeting;Electron Transport;Environment;Exhibits;FRAP1 gene;Fostering;Goals;Gold;Gold Compounds;Growth;Impairment;In Vitro;Inbred BALB C Mice;Knowledge;Lead;Libraries;Ligands;Locales;Malignant Neoplasms;Maximum Tolerated Dose;Medical;Metabolic;Metastatic Neoplasm to the Liver;Mitochondria;Modeling;Modification;Morphology;Mus;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmacodynamics;Process;Prognostic Marker;Property;Proteins;Proteomics;Regimen;Research;Respiration;Respiratory Chain;Specificity;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Therapeutic Agents;Therapeutic Index;Toxic effect;Work;analog;anti-cancer;anticancer activity;antitumor agent;antitumor effect;cancer cell;cell growth;clinical efficacy;clinical subtypes;comparative;drug development;drug discovery;effective therapy;improved;in vitro Assay;in vivo;innovation;insight;malignant breast neoplasm;mitochondrial dysfunction;mouse model;nanomolar;new therapeutic target;novel;novel strategies;novel therapeutic intervention;patient derived xenograft model;prevent;programs;rational design;response;scaffold;small molecule;targeted agent;targeted treatment;therapeutic target;tool;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor xenograft;uptake

public_health_relevance:
PROJECT NARRATIVE: Gold-derived compounds modulate mitochondrial function and exhibit efficaciousanticancer activity. Combining the unique structural and reactive features of gold compounds with mechanism-of-action studies provide a new platform for the discovery of mitochondria-targeted anticancer agents. Thisproposal seeks to expand potent gold chemotherapeutic libraries guided by functional biology to elucidate theirmode of action and inhibit metastatic tumor in vivo while sparing normal tissue.


application_id: 10684493
project_number: 3UT2GM148083-01S1
project_title: I-RED Southeast XLerator Network: Business Fundamentals for Core Facility Directors
administering_ic: NIGMS
award_notice_date: 2022-09-01
opportunity_number: PA-20-272
application_type: 3
activity_code: UT2
ic: GM
serial_number: 148083
suffix: S1
program_official: ZHOU, YANG
project_start_date: 2022-08-15
project_end_date: 2023-02-14
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryBiomedical research is increasingly reliant on sophisticated technology that requires advanced technical skills.This shift in structure of academic research environments demands sufficient resources to perpetuate cuttingedge research programs. Therefore there is an increasing need for highly functional institutionally-basedcores providing services with a rate structure that facilitates optimal use of funding sources. While service corefacilities are desired in the research landscape it is widely acknowledged that these operations face manychallenges to deliver useful products on a sustained basis.A common institutional deficiency of service core management is lack of consistent development andoversight. Core implementation and maintenance are frequently performed in the absence of formal businessand organizational training for the institute directors and staff. This gap has highlighted the need for trainingand potentially certification of those engaged with supervision and operations of service cores. This gap couldbe filled by a curriculum that covers a spectrum of considerations for developing and managing successfulcores. Based on this rationale the central theme of this proposal is to develop a curriculum providinginstitutional assistance for all offices and individuals associated with service cores to facilitate an enhancedresearch and related business acumen environment for the hosting institute.The proposed curriculum will be organized to contain the following elements:Element 1. Phases of cores for implementation and sustainability.Element 2. Staff and equipment availability plan.Element 3. Fiscal management.Element 4. User base growth of core facilities.Element 5. Value of cores to the academic mission of the institute.The plan for the implementation of the curriculum is that extensive content will be provided in a visual modethat will facilitate assimilation of the material.After piloting this curriculum with the IDeA States core personnel we intend to develop this into a product tobe offered on a continuous basis to personnel in diverse locations.

project_terms:
Advertising;Assimilations;Awareness;Biomedical Research;Budgets;Businesses;Centers of Research Excellence;Certification;Communication;Computer software;Contracts;Core Facility;Data;Depreciation;Development;Dissemination and Implementation;Educational Activities;Educational Curriculum;Effectiveness;Elements;Environment;Equipment;Evaluation;Extramural Activities;Face;Fee-for-Service Plans;Funding;Funding Agency;Funding Mechanisms;Grant;Growth;Human Resources;Individual;Institutes;Location;Maintenance;Mission;Monitor;Performance;Phase;Procedures;Process;Publications;Regulation;Research;Resources;Role;Series;Services;Standardization;Structure;Supervision;Surveys;Technical Expertise;Technology;Training;United States National Institutes of Health;Update;Visual;base;curriculum development;dissemination strategy;equipment acquisition;graduate student;improved;meetings;operation;outreach;programs;square foot;success;user-friendly;web site

public_health_relevance:
Project NarrativeBiomedical research is increasingly reliant on sophisticated technology that requires advanced technical skillsand this shift in structure of academic research environments demands sufficient resources to perpetuatecutting edge research programs. Therefore there is an increasing need for highly functional institutionally-based cores providing services with a rate structure that facilitates optimal use of funding sources. Based onthis rationale the central theme of this proposal is to develop a curriculum providing institutional assistance forall offices and individuals associated with service cores to facilitate an enhanced research and relatedbusiness acumen environment for the hosting institute.


application_id: 10684352
project_number: 3R01DA046526-04S1
project_title: Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
administering_ic: NIDA
award_notice_date: 2023-01-27
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: DA
serial_number: 046526
suffix: S1
program_official: NAIR, SUNILA GOPI
project_start_date: 2020-09-01
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1(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
project_abstract:
PROJECT SUMMARY/ABSTRACTNicotine use is a substantial burden to public health. Further craving and relapse to smoking appear to vary asa function of sex and of menstrual cycle phase in women whereby increases in 17-estradiol (E2) andprogesterone (P4) are associated with addiction vulnerability and resilience respectively. P4 has been examinedclinically as a smoking cessation agent and appears to show promise for women. However studies incorporatingmen have shown unclear or limited efficacy in men. Its derivative allopregnanolone (ALLO) was recentlyapproved by the Food and Drug Administration (FDA) as a treatment for post-partum depression although it notapproved as a smoking cessation agent. In preclinical studies hormones interact with nicotine neurobiology asa function of sex. We have found that neuroimmune signaling within the nucleus accumbens core a key brainregion associated with drug reward is driven by nicotine seeking and consumption in a sex-specific fashionwhereby female rats are more susceptible to neuroimmune consequences induced by nicotine use as comparedto males. Specifically we have shown that NAcore microglia are more activated by nicotine in females than inmales. Further we have shown that activation of the nuclear factor-kappa B (NF-B) pathway occurs followingnicotine self-administration (SA) and is necessary to inhibit in order for other pharmacotherapies to reducenicotine seeking. We have also shown that nicotine demand intensity (as measured via behavioral economics)is sensitive to synthetic and ovarian hormones. Under this diversity supplement Mr. Kendrick will uncoverpotentially critical contributions of neuroimmune signaling within the reward pathway to the therapeutic effects ofP4 and ALLO as a function of sex in reducing nicotine consumption. We will test necessity of these compoundsto inhibit neuroimmune activation within the NAcore in order to exert therapeutic effects in reducing nicotineconsumption. In Aim 1 we will test if inhibition of NAcore NF-B signaling is necessary for P4 and ALLO todecrease nicotine demand intensity. We hypothesize that this will be true in females but not males. In Aim 2 wewill establish the conditional relationship of necessity through bidirectional chemogenetic manipulation ofmicroglia while chronically administering P4 ALLO or vehicle during nicotine SA. We hypothesize that P4 andALLO will reduce nicotine consumption and microglial activation but that chemogenetic activation of microgliawill occlude this effect. We further hypothesize that this will only be evident in females. Together these studieswill be the first to establish necessity of NAcore neuroimmune inhibition (via NF-B and microglial activation) inthe efficacy of two potential steroid-based pharmacotherapies for smoking cessation across both sexes. This willalso be the first set of studies to determine if ALLO shows preclinical efficacy in decreasing nicotine demand inboth sexes. This line of research has the potential to guide strategies for promoting smoking cessation throughdiscovery of novel neural mechanisms and may justify examination of other possible therapeutics that have anti-inflammatory properties for smoking cessation which may yield higher efficacy across both sexes.

project_terms:
Allopregnanolone;Anti-Inflammatory Agents;Biological Process;Brain region;Chronic;Clinical;Clinical Data;Confocal Microscopy;Consumption;Data;Estradiol;Female;Gene Transfer;Genetic;Glutamates;Goals;Gonadal Hormones;Gonadal structure;Hormones;Investigation;Measures;Mediating;Menstrual cycle;Microglia;Morphology;Neurobiology;Neuroimmune;Neuroimmunomodulation;Neurons;Nicotine;Nicotine Dependence;Nuclear;Nucleus Accumbens;Outcome;Ovarian hormone;Pathway interactions;Pharmacotherapy;Phase;Postpartum Depression;Predisposition;Price;Progesterone;Property;Public Health;Rat Transgene;Rattus;Relapse;Reporting;Research;Rewards;Sex Differences;Signal Transduction;Smoking;Specificity;Steroids;Synaptic plasticity;Techniques;Testing;Therapeutic;Therapeutic Effect;Training;United States Food and Drug Administration;Viral;Woman;addiction;behavioral economics;biological sex;clinically relevant;clinically significant;craving;designer receptors exclusively activated by designer drugs;drug reward;genetic manipulation;glial activation;male;men;morphometry;neurobiological mechanism;neuroinflammation;neuromechanism;neurosteroids;nicotine seeking behavior;nicotine self-administration;nicotine use;novel;positive allosteric modulator;pre-clinical;preclinical efficacy;preclinical study;receptor;resilience;sex;smoking cessation;steroid hormone

public_health_relevance:
PROJECT NARRATIVE Sex differences in smoking vulnerability and cessation outcomes have been reported with long-termsmoking cessation being more difficult to achieve in women than men. Current steroid hormone-basedpharmacotherapies under investigation for smoking cessation including progesterone (P4) have not shownclear efficacy across both sexes which may be due to differential neuroimmune vulnerabilities induced bynicotine use within the reward pathway between sexes. The proposed research has the potential to uncovernovel neuroimmune mechanisms by which P4 and its derivative allopregnanolone (ALLO) modulate nicotineuse as a function of sex.


application_id: 10684327
project_number: 5R03HD109497-02
project_title: The Impact of Leukocyte-Derived OSM on Ovulation and Luteinization in the Human Ovary
administering_ic: NICHD
award_notice_date: 2023-07-21
opportunity_number: PA-20-200
application_type: 5
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;Binding;Bioinformatics;Biological;Cell Culture Techniques;Cells;Data;Dinoprostone;EGF gene;Family;Fertility;Fertilization in Vitro;Gene Expression;Genes;Gonadotropins;Human;Human Chorionic Gonadotropin;IL6 gene;Infertility;Inflammation;Inflammatory Response;Interleukin 6 Receptor;Knowledge;Leukocytes;Luteal Cells;Luteinization;MAPK3 gene;Mediator;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;aspirate;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: 10684131
project_number: 5R01AA030487-02
administering_ic: NIAAA
award_notice_date: 2023-07-06
opportunity_number: RFA-AA-21-016
application_type: 5
activity_code: R01
ic: AA
serial_number: 030487
program_official: FREEMAN, ROBERT
project_start_date: 2022-08-15
project_end_date: 2027-05-31
study_section: ZAA1-DD(17)V
contact_pi_person_id: 12488104
contact_pi: LAUCKNER, CAROLYN
other_pis: KERSHAW, TRACE S
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
budget_start_date: 2023-06-01
project_title:
Evaluation of a Combined Motivational Interviewing and Ecological Momentary Intervention to Reduce Risky Alcohol Use among Sexual Minority Males and Transgender Individuals

project_abstract:
ABSTRACTSexual and gender minority individuals are more likely to report hazardous drinking and have alcohol usedisorders (AUDs) compared to cisgender and heterosexual people. Emerging adult (aged 18-34) sexual andgender minorities are at especially high risk for AUDs compared to older adults with up to 44% meeting AUDcriteria. These trends are concerning as studies have found that alcohol use increases HIV risk behaviors andHIV disproportionately affects emerging adult sexual minority male and transgender (SMMT) individuals. Thusit is essential to test interventions for reducing alcohol use among SMMT individuals as a means of preventingHIV among this vulnerable population. One potential evidence-based method of reducing alcohol use ismotivational interviewing which incorporates a goal-oriented approach for changing behavior and has beenshown to be effective among various populations in prior literature and the investigators pilot research.However there are opportunities to use technology to extend the impact of this approach by deliveringmessaging to prevent risk behaviors in real time (i.e. outside of intervention sessions). The proposed study willconduct a 3-arm randomized controlled trial that assesses the efficacy of two interventions as compared to acontrol: 1) An 8-week motivational interviewing intervention (TRAC) delivered remotely via cell phones and 2)TRAC combined with an ecological momentary intervention designed to deliver messages reinforcing drinkingreduction strategies discussed during TRAC sessions when individuals visit risky locations (GeoTRAC). Allparticipants will also complete monitoring of alcohol use and sexual behavior by completing daily surveys andtwice-daily mobile breathalyzer readings. GeoTRAC will use an existing app developed in the investigatorsongoing research that uses GPS tracking to determine when individuals visit risky locations. Participants willreceive messages upon arrival at these locations reminding them of strategies to address triggers for drinkingand will also complete mobile surveys and breathalyzer readings when they leave these locations to determinewhat alcohol and/or risk behaviors they engaged in. If they reported drinking they will receive harm reductionmessaging to encourage them to avoid subsequent risk behavior (e.g. unprotected sex). Breathalyzer resultsand daily self-reports will be used to assess the primary and secondary outcomes of drinking daysdrinks/drinking day binge drinking episodes and HIV risk behaviors and additional assessments at baseline8 weeks 6 months and 12 months will evaluate exploratory long-term outcomes. Participants will be recruitedfrom Kentucky and Connecticut through community-based recruitment and health clinics that serve SMMTindividuals. Overall there is a strong need to determine optimal methods of reducing alcohol use amongemerging adult SMMT individuals given its relationship to increased HIV risk behaviors. The proposed work willdraw upon the high technological literacy of emerging adults by using mobile phones and will test an innovativeprecision medicine approach that offers comprehensive support in reducing hazardous alcohol consumption.

project_terms:
Address;Adherence;Affect;Alcohol consumption;Alcohols;Behavior;Behavioral;Biological;Bisexual;Cancer Survivor;Cellular Phone;Clinic;Communities;Connecticut;Data;Effectiveness;Elderly;Evaluation;Event;Gays;Goals;HIV;HIV Seronegativity;HIV risk;Harm Reduction;Health;Heterosexuals;Individual;Intervention;Kentucky;Literature;Location;Methods;Motivation;Outcome;Participant;Patient Self-Report;Persons;Population;Randomized Controlled Trials;Reading;Reporting;Research;Research Personnel;Risk Behaviors;Self Efficacy;Sex Behavior;Sexual and Gender Minorities;Surveys;Technology;Testing;Time;Unsafe Sex;Visit;Vulnerable Populations;Work;aged;alcohol behavior;alcohol monitoring;alcohol use disorder;arm;behavior change;binge drinking;cisgender;comparison group;drinking;efficacy evaluation;emerging adult;evidence base;experience;gender minority group;group intervention;hazardous drinking;high risk;high risk drinking;high risk population;innovation;intervention effect;literacy;meetings;men;mobile application;motivational enhancement therapy;pre-exposure prophylaxis;precision medicine;prevent;primary endpoint;primary outcome;recruit;reduced alcohol use;remote delivery;secondary endpoint;secondary outcome;sex;sexual minority male;substance use;therapy design;transgender;trend;young adult

public_health_relevance:
PROJECT NARRATIVEEmerging adult sexual minority male and transgender individuals are more likely to report hazardous drinkingand to have alcohol use disorders compared to those who are cisgender and heterosexual. This is concerningas alcohol use contributes to HIV risk and HIV disproportionately affects this population. Through a randomizedcontrolled trial the proposed research will evaluate an enhanced motivational interviewing intervention thatutilizes smartphones and mobile breathalyzers to provide real-time messaging that addresses triggers fordrinking when individuals visit locations associated with risky alcohol use.


application_id: 10683728
project_number: 5F30NS129251-02
project_title: The Role of Perilipin 2 in Macrophages after Experimental Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2023-08-23
opportunity_number: PA-21-050
application_type: 5
activity_code: F30
ic: NS
serial_number: 129251
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2022-08-09
project_end_date: 2024-08-08
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 12283385
contact_pi: GLASER, ETHAN PHARES
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Spinal cord injury (SCI) leads to permanent motor and sensory loss that isexacerbated by persistent inflammation months after the injury. After SCI monocyte-derived macrophages(MDMs) infiltrate the lesion to aid in cellular debris clearance. However this response is emerging as a double-edged sword. Lingering debris inhibits repair and plasticity while clearance of the debris by infiltrating MDMsinduces a proinflammatory and damaging phenotype. Clearance of cholesterol-rich myelin debris causesMDMs to resemble proinflammatory foam cells both phenotypically and morphologically. Foam cells are lipid-laden macrophages with numerous lipid droplets (LDs) that form when excessive cholesterol uptakeoverwhelms cholesterol metabolism. Foam cells also drive chronic inflammation in atherosclerosis and non-alcoholic steatohepatitis (NASH). Foam cells persist chronically in the injured cord and may contribute to thesustained proinflammatory lesion environment. However their role in the chronic inflammatory state is poorlyunderstood. Therefore elucidating the effect of foam cell formation after SCI is integral to understanding thecontribution of MDMs to injury pathology. Preliminary and published data identify Perilipin 2 (Plin2) as a keydifferentially upregulated gene in both infiltrating MDMs after SCI and foam cells in atherosclerosis. Plin2 isessential in regulating the formation and storage of cholesterol (i.e. lipid droplets (LDs)) in macrophages aslipid metabolites are either exported from these cells or stored in LDs. Plin2 coats LDs sequesters them in thecytosol and prevents lipolytic enzymes from accessing their cargo. Reducing Plin2 may therefore reduce LDaccumulation and mitigate foam cell formation after SCI. In models of atherosclerosis and NASH Plin2deficient mice produced fewer foam cells and were protected from atherosclerotic plaque formation andcirrhosis respectively. To understand the effects of Plin2 upregulation in MDMs after SCI a novel targeteddeletion of Plin2 using a LysMCre/lox system will be employed. Using this mouse model this project willdetermine (1) the role of Plin2 in myelin-induced foam cell formation using an in vitro approach and (2) theeffects of targeted Plin2 deletion in MDMs on foam cell formation inflammation and locomotor recovery afterexperimental. These experiments will test the hypothesis that cell-specific Plin2 ablation in MDMs suppressesfoam cell formation after SCI inhibits inflammation and promotes functional recovery. If successful this projectwill provide novel insight into how CNS macrophages metabolize myelin and may provide new therapeutictargets to improve SCI recovery by resolving chronic intraspinal inflammation. Through the completion of thistraining grant the PI will receive ample training regarding the implementation of project managementresponsible conduct of research and the dissemination of findings. This training will provide the PI with theskillset necessary to carry out the specific aims and lay the foundation for the PI to become an independentphysician-scientist with an extramurally supported research portfolio in the field of neurotrauma.

project_terms:
Ablation;Acute;Alzheimer's Disease;Arterial Fatty Streak;Atherosclerosis;Bone Marrow;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Cirrhosis;Custom;Cytosol;Data;Disease;Environment;Enzyme-Linked Immunosorbent Assay;Enzymes;Extramural Activities;Family;Fluorescent in Situ Hybridization;Foam Cells;Foundations;Functional disorder;Gene Expression;Genes;Genetic;Grant;Health Care Costs;Immunofluorescence Immunologic;In Vitro;Individual;Infiltration;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Interleukin-6;Lesion;Leukocytes;Lipid-Laden Macrophage;Lipids;Locomotor Recovery;Macrophage;Mediating;Metabolism;Microscopy;Modeling;Morphology;Motor;Mus;Myelin;Myeloid Cells;Nervous System Trauma;Paralysed;Pathology;Pathway interactions;Phagocytosis;Phenotype;Physicians;Process;Production;Publishing;Quantitative Reverse Transcriptase PCR;Recovery;Recovery of Function;Research Support;Role;Scientist;Sensory;Site;Sorting;Spinal Cord;Spinal cord injury;Stains;Stimulus;System;Testing;Time;Tissues;Training;Transgenic Model;Up-Regulation;Visualization;Western Blotting;Work;collected works;cytokine;design;experimental study;histological stains;improved;in vitro Model;inflammatory milieu;injured;injury recovery;insight;lipid metabolism;molecular sequence database;monocyte;mouse model;nano-string;neuroinflammation;new therapeutic target;nonalcoholic steatohepatitis;novel;perilipin;prevent;repaired;response;responsible research conduct;single-cell RNA sequencing;skills;therapeutic target;uptake

public_health_relevance:
PROJECT NARRATIVESpinal cord injury (SCI) often results in permanent paralysis and expensive health care costs for individualsand their families. After SCI normal repair processes are limited by ineffective clearance of lipid-rich cellulardebris caused by white blood cells (monocyte-derived macrophages) transforming into inflammatory cellsthereby limiting recovery. Using a novel transgenic model this study will examine the role of a potentialtherapeutic target (Plin2) that may dramatically improve this debris clearance process which will limitinflammation and improve recovery after SCI.


application_id: 10683291
project_number: 5UG1OD024954-06
project_title: The Kentucky ECHO Pediatric IDeA Research Center (KE-PIRC)
administering_ic: OD
award_notice_date: 2023-08-29
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;Acceleration;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;Communication;Communities;Development;Diabetes Mellitus;Disease;Drug abuse;Education;Educational Status;Environment;Environmental Health;Etiology;Faculty;Family;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;Occupational Exposure;Outcome;Participant;Patients;Pediatric Hospitals;Perinatal;Physicians;Population;Population Heterogeneity;Preventive;Primary 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;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: 10682967
project_number: 3R01AI148241-02S1
project_title: Iron independent role for yersiniabactin in Yersinia pestis
administering_ic: NIAID
award_notice_date: 2022-08-24
opportunity_number: PA-20-185
application_type: 3
activity_code: R01
ic: AI
serial_number: 148241
suffix: S1
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2021-06-04
project_end_date: 2026-05-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
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:
3-Dimensional;Affinity;Attenuated;Bacteria;Binding;Bubonic Plague;Cells;Characteristics;Chemicals;Crystallography;Data;Defect;Development;Drug Targeting;Foundations;Goals;Gram-Negative Bacteria;Hemochromatosis;Human;Immune response;In Vitro;Infection;Iron;Kinetics;Lead;Leukocyte L1 Antigen Complex;Leukocytes;Mammals;Mediating;Membrane;Metals;Modeling;Molecular;Mus;Mutagenesis;Nutritional Immunity;Plague;Pneumonic Plague;Predisposition;Prevention;Proteins;Pump;Research Personnel;Role;Siderophores;Solid;Specificity;System;Testing;Therapeutic;Time;Transition Elements;Virulence;Virulence Factors;Work;Yersinia pestis;Zinc;combat;efflux pump;fitness;human disease;improved;inhibitor;innovation;mouse model;mutant;neutrophil;novel;novel therapeutic intervention;novel therapeutics;pathogen;pathogenic bacteria;permease;rational design;receptor;response;therapeutic candidate;therapeutic target;transposon sequencing;yersiniabactin


application_id: 10682959
project_number: 3R01AI153275-03S1
administering_ic: NIAID
award_notice_date: 2022-08-31
opportunity_number: PA-19-056
application_type: 3
activity_code: R01
ic: AI
serial_number: 153275
suffix: S1
program_official: DUPUY, LESLEY CONRAD
project_start_date: 2020-05-21
project_end_date: 2025-04-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 10849785
contact_pi: SOKOLOSKI, KEVIN JOSEPH
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
arra_indicator: N
project_title:
Comprehensive Definition of the Critical Role(s) of the Alphaviral Noncapped Genomic RNAs to Infection and Pathogenesis

project_abstract:
Alphaviruses are vector-borne pathogens that have proven capable of causing significant outbreaks of clinical disease. Currently there is an absolute lack of safe and approved antiviral therapies / vaccines. Thus research which defines the molecular basis of infection is essential and critically important to not only understanding alphaviral pathogenesis but to the development of innovative antiviral strategies. The overarching research objective of this proposal is to define the mechanism by which a novel alphavirus RNA species impacts infection and pathogenesis. The scientific premise and rationale supporting this objective are based upon a wealth of preliminary evidence which indicates that the production of noncapped genomic RNAs (ncgRNAs) is essential for alphaviral infection as evidenced by studies involving Sindbis virus (SINV) and Ross River virus. Nonetheless the extent to which the ncgRNAs impact viral infection is unknown and represents a critical gap in the knowledge base. Thus we propose the following specific aims- i) To determine the mechanism with which the noncapped genomic vRNAs impact infection and ii) To define the impact of the noncapped genomic vRNAs on viral pathogenesis. To accomplish the first aim we will undertake an exhaustive molecular analysis of SINV infection to determine the mechanism by which the ncgRNAs effect viral infection. Specifically we will determine whether or not ncgRNA function is linked to its translatability via a novel IRES-based approach. In addition we will determine which viral process is negatively affected by ncgRNA reduction; and determine the molecular interactions required for ncgRNA function. The second aim uses a combinatorial approach of in vivo studies and IFN-competent tissue culture models to comprehensively define the contribution of the ncgRNAs to SINV pathogenesis. Briefly the contribution of the ncgRNAs to the induction of a detrimental neuroinflammatory response will be evaluated in depth histologically and at the transcriptomic and proteomic levels. Moreover the consequences of increasing and decreasing alphaviral capping efficiency on the host innate immune response will also be defined in highly tractable tissue culture models of infection. The proposed work is highly significant in that it seeks to characterize and define the molecular importance of a novel viral RNA species. Moreover the proposed research is conceptually and technically innovative as state-of-the-art techniques approaches and models of infection are used to delineate the contributions of the novel ncgRNA species to molecular infection and pathogenesis. The successful completion of this work will fundamentally expand the knowledgebase by eliminating the critical gap in understanding described above; in addition the proposed research has a high likelihood of leading to the identification of novel antiviral strategies.

project_terms:
Address;Affect;Alphavirus;Alphavirus Infections;Antiviral Agents;Antiviral Therapy;Arthritis;Attenuated;Binding;Biology;Brain;Cell Line;Cessation of life;Chikungunya virus;Clinical;Defect;Development;Disease;Disease Outbreaks;Environment;Event;Failure;Gene Expression;Genomics;Growth;Histologic;Immune response;Impairment;In Vitro;Individual;Infection;Innate Immune Response;Integration Host Factors;Interferons;Internal Ribosome Entry Site;Invertebrates;Joints;Kinetics;Link;Modeling;Molecular;Molecular Analysis;Morbidity - disease rate;Nature;Nucleocapsid;Pathogenesis;Pathologic;Process;Production;Proteins;Proteomics;Public Health;RNA;RNA chemical synthesis;Reporting;Research;Role;Ross river virus;Sindbis Virus;Structure;Techniques;Testing;Therapeutic;Vaccines;Venezuelan Equine Encephalitis Virus;Viral;Viral Encephalitis;Viral Genes;Viral Pathogenesis;Virion;Virulence;Virus Diseases;Virus Replication;Wild Type Mouse;Work;base;combinatorial;defined contribution;effective therapy;exhaustion;expectation;genomic RNA;improved;in vivo;innovation;knowledge base;knowledgebase;mortality;mutant;negative affect;neuroinflammation;novel;particle;pathogen;response;tissue culture;tissue/cell culture;transcriptomics;vaccine strategy;vector-borne pathogen;viral RNA

public_health_relevance:
Alphaviruses such as Sindbis virus Chikungunya virus and Venezuelan Equine Encephalitis virus are significant threats to public health. Alphaviral infection in otherwise healthy individuals may result in severe disease- including persistent severe multi-joint arthritis viral encephalitis and death. This proposal seeks to characterize the importance of a novel noncapped viral RNA in regards to the establishment of viral infection and pathogenesis for the purpose of improving the understanding of alphaviral biology to identify innovative therapeutic strategies.


application_id: 10682952
project_number: 3K12DA035150-11S1
project_title: Supplement for Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2022-08-25
opportunity_number: PA-20-272
application_type: 3
activity_code: K12
ic: DA
serial_number: 035150
suffix: S1
program_official: BABECKI, BETH
project_start_date: 2022-09-01
project_end_date: 2024-08-31
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTOver the past 20 years the BIRCWH Program at the University of Kentucky (UK) has been extremelysuccessful in creating a research environment to prepare early career scientists to develop the necessary skillsto become independent NIH-supported researchers who are dedicated to improving womens health. Thisadministrative supplement will add a 4th BIRCWH scholar Dr. Laneshia Conner who is from anunderrepresented racial minority group to the UK BIRCWH program with the goal of developing her researchskills necessary to become an independent researcher engaged in intervention development for older Blackwomen in real world settings. HIV remains a major public health issue with adults aged 50 and olderexperiencing an increase in HIV diagnoses over the past two decades and 82% of HIV infections transmittedthrough heterosexual contact. Black women continue to be disproportionately impacted by HIV making up lessthan 15% of the female population yet accounting for half of new HIV infections in women in the U.S. OlderBlack women are often overlooked when it comes to HIV prevention services due to ageism and stigma abouthigh-risk behaviors among older adults and lack of an empirical base about older Black. Through thisadministrative supplement and appointment to the BIRCWH Dr. Conner will acquire skills to launch herresearch program in three areas: intervention development developing sustainable community programs forolder adults and expanding methodological skills for a future RCT research. The proposed project will developa culturally relevant Woman 2 Woman (W2W) intervention that has been adapted to address unique gaps inHIV prevention that target older Black women. Working with two low-income housing complexes for adults overthe age of 50 older Black women will be recruited to participate in a multisession group-level behavioralintervention adapted to address both physiological risk as well as low perception of risk. High unknownserostatus suggest that HIV prevalence may be higher than reported among older adults. This project willprovide information on how to develop a culturally adapted HIV prevention intervention for older Black womenand provide data on the feasibility and acceptability of the intervention in addition to the measuring behavioraland knowledge outcomes. Implementation and assessment procedures and protocols will inform a subsequentfull-scale R01 randomized clinical trial. The overall objective of this innovative project is to develop and test thefeasibility acceptability usability and preliminary efficacy of Woman to Woman (W2W) an HIV intervention forolder Black women using a mixed methods approach. Specific aims are: (1) Adapt the group-level intervention(W2W) focused on reducing HIV risk and increasing decision making skills in older Black women to includereproductive health histories in exploring the impact on sexual decision making and risk behaviors and (2)Conduct a pilot study of the revised W2W intervention in two community sites to evaluate acceptability andfeasibility. This administrative supplement will provide Dr. Conner with career development activities.

project_terms:
AIDS prevention;Accounting;Address;Administrative Supplement;Adult;Age;Ageism;Appointment;Area;Behavior Therapy;Black race;Communities;Complex;Data;Decision Making;Elderly;Environment;Female;Future;Goals;HIV;HIV Infections;HIV diagnosis;HIV risk;Heterosexuals;Housing;Intervention;Kentucky;Knowledge;Low income;Methodology;Methods;Outcome;Physiological;Pilot Projects;Population;Prevalence;Procedures;Protocols documentation;Public Health;Randomized Clinical Trials;Recording of previous events;Reporting;Reproductive Health;Research;Research Personnel;Risk;Risk Behaviors;Scientist;Site;Training Programs;United States National Institutes of Health;Universities;Woman;Women's Health;acceptability and feasibility;aged;base;behavior measurement;black women;career;career development;experience;feasibility testing;high risk behavior;implementation evaluation;improved;innovation;next generation;prevention service;preventive intervention;programs;racial minority population;recruit;risk perception;skills;social stigma;therapy development;usability

public_health_relevance:
Project NarrativeThere are no known evidence-based interventions targeting the prevention of HIV transmissionamong older Black women in the U.S. which is a major public health concern as there is agrowing aging Black American population living with HIV. The objective of this innovative projectis to develop and test the feasibility acceptability usability and preliminary efficacy of Womanto Woman (W2W) an HIV intervention for older Black women. The mentorship and trainingactivities combined with the implementation of the feasibility trial within this BIRCWH diversitysupplement will provide the needed skills and data for the BIRCWH scholar to submit acompetitive R01 to conduct a large scale randomized controlled trial to assess the impact of theW2W intervention in reducing HIV risk among older Black women.


application_id: 10682908
project_number: 3R01AI144126-03S1
project_title: SpoVG and PlzA Regulation of Lyme Disease Spirochete Infection Processes
administering_ic: NIAID
award_notice_date: 2022-08-26
opportunity_number: PA-19-056
application_type: 3
activity_code: R01
ic: AI
serial_number: 144126
suffix: S1
program_official: BOWDEN, NADINE
project_start_date: 2020-04-01
project_end_date: 2024-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
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
project_abstract:
v ABSTRACTBacterial infections require that the pathogen accurately produce essential factors at appropriate levels duringeach stage of infection processes. Understanding how bacteria control levels of their proteins in response tocues from their hosts provides important insights on microbial infectious properties. Such knowledge can alsoreveal new targets for improved preventative and curative therapies.The Lyme disease spirochete Borrelia burgdorferi survives in nature through cycles of infecting vertebratesand ticks. The CDC calculates that there are approximately 300000 new cases of human Lyme disease in theUSA each year. B. burgdorferi can persistently infect immunocompetent humans and other mammals for manyyears. Failure to treat Lyme disease promptly and adequately can result in persistent debilitating effects orsometimes death. Long-term infections may require extensive periods of antibiotic treatment. In order to bettertreat Lyme disease it is critical to develop a more thorough understanding of B. burgdorferi biology includingthe mechanisms by which the spirochete controls production of virulence factors.We discovered that a borrelial protein SpoVG binds with specificity and high affinity to DNA and RNA.Deletion of spoVG significantly impaired B. burgdorferi's ability to colonize ticks and be transmitted from ticksto mammals. Dysregulation of spoVG transcription caused significant changes in bacterial physiology. Wefurther found that SpoVG directly interacts with another B. burgdorferi protein PlzA the Lyme spirochete'scyclic-di-GMP-binding protein. Our studies revealed that PlzA is also a site-specific nucleic acid-bindingprotein and plzA mutants are defective in their infectivity. Among the many regulated targets we identified forSpoVG and PlzA is the antigenically-variable VlsE surface protein which is essential for persistent B.burgdorferi infection.The planned studies will simultaneously investigate SpoVG and PlzA as well as the effects of c-di-GMP ontheir functions. These preliminary data stemmed from long-standing collaborations between the P.I. and co-investigators of this proposal. Our combined efforts will yield a comprehensive view of the mechanisms throughwhich B. burgdorferi controls production of these critical regulatory factors and deep insights on how SpoVGPlzA and c-di-GMP regulate VlsE and other virulence-associated proteins.In addition many other pathogenic bacteria produce homologs of SpoVG and our observations on B.burgdorferi SpoVG bear similarities with the protein's known effects in other bacterial pathogens. To date littleis known about how SpoVG affects virulence and physiology in any bacterial species. The interactions wediscovered between SpoVG and PlzA raise the possibilities that other bacteria also control SpoVG functionthrough c-di-GMP-binding proteins. Results of the planned investigations will provide useful insights on theregulatory mechanisms and infectious properties of numerous important human pathogens.

project_terms:
Affect;Affinity;Anti-Bacterial Agents;Antibiotic Therapy;Antibiotics;Back;Bacteria;Bacterial Infections;Bacterial Physiology;Binding;Binding Proteins;Binding Sites;Biology;Borrelia;Borrelia burgdorferi;Centers for Disease Control and Prevention (U.S.);Cessation of life;ChIP-seq;Collaborations;Cues;DNA;DNA Binding;Data;Development;Environment;Failure;Gene Expression;Genes;Genetic Transcription;Genome;Human;Immunocompetent;Impairment;Infection;Infection Control;Infectious Agent;Invaded;Investigation;Joints;Knowledge;Lyme Disease;Mammals;Maps;Mechanics;Membrane Proteins;Mus;Nature;North America;Order Spirochaetales;Organism;Pathogenesis;Pathogenicity;Patients;Periodicity;Physiology;Preventive therapy;Process;Production;Property;Proteins;Proteomics;RNA;RNA Sequences;RNA immunoprecipitation sequencing;RNA-Binding Proteins;Recording of previous events;Regulation;Regulatory Pathway;Regulon;Research Personnel;Role;Site;Specificity;Spirochaetales Infections;Ticks;Ursidae Family;Vertebrates;Virulence;Virulence Factors;Work;arthropod-borne;curative treatments;genetic regulatory protein;human disease;human pathogen;improved;insight;member;microbial;mutant;novel therapeutics;nucleic acid binding protein;pathogen;pathogenic bacteria;protein expression;response;stem;tick feeding;tick transmission;transcriptome;transcriptomics;vector-borne pathogen

public_health_relevance:
v NARRATIVEThe SpoVG and PlzA proteins of the Lyme disease bacterium Borrelia burgdorferi operate in conjunction tocontrol infection-associated functions. Elucidating their regulatory networks will provide substantial insight oninfectious properties of B. burgdorferi and will identify key checkpoints that can be exploited for developmentof improved antibacterial therapies.


application_id: 10682393
project_number: 5F31DA057050-02
project_title: Calcium Imaging of Central Amygdala Activity after Fentanyl Escalation
administering_ic: NIDA
award_notice_date: 2023-06-08
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: DA
serial_number: 057050
program_official: BABECKI, BETH
project_start_date: 2022-07-03
project_end_date: 2023-12-16
study_section: Special Emphasis Panel[ZRG1-F02A-K(20)L]
contact_pi_person_id: 16596090
contact_pi: MALONE, SAMANTHA
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:
Evidence suggests that rats given long access (LgA) sessions to self-administer (SA) opioids escalate theirintake while also showing greater withdrawal severity and drug-induced reinstatement compared to ratsmaintained on short access (ShA) daily SA sessions. Little is known about the neural changes that occur duringcontingent opioid escalation that may impact withdrawal and relapse. Past work examining opioid SA using ShAsessions in rodents has identified the central amygdala (CeA) as an area of interest that becomes hyperactivein acute withdrawal and may be involved in the incubation of craving that occurs after protracted withdrawal.However these studies have not examined the impact of escalated opioid intake using LgA sessions on CeAactivity during acute withdrawal when individuals experience heightened craving and negative emotionality orfollowing protracted withdrawal during extended abstinence when individuals experience an increasedsusceptibility to relapse. Furthermore no study has determined if changes in CeA activity depend on theescalation of fentanyl intake that is self-administered contingently or merely from exposure to fentanyl per seeven if it were administered non-contingently. The specific aims of this research are to determine if contingentfentanyl escalation alters basal ex vivo CeA activity following either acute withdrawal (Aim 1) or protractedwithdrawal (Aim 2). The effect of ex vivo application of fentanyl on the activity of CeA slices obtained followingacute or protracted withdrawal will also be determined. Male and female Sprague Dawley rats will be dividedinto three groups: (1) contingent fentanyl (2) yoked fentanyl or (3) yoked saline. Rats in the contingent fentanylgroup will undergo 7 days of fentanyl (2.5 ug/kg/inf) acquisition and 21 days of 6 h SA. Yoked rats will receivenon-contingent infusions of fentanyl or saline dependent upon responding emitted by the contingent fentanyl rat.In preparation for calcium (Ca2+ ) imaging rats will be euthanized either 17 h into withdrawal or after 30 days offorced abstinence. Ca2+ imaging will be conducted at baseline and in the presence of fentanyl (0.1 uM or 1 uM)to determine differences in CeA Ca2+ fluorescence a measure of neural activity. We hypothesize that at bothstages of abstinence fentanyl rats will demonstrate greater Ca2+ transients than yoked saline rats; contingentfentanyl rats may also display a greater effect than yoked fentanyl rats. We also hypothesize that at both stagesof abstinence all rats will demonstrate a fentanyl dose-dependent decrease in Ca2+ transients an effect that willbe greater in saline rats than fentanyl rats. Finally we predict that greater basal CeA activity will be observedafter protracted withdrawal compared to acute withdrawal particularly for contingent fentanyl rats. Studying themechanisms underlying differences in withdrawal and relapse after opioid escalation using Ca2+ imaging is highlynovel and will elucidate the role of the CeA in driving withdrawal and relapse in OUD. The long-term goal of thiswork is to inform the development of novel treatments for OUD particularly those that may target the CeA toreduce the negative emotionality and craving that occurs during acute withdrawal and throughout abstinence.

project_terms:
Abstinence;Acute;Amygdaloid structure;Area;Automobile Driving;Behavior;Behavioral;Brain;Calcium;Cell Nucleus;Characteristics;Development;Dose;Emotional;Euthanasia;Exposure to;Female;Fentanyl;Fluorescence;Frequencies;Future;Goals;Home;Hyperactivity;Image;Incubated;Individual;Infusion procedures;Intake;Measures;Opioid;Oxycodone;Pattern;Pharmaceutical Preparations;Phase;Predisposition;Preparation;Rattus;Recording of previous events;Recovery;Relapse;Research;Rodent;Role;Saline;Self Administration;Severities;Slice;Sprague-Dawley Rats;Structure;Time;Withdrawal;Work;addiction;behavior influence;craving;experience;interest;male;neural;neuromechanism;novel;novel therapeutic intervention;opioid use;opioid use disorder;overdose death;pre-clinical;prolonged abstinence;response;treatment group;trend

public_health_relevance:
Evidence suggests that rats with a history of escalated opioid intake express greater withdrawal severity anddrug-induced reinstatement compared to non-escalated rats; however the neural mechanisms driving theseheightened responses are unknown. The proposed study seeks to elucidate the neural activity and structuralchanges in the central amygdala (CeA) associated with contingent fentanyl escalation following either acute orprotracted withdrawal. This work will inform us about the impact of fentanyl on CeA activity related to opioid usedisorder (OUD) phases vital for recovery.


application_id: 10681944
project_number: 1R01EY034092-01A1
project_title: Cortical basis of binocular depth perception
administering_ic: NEI
award_notice_date: 2023-06-13
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: EY
serial_number: 034092
suffix: A1
program_official: GREENWELL, THOMAS
project_start_date: 2023-07-01
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZRG1 ICN-U (02)]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: SAMONDS, JASON M
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
AbstractThe functional properties of the visual system are most sensitive to disruptions of normal vision duringdevelopmental critical periods. Interestingly the critical periods for several functional properties such as oculardominance and acuity overlap during development. Abnormal vision during these overlapping critical periodsbecause of cataracts or misalignment of the two eyes for example is the cause of amblyopia. Amblyopia is aprevalent visual disorder in children and can present with any of several visual problems including lower visualacuity and impaired depth perception. Yet how depth perception is affected by abnormal vision has remainedelusive. In the proposed research we investigate the circuit basis for the development and plasticity of depthperception in the mouse. The development of stereoscopic vision is much slower than other characteristics ofvision and relies on complex properties of binocular disparity. Disparity between the eyes is what produces theperception of depth. We will characterize multiple dimensions of its development and plasticity by takingadvantage of a natural depth discrimination task that depends on binocular vision. Over this same period wewill measure with two-photon microscopy how complex disparity properties are refined in the visual cortex andarea LM (a secondary binocular visual area) as well as how and when they are sensitive to abnormal vision.Understanding the properties of binocular depth perception and the development of those properties will providea foundation for developing therapeutic approaches to treat developmental visual disorders such as amblyopiathat cause stereovision deficits.

project_terms:
Adult;Affect;Age;Amblyopia;Attenuated;Behavioral;Binocular Vision;Biological Assay;Blindness;Calcium;Cataract;Characteristics;Child;Childhood;Complex;Data;Depth Perception;Development;Dimensions;Discrimination;Disease;Disparity;Eye;Felis catus;Foundations;Genetic;Image;Impairment;Knowledge;Lazy Eyes;Measures;Mission;Monocular Vision;Mus;Neurons;Ocular Dominance;Perception;Performance;Population;Primates;Property;Psychometrics;Public Health;Rattus;Refractive Errors;Research;Rodent;Role;Surgical sutures;Symptoms;Systems Development;Task Performances;Testing;Therapeutic;Therapeutic Intervention;United States National Institutes of Health;Vision;Vision Disorders;Vision Disparity;Visual;Visual Acuity;Visual Cortex;Visual System;Visual impairment;area striata;critical developmental period;critical period;deprivation;designer receptors exclusively activated by designer drugs;excitatory neuron;experience;experimental study;extrastriate visual cortex;improved;in vivo calcium imaging;monocular deprivation;mouse model;neural circuit;postnatal;response;spatial vision;stereoscopic;targeted treatment;timeline;tool;two photon microscopy;vision development

public_health_relevance:
Project NarrativeAbnormal vision during a childhood critical period can cause amblyopia also known as lazy eye a disordercomprising several deficits in spatial vision including impaired binocular depth perception. The proposedresearch is relevant to public health because knowledge of the neuronal basis and developmental timeline ofbinocular depth perception will improve our understanding of targets for therapeutic intervention. The proposedresearch is relevant to the mission of the NEI/NIH to increase understanding of how the development of thevisual system and visual experience results in binocular depth perception.


application_id: 10681487
project_number: 5R01DA055872-02
administering_ic: NIDA
award_notice_date: 2023-06-26
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: DA
serial_number: 055872
program_official: GOLDSTEIN, AMY B
project_start_date: 2022-08-15
project_end_date: 2027-06-30
study_section: Health Promotion in Communities Study Section[HPC]
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
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
budget_start_date: 2023-07-01
project_title:
Kentucky Outreach Service Kiosk (KyOSK): Reducing HIV HCV and Overdose Risk in Rural Appalachia through Harm Reduction Kiosks

project_abstract:
AbstractThe proposed project will test an innovative approach to reducing harms related to the epidemics of injectiondrug use overdoses hepatitis C (HCV) and to imminent HIV outbreaks in rural Appalachian Kentucky whichhas long been an epicenter of these intertwined crises. Our research has shown that the region has high ratesof HCV overdose injection drug use condomless sex and dense risk networks that could kindle an HIVoutbreak. Following a 2014 HIV outbreak in neighboring Indiana and a national analysis of HIV/HCV outbreakvulnerability among people who inject drugs (PWID) revealing that 54 of Kentuckys 120 counties ranked in thetop 5% nationally Kentucky passed landmark legislation permitting counties to operate syringe serviceprograms (SSPs). Despite an arduous county-level approval process Kentucky has succeeded in opening 80SSPs more than any other U.S. state. Unfortunately this robust harm reduction infrastructure remains under-utilized in rural settings. Data from our research funded by NIDAs National Rural Opioid Initiative revealed thatnearly half of PWID had never used the existing staffed SSPs and over 24 months of follow-up SSP uptakeremained low and program drop-out was not uncommon. The most frequent reason cited for having neverused an SSP was fear of stigma. Evidence suggests that PWID in the region want a range of harm reductionservice models and among those who report stigma as a reason for not using the staffed SSPs the mostdesired model is a vending machine or kiosk. Harm reduction kiosks have been operating globally for morethan 30 years and research has demonstrated that they can expand syringe access. Yet very few kiosksoperate in the U.S. and none operate in rural areas where they might be especially beneficial. Researchsuggests that kiosks might be a cost-effective way to expand syringe access when coupled with staffed SSPsbut their implementation impact and cost-effectiveness have not been rigorously evaluated. In response wepropose a type 1 hybrid effectiveness trial to test the effectiveness implementation outcomes and costeffectiveness of a community-tailored harm reduction kiosk in reducing HIV hepatitis C and overdose riskbehavior in rural Appalachia. Our kiosk or KyOSK (KY Outreach Service Kiosk) will be supplied withinjection equipment naloxone fentanyl test strips hygiene kits condoms and other supplies as well as aninnovative call-back feature for facilitated referral to needed services by trained recovery coaches. The KyOSKwill be tailored to the local context through a community-engaged process and a Kiosk Design Team involvingpeople who use drugs and local and state leaders. Interest in reduction kiosks is soaring nationwide and theproposed project would provide critical and timely data to inform scale-up of this model especially in ruralareas of the country that have been severely impacted by substance use related harms.

project_terms:
Appalachian Region;COVID-19;Callback;Communities;Country;County;Coupled;Data;Disease Outbreaks;Dropout;Drug user;Effectiveness;Epidemic;Epidemiology;Equipment;Fright;Funding;HIV;HIV/HCV;Harm Reduction;Health;Hepatitis C;Hepatitis C Therapy;Hepatitis C Transmission;Home;Hour;Huntington Disease;Hybrids;Hygiene;Indiana;Infrastructure;Injecting drug user;Injections;Judgment;Kentucky;Laws;Letters;Medicaid;Methods;Modeling;Naloxone;Names;National Institute of Drug Abuse;Needle-Exchange Programs;Nevada;Newly Diagnosed;Opioid;Overdose;Persons;Pharmaceutical Preparations;Process;Puerto Rico;Qualitative Research;Quasi-experiment;Recording of previous events;Recovery;Reporting;Research;Research Infrastructure;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Appalachia;Science;Service delivery model;Services;Sorbus;Statutes and Laws;Surveys;Syringes;Testing;Time;Training;Transportation;Unsafe Sex;West Virginia;austin;cohort;condoms;cost effective;cost effectiveness;design;effectiveness study;effectiveness testing;effectiveness trial;experience;fentanyl test;flexibility;follow-up;implementation evaluation;implementation outcomes;improved;injection drug use;innovation;interest;lectures;outreach services;overdose death;overdose risk;programs;response;rural area;rural setting;scale up;social stigma;substance use;test strip;uptake

public_health_relevance:
NarrativeThe proposed study will test the effectiveness implementation outcomes and cost effectiveness of acommunity-tailored harm reduction kiosk in reducing HIV hepatitis C and overdose risk behavior in ruralAppalachia. The proposed project will take place in two counties in Appalachian Kentucky an epicenter for theintertwined national crises of injection drug use overdoses and hepatitis C.


application_id: 10681386
project_number: 5UL1TR001998-07
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2023-06-30
opportunity_number: PAR-18-940
application_type: 5
activity_code: UL1
ic: TR
serial_number: 001998
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2026-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: HARTMANN, KATHERINE E
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Contact PD/PI: Kern Philip A.PROJECT SUMMARY  OVERALL The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) has created anintegrated home for clinical and translational research which promotes scientific progress and discoveries atevery phase of the translational continuum. The CCTS has partnered with communities in Central Appalachiato address multiple generations of recalcitrant health inequities related in part to the economic distress of ruralcommunities. The CCTS has fundamentally transformed UK and Central Appalachia through the developmentof strong academic-community research networks and collaborations within the CTSA consortium.Appalachian health disparities are further magnified by the opioid and substance abuse epidemic which hasgreatly impacted eastern Kentucky and West Virginia. The strong UK research portfolio puts the UK CCTS inan optimal position to lead local regional and national research efforts focused on rural health inequities. The aligned missions of UK UK HealthCare and the CCTS focus on achieving health equity by engaging inhighly innovative collaborative and dynamic translational research to address rural health needs. The CCTSwill continue to educate the translational workforce of the future engage rural communities in translational andbi-directional team science and work with the national network to advance transdisciplinary research andclinical trials through the following Specific Aims: 1) develop innovate and transform our research environmentto promote impactful science and discovery within our integrated health care system to meet the unique healthneeds of Central Appalachian residents; 2) lead institutional innovation in the delivery of impactful clinical andtranslational research that covers the lifespan fully engages the community and embraces team science; 3)catalyze an efficient university-wide clinical trials organization which adds value to the CTSA consortium byengaging participants from rural Central Appalachia; and 4) foster and enhance a workforce characterized bydiversity and inclusivity across all translational science disciplines and populations. The UK CTSA hub isuniquely positioned in the National CTSA Consortium to foster novel technologies team science clinical trialstart-up and cutting-edge translational research across the lifespan with a focus on rural communities. Wehave a particular focus on the Central Appalachian community a rural area with many of the highest levels ofhealth disparities in the nation. This focus will ultimately elevate the health and quality of life of ruralcommunities throughout the United States.Project Summary/Abstract Page 276Contact PD/PI: Kern Philip A.

project_terms:
Academic Medical Centers;Acceleration;Address;Agriculture;Appalachian Region;Award;COVID-19 pandemic;Cardiovascular system;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical and Translational Science Awards;Collaborations;Communities;Complement;Computer software;Dedications;Development;Diabetes Mellitus;Discipline;Distress;Economics;Engineering;Environment;Epidemic;Fostering;Funding;Future;Generations;Grant;Growth;Health;Health Sciences;Health Status;Healthcare;Home;Institution;Integrated Health Care Systems;Intervention;Investments;Kentucky;Lead;Longevity;Malignant Neoplasms;Medical;Medical center;Mission;Modeling;National Center for Advancing Translational Sciences;Neurosciences;Obesity;Participant;Patients;Persons;Phase;Policies;Population;Positioning Attribute;Quality of life;Reporting;Research;Resources;Rural;Rural Community;Rural Health;Science;Sports;Substance Use Disorder;Substance abuse problem;Translational Research;Translations;Underserved Population;United States;Universities;West Virginia;Work;austin;clinical center;clinical research site;collaborative environment;college;community based participatory research;community engagement;diversity and inclusion;health disparity;health equity;health inequalities;improved;innovation;inter-institutional;new technology;opioid abuse;patient engagement;programs;recruit;response;rural area

public_health_relevance:
PROJECT NARRATIVE  OVERALLThe UK CTSA program hub is uniquely positioned in the National CTSA Consortium to foster noveltechnologies team science clinical trial start-up and cutting-edge translational research across the lifespan.Our UK CTSA hub has a significant presence on the national stage and our focus on the Central Appalachiancommunity a rural region with many of the highest priorities (i.e. cardiovascular neuroscience cancerobesity/diabetes) of health disparities in the nation and an epicenter for the opioid and substance abuseepidemic distinguishes our mission and activities. The programs in this proposal will ultimately elevate thehealth and quality of life for people of this region and provide a national model for rural underservedpopulations.Project Narrative Page 277


application_id: 10680932
project_number: 1R01CA274981-01A1
project_title: The PLOD2/succinate axis in cancer cell plasticity and stemness
administering_ic: NCI
award_notice_date: 2023-08-30
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 274981
suffix: A1
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: Biochemical and Cellular Oncogenesis Study Section[BCO]
contact_pi_person_id: 10533977
contact_pi: XU, REN
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:
AbstractTumor cells in TNBC tissue exhibit enhanced cell plasticity and stemness which is crucial for cancer metastasis.Metabolic and epigenetic reprogramming plays crucial roles in the regulation of cell plasticity. Succinate is anintermediate metabolite of the tricarboxylic acid (TCA) cycle. Aberrant accumulation of succinate has beendetected in many cancers. However the cellular function and regulation of succinate in breast cancerdevelopment and progression have not been well investigated. We showed that the epithelial-to-mesenchymaltransition (EMT) was associated with profound changes in metabolites including elevation of cytoplasmicsuccinate. Importantly treatment with the membrane permeable succinate was sufficient to induce mesenchymalphenotypes enhance cancer cell stemness and colonization and reduce DNA hydroxymethylation and genetranscription in mammary epithelial cells. Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2)catalyzes lysine hydroxylation in endoplasmic reticulum and generates succinate as another product. We foundthat PLOD2 expression was induced in cancer cells in TNBC tissue and increased PLOD2 expression correlateswith poor prognosis and high chances of cancer metastasis. Silence of PLOD2 in cancer cells significant reducedcancer cell colonization and metastasis. PLOD2 expression was induced during EMT and associated withelevation of cytoplasmic succinate levels. Using gain- and loss-of function approaches we showed thatincreased PLOD2 expression is necessary and sufficient to enhance the accumulation of cytoplasmic succinate.Importantly silencing PLOD2 in breast cancer cells inhibited cancer cell stemness. The overall objective of thisproject is to define roles of the PLOD2/succinate axis in regulating cancer cell plasticity and stemness and toevaluate biological activity of the new PLOD2 inhibitor in suppressing TNBC progression and metastasis. Thecentral hypothesis of this proposal is that PLOD2-induced succinate accumulation enhances cancer cellplasticity and metastasis by reducing DNA hydroxymethylation; therefore targeting the PLOD2/succinate axis isa potential strategy to halt TNBC progression and metastasis. To test this hypothesis we propose the followingaims: Aim 1. Elucidate the molecular and cellular mechanisms by which succinate enhances cancer cell plasticityand stemness. Aim 2. Define roles of the PLOD2/succinate axis in regulating breast cancer progression. Aim 3.Evaluate the potential of targeting PLOD2 to suppress breast cancer metastasis. Successfully completion of theproject will reveal novel function of collagen hydroxylation enzymes in regulating succinate-associated epigeneticreprogramming and identify PLOD2 as a potential therapeutic target to suppress breast cancer metastasis.

project_terms:
Aftercare;Biochemistry;Biological;Biometry;Breast;Breast Cancer Cell;Breast Epithelial Cells;Breast cancer metastasis;Cell Membrane Permeability;Cell physiology;Cells;ChIP-seq;Chromatin;Citric Acid Cycle;Clinical;Collagen;CpG Islands;Cytoplasm;DDR1 gene;DNA;Development;Dioxygenases;Endoplasmic Reticulum;Enzymes;Epigenetic Process;Exhibits;FDA approved;Fibroblasts;Fibrosis;Gene Expression Profiling;Genetic Transcription;Human;Hydroxylation;In Vitro;Incidence;Knockout Mice;Knowledge;Loperamide;Lysine;Malignant Neoplasms;Mediating;Mesenchymal;Metabolic;Modeling;Modification;Molecular;Mouse Mammary Tumor Virus;Mus;Neoplasm Metastasis;Pathologist;Pathway interactions;Pharmaceutical Preparations;Phenotype;Play;Positioning Attribute;Procollagen;Prognosis;Regulation;Relapse;Repression;Research;Role;Scheme;Succinates;TP53 gene;Testing;Tissue Sample;Tissues;Weight;Xenograft Model;alpha ketoglutarate;breast cancer progression;cancer cell;cancer subtypes;cell growth regulation;conditional knockout;crosslink;epigenetic regulation;epithelial to mesenchymal transition;experimental study;gain of function;inhibitor;loss of function;malignant breast neoplasm;metabolomics;mid-career faculty;mouse model;multidisciplinary;neoplastic cell;novel;patient derived xenograft model;screening;small hairpin RNA;stable isotope;stemness;therapeutic target;transcription factor;transcriptome sequencing;triple-negative invasive breast carcinoma

public_health_relevance:
Defining roles of succinate in regulating cancer cell plasticity and stemness will fill critical gaps in our knowledgeabout function of metabolites in breast cancer progression. The study of PLOD2 in regulating cytoplasmicsuccinate will reveal a novel pathway in succinate regulation; and further evaluating the PLOD2 inhibitor in TNBCxenograft model and PDX models will identify a potential target to halt TNBC progression and metastasis.


application_id: 10678995
project_number: 5R01AG079525-02
project_title: The impact of insulin sensitivity on the potential of metformin to delay age-related inflammation
administering_ic: NIA
award_notice_date: 2023-05-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 079525
program_official: JOSEPH, LYNDON
project_start_date: 2022-08-15
project_end_date: 2026-04-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Inflammatory diseases limit healthspan defined as the length of one's life spent in good health. We propose anancillary study on deidentified samples from a recent NIA-funded trial Antecedent Metabolic Health andMetformin (ANTHEM) that will define traits of healthy people who would benefit from metformin interventionbefore onset of age-related health risks like chronic inflammation. ANTHEM queries an unexpected outcome ofdual interventions of metformin and exercise: metformin improved metabolic health over exercise alone inoverweight/obese insulin resistant subjects but metformin blunted exercise-mediated improvements inmetabolic health of otherwise similar insulin sensitive subjects. ANTHEM tests the impact of baseline metabolichealth on the effects of metformin monotherapy on insulin sensitivity and skeletal muscle mitochondria byrecruiting overall healthy subjects to address the general paradigm that lifespan enhancers must start prior toonset of age-related co-morbidities for maximal benefit. The proposed work will add an inflammation arm toANTHEM. The primary endpoint of our ancillary study will be cytokine profiles a bioinformatic combination ofcytokines that revealed a previously unappreciated Th17 profile that naturally develops systemically with age.This profile is similar to the systemic profile in type 2 diabetes and thus suggests a mechanistic link betweeninflammation and this major challenge to healthspan. Metformin-mediated repair of mitochondrialbioenergetics in combination with improved non-mitochondrial autophagy lowered the Th17 profile in samplesfrom older subjects. In contrast metformin lowered IL-10 production by cells from younger subjects arguablyincreasing inflammation. Our unique approach to defining inflammation thus clarified mechanisms ofmetformin action while echoing concepts from the exercise study summarized above: metformin may benefitsubjects with sub-clinical health challenges while having a negative effect on healthier people. We will applysimilar approaches to query metformin's effect on inflammation by analyzing deidentified ANTHEM samples totest the hypothesis that metformin intervention in healthy subjects with naturally low insulin sensitivity reducescytokines known to fuel chronic inflammation by improving mitochondrial bioenergetics and increasing non-mitochondrial autophagy in immune cells. The secondary hypothesis is that metformin will have either anegative or no impact on immune cells from highly insulin sensitive subjects. Mechanistic insights intometformin action on immune cells will be analyzed relative to changes in body composition aging biomarkersglycemic control and skeletal muscle outcomes collected for ANTHEM. Parallel ex vivo manipulation ofmitochondrial function and autophagy in immune cells will establish cause/effect relationships amongstmetformin cell physiology and cytokine profiles. Success with the proposed project coupled with ANTHEMoutcomes will define traits of people who would benefit from preventative metformin and perhaps moreimportantly to identify those who may be harmed by proactive metformin use.

project_terms:
Address;Age;Age of Onset;Aging;Ancillary Study;Anti-Inflammatory Agents;Autophagocytosis;Bioenergetics;Bioinformatics;Biological Markers;Blood specimen;Body Composition;Cell physiology;Cells;Chronic;Clinical Trials;Complex;Confusion;Coupled;Data;Defect;Diabetes Mellitus;Disease;Double-Blind Method;Enhancers;Equilibrium;Exercise;FRAP1 gene;Funding;Goals;Health;Human;Immune;In Vitro;Inflammaging;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-10;Interleukin-6;Intervention;Length;Life;Link;Longevity;Mediating;Metabolic;Metabolism;Metformin;Methods;Mitochondria;Muscle Fibers;Muscle Mitochondria;Muscle function;Myeloid Cells;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organelles;Outcome;Overweight;Oxidation-Reduction;Pathogenicity;Pathway interactions;Persons;Pharmaceutical Preparations;Placebos;Positioning Attribute;Production;Reporting;Risk;Sampling;Serum;Skeletal Muscle;Source;T-Lymphocyte;Testing;Tissues;Variant;Work;age related;aged;arm;clinical practice;comorbidity;cytokine;glycemic control;healthspan;improved;inflammatory marker;insight;insulin sensitivity;predictive modeling;primary endpoint;recruit;repaired;response;success;systemic inflammatory response;trait

public_health_relevance:
Numerous studies support the premise that inflammation rises in aging. Drugs with anti-inflammatory actions such as metformin may promote healthspan the length of one's life spentin good health especially if given prior to onset of age-related declines. We will analyzedeidentified samples from an NIA-funded clinical trial to test the possibility that baseline insulinsensitivity impacts the ability of metformin to ameliorate pathogenic inflammation.


application_id: 10678945
project_number: 5K23AR079583-02
project_title: Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness
administering_ic: NIAMS
award_notice_date: 2023-07-13
opportunity_number: PA-20-205
application_type: 5
activity_code: K23
ic: AR
serial_number: 079583
program_official: LINDHURST, MARJORIE JEAN
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
arra_indicator: N
project_abstract:
Project Summary Survival of critical illness such as sepsis and acute respiratory failure is accompanied by seriousphysical complications with many patients acquiring long-term impairments. Mechanisms and factors thatimpede the recovery of muscle size and function after hospitalization are not understood. It is unclear ifrecovery after critical illness leads to a subsequent deficiency in the ability to make new proteins (proteinsynthesis) or if a catabolic/inflammatory environment persists preventing muscle regrowth which involvesmuscle stem cell (satellite cell) fusion to myofibers. We will address gaps in knowledge by studying skeletalmuscle proteostasis cellular environment and RNA and mitochondrial biogenesis after critical illness withclosely aligned physical function outcomes. Understanding the cellular environment in the period after hospitalrelease and how it impacts muscle protein turnover will direct efforts to effective therapies to acceleratemuscle regrowth. The overall goal of this application is to identify cellular properties of muscle that maycontribute to long-term physical disability in survivors of critical illness. Overall I hypothesize that aberrantcellular processes in muscle are underlying prolonged functional impairments in patients after critical illness. InAim 1 we will determine the longitudinal trajectory of muscle and physical function recovery and establishmuscle morphological and cellular characteristics in patients after critical illness. We hypothesize that patientswith higher severity of illness in the ICU and with longer duration of mechanical ventilation will have the mostpersistent muscle weakness and deficits in muscle power in recovery. In Aim 2 we will identify cellularmechanisms that contribute to muscle dysfunction after critical illness. We hypothesize that patients withpersistent muscle weakness and fatigue have impaired mitochondrial function compared to controls. Moreoverwe hypothesize that survivors of critical illness have elevated myofibrillar protein synthesis and ribosomebiogenesis in early recovery but muscle regrowth does not occur due to elevated proteolysis. The overarchinggoal of this proposal focuses on elucidating the factors that lead to muscle mass dysregulation in recovery andinform why some patients develop persistent disability and others gradually improve. The proposed mentoringteam provides the knowledge and training to develop into an independent clinical investigator integrating basicand applied science. The proposed training plan in Aim 1 emphasizes clinical trial methodologies and complexlongitudinal analyses. For aim 2 the training focuses on skeletal muscle experiments; specifically knowledgeto assess muscle proteostasis mitochondrial content and function and muscle morphology. I will learn thetechnical skills to examine skeletal muscle including stable isotope labeling immunohistochemistry westernblot analysis and microscopy will be gained. Moreover the proposed research and training plan provides thenecessary training and mentorship to translate findings in this proposal into the development of targetedrehabilitation and pharmacological interventions in future R01 studies.

project_terms:
Acceleration;Acute respiratory failure;Address;Adult;Applied Research;Basic Science;Biogenesis;Biopsy;COVID-19;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;Growth;Health;Hospitalization;Hospitals;Human;Immunohistochemistry;Impairment;Inflammatory;Intensive Care Units;Intervention;Knowledge;Knowledge acquisition;Label;Learning;Lower Extremity;Macrophage;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;Phase;Phenotype;Physical Function;Physical Rehabilitation;Property;Protein Biosynthesis;Proteins;Proteolysis;Quality of life;RNA;Recovery;Recovery of Function;Regression Analysis;Rehabilitation therapy;Research;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;comparison control;disability;effective therapy;experimental study;functional disability;functional outcomes;improved;inflammatory milieu;longitudinal analysis;muscle form;muscle strength;novel;patient subsets;pharmacologic;physically handicapped;prevent;protein degradation;proteostasis;rehabilitation research;rehabilitation strategy;satellite cell;skeletal muscle wasting;skills;stem

public_health_relevance:
Project NarrativePatients surviving critical illness acquire impairments in muscle and physical function that can persist for yearsafter hospital discharge. The planned study will identify cellular and physical function outcomes that contributeto failed muscle regrowth in the recovery phase of critical illness. My training will entail statistical analyses forbasic and applied science and the experiments to assess human skeletal muscle to determine cellularmechanisms that drive impairments in muscle and contribute to sustained physical functional deficits.


application_id: 10678926
project_number: 5R01HL149164-04
project_title: Length-dependent activation in human myocardium
administering_ic: NHLBI
award_notice_date: 2023-07-28
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 149164
program_official: ADHIKARI, BISHOW B
project_start_date: 2020-09-15
project_end_date: 2025-07-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: TANNER, BERTRAND C.W.
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:
ABSTRACTThis translational project uses human biospecimens procured from organ donors and patients undergoingcardiac transplant to advance understanding of a cellular-level mechanism that underpins the Frank-Starlingrelationship. Specifically the project focuses on length-dependent activation defined as the increased maximumforce and Ca2+ sensitivity of contraction induced by myocardial stretch. The mechanisms that underlie length-dependent activation remain unclear but may involve thick-filament regulation and transitions between the newlydiscovered OFF and ON states of myosin.Co-PI Campbell has spent a decade building a biobank that now contains >10000 myocardial specimens from>360 patients. Pilot experiments performed by Co-PI Tanner with these samples show that length-dependentchanges in Ca2+ sensitivity are eliminated in myocardium from patients who have non-ischemic heart failure butpreserved in myocardium from organ donors and patients who have ischemic heart failure. New computermodeling predicts that these functional effects reflect destabilization of the myosin OFF state in patients whohave non-ischemic heart failure. This hypothesis is supported by additional experiments that used fluorescentpolarization techniques to assess OFF/ON dynamics in the thick filaments of human myocardium. Further pilotstudies tested the effects of peptides targeted to the thick filament. Peptides that stabilize the OFF state reducedthe Ca2+ sensitivity of contraction at long sarcomere length while destabilizing peptides enhanced Ca2+ sensitivityat short length. The length-dependence of these effects was predicted by our computer modeling.The project builds on these data from human biospecimens and integrates the skills and resources of fivecardiovascular researchers a statistician and a physician-scientist who specializes in advanced heart failure.The Aims explore the global hypothesis that length-dependent activation is reduced in patients who have non-ischemic heart failure because their cardiac thick filaments are biased towards the ON state.Aim 1: Test the hypothesis that length-dependent changes in Ca2+ sensitivity are reduced in myocardium from patients who have non-ischemic heart failure.Aim 2: Test the hypothesis that the OFF state of the thick filament is destabilized in myocardium from patients who have non-ischemic heart failure.Aim 3: Target OFF/ON transitions to manipulate the Ca2+ sensitivity of human myocardium.

project_terms:
Acceleration;American;Biochemical;Biological Assay;Biophysics;Calcium;Cardiac;Cardiomyopathies;Cardiovascular system;Computer Models;Data;Data Set;Dependence;Development;Disease;Electric Stimulation;Electrophoresis;Genetic;Genomics;Heart Transplantation;Heart failure;Histologic;Histology;Human;Impairment;Infarction;Ischemia;Kentucky;Length;Levosimendan;Mus;Muscle Cells;Muscle Contraction;Mutation;Myocardial;Myocardial Ischemia;Myocardium;Myosin ATPase;Organ Donor;Organ Procurements;Patients;Penetrance;Peptides;Permeability;Pharmacologic Substance;Phenotype;Physicians;Physiologic pulse;Pilot Projects;Preparation;Property;Regulation;Relaxation;Research;Research Personnel;Resources;Sampling;Sarcomeres;Scientist;Specimen;Stretching;Structure;Sturnus vulgaris;Techniques;Testing;Thick Filament;Transplantation;Universities;biobank;biophysical techniques;data integration;design;experimental study;gel electrophoresis;genomic data;human data;organ transplant recipient;predictive modeling;preservation;skills

public_health_relevance:
NARRATIVEThis project analyzes samples of cardiac muscle procured from organ donors and patients who have heartfailure. Experiments will test how the muscle contraction changes as the samples are stretched and whether thecontraction can be modulated with specially designed molecules. The results of this project will accelerate thedevelopment of better therapies for patients who have different types of heart failure.


application_id: 10678905
project_number: 5R21DA055028-02
administering_ic: NIDA
award_notice_date: 2023-07-17
opportunity_number: PAR-19-064
application_type: 5
activity_code: R21
ic: DA
serial_number: 055028
program_official: CREAMER, MELISA RAY
project_start_date: 2022-08-15
project_end_date: 2025-07-31
study_section: ZDA1-SXC-G(19)S
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
budget_start_date: 2023-08-01
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;Characteristics;Collaborations;Communities;Data;Detection;Disease Outbreaks;Drug usage;Drug user;Emergency medical service;Fentanyl;Fostering;Funding;Goals;Harm Reduction;Health;Individual;Intervention;Interview;Kentucky;Law Enforcement;Life;Marketing;Measures;Methods;Naloxone;Natural Disasters;Overdose;Participant;Persons;Pharmaceutical Preparations;Policies;Recommendation;Recording of previous events;Research;Research Infrastructure;Risk;Risk Factors;Rural;Rural Appalachia;Rural Population;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;fentanyl overdose;fentanyl test;fentanyl use;high risk;improved;novel;opioid epidemic;overdose death;overdose risk;peer;post-COVID-19;resilience;response;scale up;stay-at-home order;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: 10678088
project_number: 1F31AG082521-01A1
project_title: The Effect of Cytomegalovirus Infection on Daily Stress Processes in Early Adulthood
administering_ic: NIA
award_notice_date: 2023-03-29
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: AG
serial_number: 082521
suffix: A1
program_official: ELDADAH, BASIL A
project_start_date: 2023-04-09
project_end_date: 2024-04-08
study_section: Special Emphasis Panel[ZRG1 F01A-V (20)]
contact_pi_person_id: 16320688
contact_pi: GLOGER, ELANA 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
project_abstract:
Stress is acutely beneficial for survival but can increase risk for chronic disease development across thelifespan. Understanding the biological mechanisms that increase vulnerability to experience more stressors orreact more negatively to them can identify who is at risk for negative health outcomes associated with stressand assist targeted prevention and mitigation efforts aimed at improving well-being increasing years of healthyliving and decreasing healthcare burden through aging. A positive feedback loop called the ImmunologicModel of Self-Regulatory Failure (Shields et al. 2017) provides one potential framework for studying biologicaland physiological vulnerabilities to daily stress: increased physiological activation leads to neurologicaldysfunction which leads to subsequent self-regulatory deficits and increased experiences of future stressorsand the cycle repeats. This model suggests that increased immune activation dysregulation or neurologicalchanges may increase vulnerability to stress by way of self-regulatory deficits. Cytomegalovirus (CMV) anasymptomatic latent herpesvirus is one such immunological factor that may increase vulnerability to stressand its effects. CMV is associated with faster immune system aging and heightened systemic inflammatorybiomarkers in older age but may affect health and increase vulnerability to stress earlier in life. Importantlyneurological regions affected by CMV coordinate higher-order psychological abilities such as planninginhibiting and regulating oneself called self-regulation. In older adults CMV seropositivity is associated withdeclines in self-regulation assessed via self-report but this has yet to be tested in younger adults (Segerstromet al. 2022). Further individuals with poor self-regulation may experience more stressors (e.g. relationshipproblems debt etc.) and be more reactive to them (e.g. report a more intense negative mood following astressor) compared to someone with better self-regulation. Though studies on self-regulation and stress theeffects of CMV at older ages and preliminary investigations on CMV and stress have been conducted little isknown about biological mechanisms linking CMV self-regulation and daily stress in younger populations whomay still be able to modify or prevent CMV-related interference on daily life and future health. The proposedproject aims to fill these gaps by evaluating the relationships between CMV infection daily stress and self-regulatory abilities. The research component of this proposal involves a single in-person laboratory visit forquestionnaires and dried blood spot collection and a 14-day daily diary to test (a) how CMV is related to dailystress processes in early adulthood and (b) the mechanisms that may explain these associations. The trainingcomponent of this proposal includes (1) training collection and analysis of biological specimen (2) primarydata collection from an undergraduate sample (3) advanced training in statistical methodology and Rprogramming (4) advanced training and expertise building in psychoneuroimmunology and (5) extensiveprofessional development and ethics training in preparation of a competitive academic career.

project_terms:
Acute;Address;Adult;Affect;Affective;Age;Aging;Behavior;Behavioral inhibition;Biological;Biological Markers;Blood;Chronic;Chronic Disease;Cognition;Collection;Cytomegalovirus;Cytomegalovirus Infections;Data Collection;Development;Dryness;Elderly;Emotions;Ethics;Exposure to;Failure;Feedback;Feeling;Future;Health;Healthcare;Herpesviridae;Immune System Diseases;Immune system;Immunologic Factors;Immunological Models;Impaired cognition;Individual;Inflammatory;Informal Social Control;Intelligence;Investigation;Laboratories;Life;Link;Longevity;Methodology;Modeling;Neurologic;Neurologic Dysfunctions;Neurons;Neuropsychology;Outcome;Patient Self-Report;Personal Satisfaction;Persons;Physiological;Population;Prefrontal Cortex;Preparation;Prevention;Process;Psychoneuroimmunology;Questionnaires;Reaction;Reporting;Research;Risk;Sampling;Self-control as a personality trait;Seroprevalences;Specimen;Spottings;Stress;Stressful Event;Testing;Thinking;Time;Training;Visit;care burden;career;diaries;emerging adult;emotion regulation;executive function;experience;high risk;human old age (65+);immune activation;improved;mortality;negative affect;negative mood;prevent;psychologic;seropositive;stressor;undergraduate student;young adult

public_health_relevance:
Stress is beneficial for survival in the short-term but can negatively affect long-term health and mortality whenendured chronically. The proposed project will investigate Cytomegalovirus an asymptomatic latentherpesvirus as an immunological factor that may increase vulnerability to experience more daily stressors andreact more negatively to those stressors in young adults by way of deficits in self-regulatory abilities such asemotion regulation self-control and inhibition. Understanding the biological mechanisms that increasevulnerability to stress can identify who is at later risk for negative health outcomes associated with stress andassist future targeted prevention and mitigation efforts aimed at improving well-being increasing years ofhealthy living and decreasing healthcare burden during aging.


application_id: 10677711
project_number: 5R03CA267326-02
project_title: Alterations in DNA Damage following Major Surgery and Hyperthermic Intraperitoneal Chemotherapy
administering_ic: NCI
award_notice_date: 2023-08-21
opportunity_number: PAR-20-052
application_type: 5
activity_code: R03
ic: CA
serial_number: 267326
program_official: THURIN, MAGDALENA
project_start_date: 2022-08-05
project_end_date: 2024-07-31
study_section: ZCA1-PCRB-E(M1)S
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
arra_indicator: N
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 Disorder;Data;Defect;Deposition;Disease;Disease Progression;Disseminated Malignant Neoplasm;Eligibility Determination;Excision;Exhibits;Genomic Instability;Greater sac of peritoneum;Heat shock proteins;Human;Hyperthermia;Immune System Diseases;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Inflammation;Inflammatory Response;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;Therapeutic heat application;Tissue Sample;Tissues;Toxic effect;Tumor Debulking;anti-PD-1;cancer cell;cancer surgery;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: 10676813
project_number: 5R01AA028503-04
project_title: Sex Differences in Risk for Alcohol Use Disorder: Neural and Hormonal Influences
administering_ic: NIAAA
award_notice_date: 2023-08-11
opportunity_number: PA-19-091
application_type: 5
activity_code: R01
ic: AA
serial_number: 028503
program_official: MATOCHIK, JOHN A
project_start_date: 2020-09-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-C(90)S]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe sex gap in alcohol consumption is closing rapidly due to alarming increases in alcohol consumptionamong young women. As such there is an urgent need to determine the factors underlying sex differences inrisk for AUD. Current addiction models propose three neurofunctional domains that drive problematic alcoholuse and therefore serve as candidate sex-specific risk factors: executive function negative emotionality andincentive salience. Data from our lab and others suggest that poor inhibitory control a key component ofexecutive function is a stronger risk factor for women than for men. Moreover we have preliminary evidencethat female drinkers show less engagement of neural circuitry underlying inhibitory control and that this sexdifference is influenced by circulating levels of estradiol. However the degree to which hormonally-moderatedsex differences in executive function extend to the negative emotionality and incentive salience domains andhow these sex differences influence current and future drinking is unknown. Here we will determine: 1) theneurobiological factors contributing to sex-specific risk for AUD in each of these three addiction domains and 2)the degree to which sex differences in each domain influence current and prospective drinking. Femaledrinkers will undergo fMRI to assess neural correlates of inhibitory control (i.e. executive function) negativeemotionality and alcohol cue reactivity (i.e. incentive salience) at three phases of their menstrual cycle: earlyfollicular phase (low estradiol low progesterone) late follicular phase (high estradiol low progesterone) andmid-luteal phase (moderate estradiol high progesterone). Male drinkers will undergo three fMRI scans atmatched intervals. Immediately following each scan participants will complete a session of free-accessintravenous alcohol self-administration. We will then follow participants for 18 months to longitudinally assesschanges in drinking patterns. We hypothesize that hormonally-moderated neural function underlying inhibitorycontrol and negative emotionality will be stronger predictors of current and future alcohol consumption inwomen compared to men whereas neural alcohol cue reactivity will be a stronger predictor for men. Theproject capitalizes on the unique skill sets of the PI (an Early Career Investigator) and a strong collaborativeinvestigative team. The innovative design will provide essential information regarding neural factors influencingdevelopment and maintenance of AUD and critically how this risk is influenced by sex and fluctuations in sexhormones. Ultimately this proposal is a crucial step in a line of research that will lead to the development ofsex-specific prevention and treatment efforts for AUD.

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

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


application_id: 10676616
project_number: 1F31NS129159-01A1
project_title: Role of C. elegans RAPGEF in Synapse Development at the Neuromuscular Junction
administering_ic: NINDS
award_notice_date: 2023-04-06
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: NS
serial_number: 129159
suffix: A1
program_official: LEENDERS, MIRIAM
project_start_date: 2023-05-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1 F03A-E (20)]
contact_pi_person_id: 78425059
contact_pi: LAMB, REAGAN ELIZABETH MAYFIELD
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
project_abstract:
PROJECT SUMMARY/ABSTRACTSynaptic dysfunction is a major contributor towards the development of a large range of neurologicaldisorders. For proper formation synapses require a series of signaling pathways to guide them butnot all of those pathways are well understood. Rap Guanine Exchange Factors or RapGEFs aresignaling proteins that act to accelerate the rate of activation of GTPases that achieve downstreamfunctions. RAPGEF subfamily members are associated with multiple neurological disorders includingschizophrenia. In murine models disruption of RAPGEF6 function results in reduced anxietybehaviors like that observed in patients with schizophrenia and increased long term potentiation. Inaddition they found no changes in gross brain morphology. Although these studies suggest thatRAPGEFs modulate synaptic function the exact mechanism is currently unknown. To addresswhether loss of RapGEF function influences synapses mutations within pxf-1 a C. elegans RapGEForthologue were studied. When exposed to the acetylcholinesterase inhibitor aldicarb pxf-1 mutantsdisplayed decreased sensitivity indicating altered synaptic function. Additionally pxf-1 and rac-2GTPase mutants display decreased synaptic vesicle intensity in cholinergic synapses. Based onthese preliminary findings the central hypothesis is that PXF-1 alters cytoskeletal reorganizationwithin neurons to influence synaptic formation and accomplishes this through activation of RacGTPase signaling. To test this hypothesis this study will use the C. elegans neuromuscular junction.C. elegans are an advantageous model system for the study of neuronal function due to their well-defined genome translucent body for imaging techniques and overall ease of genetic manipulation.The goal of this project is to determine the mechanism of PXF-1 function within the neuromuscularjunction through the following aims. Aim 1. To identify the downstream GTPase that PXF-1 isactivating in this pathway. Aim 2. To investigate whether inhibiting a GAP protein in the PXF-1pathway can restore synaptic development and function. Overall this research will provide insight intothe molecular mechanisms that govern synaptic formation and how their dysregulation may lead todevelopment of disorders. This research will support the development of future treatments forsynaptopathologies.

project_terms:
Acceleration;Acetylcholinesterase Inhibitors;Actins;Address;Affect;Aldicarb;Animals;Appearance;Auxins;Behavior;Biological Assay;Biological Models;Biosensor;Caenorhabditis elegans;Calcium;Cholinergic Receptors;Complementary DNA;Copy Number Polymorphism;Cytoskeletal Modeling;Data;Defect;Development;Disease;Dissociation;Docking;Epilepsy;Exposure to;F-Actin;Fluorescence Microscopy;Functional disorder;Future;GTP Binding;GTPase-Activating Proteins;Genetic Diseases;Genetic Engineering;Genome;Goals;Guanine;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate;Guanosine Triphosphate Phosphohydrolases;Heritability;Homologous Gene;Hydrolysis;Image;Imaging Techniques;Knowledge;Location;Long-Term Potentiation;Malignant Neoplasms;Mammals;Measures;Mediating;Mission;Molecular;Morphology;Mus;Mutation;Nature;Nervous System;Neuromuscular Junction;Neurons;Organism;Pathway interactions;Patients;Phenotype;Polymers;Population;Presynaptic Terminals;Proteins;Public Health;RAPGEF2 gene;Research;Role;Schizophrenia;Series;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Protein;Stereotyping;Synapses;Synaptic Transmission;Synaptic Vesicles;System;Testing;Therapeutic;Tissues;Transmission Electron Microscopy;United States National Institutes of Health;Vesicle;Work;anxiety reduction;brain morphology;cholinergic synapse;connectome;density;disability;genetic manipulation;in vivo;insight;member;mouse model;mutant;nervous system disorder;neuronal circuitry;new therapeutic target;non-invasive imaging;polymerization;presynaptic;restoration;synaptic function;therapeutically effective

public_health_relevance:
PROJECT NARRATIVE The proposed research is relevant to public health because synaptic dysfunction is associatedwith many neurological disorders that lack effective therapeutic options. Moreover understanding thesignaling proteins that promote synaptic development will provide significant advances in ourknowledge of how the nervous system is organized. Therefore the proposed research is relevant toNIHs mission to seek fundamental knowledge about living systems and to reduce illness anddisability.


application_id: 10676160
project_number: 5F30HD103319-04
administering_ic: NICHD
award_notice_date: 2023-07-20
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: HD
serial_number: 103319
program_official: CHINN, JUANITA JEANNE
project_start_date: 2020-08-02
project_end_date: 2024-05-04
study_section: Special Emphasis Panel[ZRG1-F18-Z(20)]
contact_pi_person_id: 16164179
contact_pi: HANSEN, ANNA
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-02
project_title:
Social and biological determinants of pregnancy-related mortality and morbidity among rural underserved women

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

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

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


application_id: 10675851
project_number: 1R01EY035110-01
project_title: Functions of chromatin remodeler Chd7 in retinal cell development
administering_ic: NEI
award_notice_date: 2023-08-29
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: EY
serial_number: 035110
program_official: NEUHOLD, LISA
project_start_date: 2023-09-30
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1 CDB-M (02)]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: MARTIN, DONNA M.;MEYER, JASON STEPHEN
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:
CHD7 (Chromodomain helicase DNA-binding 7) is an ATP-dependent chromatinremodeling protein that has critical functions in neurogenesis and neural crest celldevelopment. Pathogenic variants in CHD7 are the most common cause of CHARGEsyndrome or CHD7 disorder a complex genetic syndrome characterized by ocularcoloboma heart abnormalities choanal atresia retardation of growth genitourinarydefects and hearing loss as well as other developmental defects. Although somestudies have examined the molecular basis for the early ocular defects (such ascoloboma) resulting from CHD7 pathogenic variants it is not known whether there is acontinuing requirement for CHD7 in the developing retina once ocular morphogenesis iscomplete. We have recently shown that CHD7 is robustly expressed in subsets of newlydifferentiated retinal cell types including rod and cone photoreceptors as well as inproliferating retinal progenitor cells. Furthermore zebrafish and mouse Chd7 mutantsdisplay reductions in cone photoreceptor number and abnormally small photoreceptorouter segments suggesting a critical role for CHD7 in photoreceptor differentiation andouter segment morphogenesis. We hypothesize that the chromatin remodeling functionof CHD7 is necessary for the transcriptional activation of genes promoting retinal celltype differentiation and genes involved in photoreceptor outer segment morphogenesis.In this proposal we will test this hypothesis through a combination of zebrafish andmouse genetics transcriptomic and epigenomic analyses and studies of human retinalorganoids and human retinal imaging. Results from these studies will contribute to ourunderstanding of the genetic and epigenetic regulation of retinal cell type developmentas well as the pathogenesis of visual system defects associated with CHD7 disorder.

project_terms:
ATAC-seq;Applications Grants;Blindness;Brain;CHARGE syndrome;CHD7 gene;Cells;Childhood;Choanal Atresia;Chromatin;Chromatin Remodeling Factor;Coloboma;Complex;Congenital Abnormality;DNA Binding;Data;Data Set;Defect;Development;Disease;Ear;Embryonic Development;Epigenetic Process;Event;Eye;Eye Abnormalities;Eye Development;Functional disorder;Gene Activation;Gene Expression;Genes;Genetic;Genetic Diseases;Genetic Transcription;Genitourinary system;Growth;Heart;Heart Abnormalities;Human;Image;Individual;Knock-out;Knowledge;Mediating;Molecular;Morphogenesis;Mus;Mutagenesis;Mutation;Neural Crest Cell;Nose;Organoids;Pathogenesis;Pathogenicity;Phenotype;Photoreceptors;Process;Proliferating;Proteins;Retina;Retinal Cone;Role;Structure;Syndrome;Testing;Transcriptional Activation;Variant;Vertebrate Photoreceptors;Vision;Visual System;Visual impairment;Zebrafish;cell type;chromatin remodeling;epigenetic regulation;epigenomics;experience;experimental study;eye formation;gene regulatory network;hearing impairment;helicase;improved;mouse genetics;mouse model;mutant;neurogenesis;novel;retinal imaging;retinal progenitor cell;transcriptome sequencing;transcriptomics

public_health_relevance:
Disruptions to the process of eye formation can result in ocular birth defects andpediatric blindness; although some of the genetic causes of ocular birth defects havebeen identified we still dont have a good understanding of exactly how mutations inthese genes cause visual system dysfunction. In this grant proposal we will study thefunction of the chromatin remodeling factor CHD7 during eye development; thesestudies are important because loss of expression of CHD7 causes CHARGE syndrome(also known as CHD7 disorder) a genetic disorder that results in defects in the eyesears heart brain nose and genitourinary system. The results of our experiments willhelp us better understand the chain of events that leads to abnormal eye formationduring embryonic development and this knowledge may improve the identificationmanagement and treatment of congenital sight-threatening diseases.


application_id: 10675771
project_number: 5R01DK126777-03
project_title: ABIN1 dysfunction in Lupus Nephritis
administering_ic: NIDDK
award_notice_date: 2023-06-21
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_abstract:
Project SummaryLupus nephritis (LN) is a common and severe complication of systemic lupus erythematosus (SLE) andcurrent therapies are toxic and frequently ineffective. LN is more prevalent and more likely to cause kidneyfailure in African American patients [1-3]. SLE has strong genetic components but the relationship ofgenetic susceptibility to prognosis in African Americans is poorly understood. Previous studies showedvariants of TNIP1 are associated with SLE and LN susceptibility [4-7]. We reported a strong association forthe TNIP1 rs4958881 polymorphism with LN in African American patients from a large-scale SLEgenotyping study [8]. Our preliminary data show an association of the rs4958881 variants with severity andprogression of LN in African Americans. TNIP1 encodes the protein ABIN1 that functions as a physiologicalinhibitor of NF-B a prominent immune regulator [9 10]. We reported previously that loss of the molecularfunction of ABIN1 in mice results in SLE-like autoimmunity and glomerulonephritis [8 11 12].While there is evidence that ABIN1 regulation of NF-B plays a role in autoimmunity and development ofLN a number of critical gaps in knowledge remain. First what molecular mechanisms mediate ABIN1-dependent enhanced risk of LN and are they specific for different immune cell types? Second does alteredABIN1 function induced by TNIP1 polymorphisms play a role in the racial disparity of LN? Third do TNIP1polymorphisms have different pathologic molecular and cellular effects in African Americans comparedwith White Americans?Three Specific Aims are proposed to address these significant questions. Aim 1: Compare the Associationof theTNIP1 variant rs4958881 on LN in White and African Americans. Aim 2: Determine the effects of theTNIP1 variant rs4958881 on monocyte neutrophils and B cell activity in patients with LN. Aim 3. Determinethe mechanisms by which loss of ABIN1 molecular function alters monocyte neutrophil and B cell functionusing ABIN1 transgenic mice. The animal experiments will be interpreted in conjunction with similarexperiments in Aim 2 using the same cells isolated from blood of LN patients with the TNIP1 rs4958881 riskvariant.This is a Multi-PI proposal with a Cell and Molecular Biologist/Biochemist (Dr. David W. Powell) and aClinical Nephrologist/Scientist (Dr. Dawn J. Caster). These investigators have published many of thereports pertaining to TINIP1/ABIN1 function in LN via genetic and animal studies and are now poised withrecent preliminary findings to evaluate causative roles for a TNIP1 polymorphism in severity andprogression and specific cellular and molecular events in human LN. The translational and population-targeted nature of these studies will provide impactful insights that will lead to precision diagnostics andtherapeutics for high-risk African American LN patients.

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;CXCR3 gene;Cell Maturation;Cell Separation;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;Nuclear;Outcome;Pathologic;Patients;Peripheral;Physiological;Polyubiquitin;Precision therapeutics;Predisposition;Production;Prognosis;Proteins;Proteinuria;Publishing;Race;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

public_health_relevance:
Project NarrativeThis study will determine the cellular and molecular mechanisms by which genetic variants for theABIN1 gene TNIP1 regulates monocyte neutrophil and B cell activity in lupus nephritis. Successfulcompletion of this study will define novel and precision diagnostics and targets for the treatment ofhigh-risk African American systemic lupus erythematosus patients with lupus nephritis.


application_id: 10674098
project_number: 1F30AG079506-01A1
administering_ic: NIA
award_notice_date: 2023-04-18
opportunity_number: PA-21-050
application_type: 1
activity_code: F30
ic: AG
serial_number: 079506
suffix: A1
program_official: LUO, YUAN
project_start_date: 2023-05-10
project_end_date: 2025-11-09
study_section: Special Emphasis Panel[ZRG1 F01A-V (20)]
contact_pi_person_id: 78025226
contact_pi: LIBECAP, TJ
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_title:
Investigating Enlarged Perivascular Spaces as a Neuroimaging Biomarker of Cerebral Small Vessel Disease

project_abstract:
ABSTRACTCerebral small vessel disease (cSVD) is an important risk factor that may arise years before the onset of vascularcontributions to cognitive impairment and dementia (VCID). cSVD is characterized by in-vivo neuroimagingbiomarkers including enlarged perivascular spaces (ePVS). PVS are the site of interchange between interstitialfluid and cerebrospinal fluid which is believed to play a role in the removal of brain waste. Reduced clearancemay lead to enlargement of the PVS and subsequent accumulation of toxic solutes characteristic ofneurodegeneration. Given their presence in brain regions that support cognition we hypothesize thatquantitative cross-sectional ePVS counts in cognitively normal older adults could serve as an early biomarkerof VCID. Specifically we anticipate ePVS will predict cognitive dysfunction and increased white matter lesionburden after three years. We will test this hypothesis in a cohort of 121 cognitively normal older adults rangingin age from 60-86 at baseline. Participants are scanned on a 3T Siemens Prisma magnetic resonance imagingscanner with a 64-channel head coil. ePVS are manually counted by an experienced rater blinded to participantdemographics following consensus guidelines using T1 MPRAGE T2 FLAIR and Quantitative SusceptibilityMapping images. All ePVS are counted in a single axial slice of four brain regions with high ePVS burdenincluding the centrum semiovale (CS ePVS) basal ganglia (BG ePVS) hippocampus and midbrain. Aim 1 willtest the hypothesis that CS ePVS predict longitudinal changes in executive function a specific cognitive domainaffected in VCID. Our preliminary data using the same cohort include a negative relationship between CS ePVSand baseline Montreal Cognitive Assessment (MoCA) score a standardized screening tool of global cognition.Aim 2 will test the hypothesis that baseline CS ePVS burden predicts increased deep white matter hyperintensity(WMH) volume in the centrum semiovale after three years. This expands on preliminary findings that CS ePVSare positively related to whole brain WMH volume a marker of advanced cSVD. In Aim 3 regionalcerebrovascular reactivity (CVR) a measure of microvascular dysfunction will be analyzed using a novel BOLD-fMRI testing paradigm as a potential mechanistic contributor of ePVS. The cross-sectional relationship betweenBG ePVS and basal ganglia CVR will be analyzed to capitalize on our preliminary data which show a negativerelationship between BG ePVS and global CVR. We will further test an alternative hypothesis that thecerebrospinal fluid amyloid-beta 42/40 ratio a biomarker of amyloid burden is more closely associated withePVS than CVR. These experiments will be carried out at the University of Kentucky Magnetic Resonance andImaging Center and the Sanders-Brown Center on Aging under the direction of an expert team of scientist andclinician mentors. This F30 predoctoral fellowship will provide the requisite experience training and knowledgeto aid the trainees transition into the next step of his career as a scientist-neuroradiologist in the field ofneuroscience of aging measuring similar endpoints using basic and translational neuroimaging techniques.

project_terms:
Affect;Age;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Amyloid beta-42;Amyloid beta-Protein;Basal Ganglia;Biological Markers;Blinded;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain region;Cerebral small vessel disease;Cerebrospinal Fluid;Cerebrovascular Disorders;Characteristics;Clinical;Cognition;Cognitive;Consensus;Data;Data Analyses;Dementia;Development;Disease;Early Diagnosis;Elderly;Excision;Experimental Designs;Fellowship;Flushing;Foundations;Functional Magnetic Resonance Imaging;Gases;Gold;Growth;Guidelines;Head;Hematological Disease;Hippocampus;Image;Impaired cognition;Intercellular Fluid;Kentucky;Knowledge;Laboratories;Lesion;Liquid substance;MRI Scans;Magnetic Resonance;Magnetic Resonance Imaging;Manuals;Maps;Measures;Mentors;Methods;Microvascular Dysfunction;Midbrain structure;Nerve Degeneration;Neuropsychological Tests;Neurosciences;Participant;Patients;Persons;Predisposition;Protocols documentation;Psyche structure;Regression Analysis;Risk;Risk Factors;Scanning;Scientist;Screening procedure;Site;Slice;Standardization;Techniques;Testing;Therapeutic;Time;Training;Universities;White Matter Hyperintensity;biomarker development;blood oxygen level dependent;burden of illness;career;cerebrovascular;cognitive function;cognitive testing;cohort;constriction;demographics;early detection biomarkers;environmental change;executive function;experience;experimental study;follow-up;imaging facilities;improved;in vivo;indexing;innovation;interest;longitudinal design;modifiable risk;neuroimaging;neuroimaging marker;neurovascular coupling;novel;pre-doctoral;predictive marker;prisma;response;solute;tool;vascular cognitive impairment and dementia;wasting;white matter;-amyloid burden

public_health_relevance:
PROJECT NARRATIVEDisease of the blood vessels in the brain known as cerebral small vessel disease (cSVD) is an importantmodifiable risk factor for decline of mental abilities and dementia. This novel longitudinal experimental designwill use neuroimaging in cognitively normal older adults to study enlarged perivascular spaces a poorlydefined biomarker of cSVD. Clinically informative biomarkers could identify people most at risk for developingcSVD-related cognitive dysfunction and point to avenues of therapeutic improvements for patients withcerebrovascular disease.


application_id: 10674048
project_number: 5R21CA267152-02
project_title: Circulating HPV DNA as a Prediagnostic Marker of Oropharyngeal Cancer
administering_ic: NCI
award_notice_date: 2023-08-16
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: CA
serial_number: 267152
program_official: WANG, WENDY
project_start_date: 2022-07-29
project_end_date: 2025-06-30
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
arra_indicator: N
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 Detection;Cancer Patient;Clinical;Cohort Studies;Colorectal;Communities;Custom;DNA;Data;Detection;Development;Diagnosis;Diagnostic;Early Diagnosis;Genotype;HPV oropharyngeal cancer;Head and Neck Cancer;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papillomavirus 16;Incidence;Individual;Joints;Kinetics;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;Recurrence;Recurrent Malignant Neoplasm;Research;Risk;Sampling;Screening for cancer;Specificity;Testing;Time;Tumor Burden;United States;Virus;Woman;Work;biological specimen archives;cancer cell;cancer diagnosis;cancer recurrence;cohort;comparison control;detection assay;diagnostic biomarker;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: 10673063
project_number: 5R01DA048892-04
project_title: DAT- Integrated Outpatient Treatment of Opioid Use Disorder and Injection-Related Infections
administering_ic: NIDA
award_notice_date: 2023-08-15
opportunity_number: PA-19-055
application_type: 5
activity_code: R01
ic: DA
serial_number: 048892
program_official: FITZ-RANDOLPH, MARCY ESTHER
project_start_date: 2020-09-30
project_end_date: 2026-08-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14788426
contact_pi: FANUCCHI, LAURA
other_pis: LOFWALL, MICHELLE RENEE
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTDAT18-06: Hospitalizations for complications of opioid use disorder (OUD) like infectious endocarditis (IE) andother severe injection-related infections (SIRI) have increased dramatically along with the opioid epidemic.Persons with OUD hospitalized with SIRI often remain inpatient to complete prolonged intravenous (IV)antibiotic courses due to several assumptions such as 1) if outpatient patients will inject illicit drugs into the IVcatheter and will fail to complete prescribed antibiotic regimens and 2) if inpatient patients will not inject drugsbecause of the increased supervision and will complete the antibiotic regimen. No evidence supports theseassumptions and unfortunately the inpatient stay is not only very costly to the healthcare system butinfrequently includes comprehensive OUD treatment. In contrast outpatient parenteral antibiotic therapy(OPAT) via a peripherally-inserted central catheter (PICC) is the standard of care for continuing IV medicationsfor patients without injection drug use (IDU) once medically stable and is commonly used in treatmentinfections requiring prolonged IV antibiotics. OPAT is cost-effective associated with improved patientsatisfaction and with decreased risks of hospital-acquired infections. Development of innovative outpatientclinical models is urgently needed to improve the management and transition plan of persons with OUD andSIRI given the costs and risks associated with prolonged hospitalizations. We conducted a successful pilotproof-of-concept randomized study to establish the safety and feasibility of discharging inpatients with OUDand SIRI to complete IV antibiotics in an innovative integrated outpatient model combining BUP treatmentwith OPAT. This 12-week outpatient randomized parallel-group study builds on our preliminary work todemonstrate efficacy of the integrated outpatient care model (B-OPAT: BUP treatment with OPAT). Patientswith OUD and SIRI will be randomized (1:1) to either B-OPAT (n=45) or treatment-as-usual (TAU) (n=45) andcompared on the primary outcome of the proportion of urine samples negative for illicit opioids and on criticalsecondary outcomes including completion of recommended IV antibiotic therapy self-reported number of daysof illicit opioid abstinence and retention in outpatient treatment. The study will also incorporate acomprehensive economic evaluation of the integrated outpatient care model as well as a qualitativeinvestigation to inform future implementation and dissemination. These results will demonstrate the efficacyand cost effectiveness of an integrated outpatient care model to provide outpatient treatment of OUD and SIRIafter hospitalization.

project_terms:
Abstinence;Address;Adoption;Alcohol consumption;Ambulatory Care;Antibiotic Therapy;Antibiotics;Buprenorphine;Catheters;Client satisfaction;Clinical;Counseling;Criminal Justice;Development;Dissemination and Implementation;Dose;Drug usage;Educational process of instructing;Effectiveness of Interventions;Endocarditis;Enrollment;Evidence based treatment;Health Care Costs;Health Care Sector;Health Services;Healthcare Systems;Home;Hospitalization;Hospitals;Illicit Drugs;Infection;Injections;Inpatients;Intervention;Interview;Intravenous;Investigation;Length of Stay;Medical;Medical Care Team;Methadone;Modeling;National Institute of Drug Abuse;Nosocomial Infections;Observational Study;Outcome;Outpatients;Participant;Patient Self-Report;Patient-Focused Outcomes;Patients;Peripheral;Persons;Pharmaceutical Preparations;Phase;Pilot Projects;Population;Productivity;Provider;Quality-Adjusted Life Years;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Regimen;Research;Resources;Risk;Running;Sampling;Schedule;Self Administration;Supervision;Testing;Time;Tobacco Use Disorder;Urine;Work;addiction;buprenorphine treatment;clinical practice;cost;cost effective;cost effectiveness;economic evaluation;effectiveness outcome;future implementation;health care model;health care settings;health economics;illicit drug use;illicit opioid;improved;injection drug use;innovation;intravenous administration;opioid epidemic;opioid use;opioid use disorder;primary outcome;randomized clinical trials;response;safety and feasibility;secondary outcome;standard of care;treatment as usual

public_health_relevance:
PROJECT NARRATIVEHospitalizations for severe injection-related infections have increased along with the opioid epidemic andsome of these infections require prolonged courses of intravenous (IV) antibiotic therapy. There are currentlyno outpatient care models that incorporate evidence-based treatment of opioid use disorder withbuprenorphine with management of IV antibiotics. Demonstration of a successful integrated outpatient modelincorporating buprenorphine treatment and outpatient parenteral antibiotic therapy may change current clinicalpractice improve patient outcomes and be cost-effective.


application_id: 10672919
project_number: 5U01DA051377-03
project_title: Development of Agents for Synthetic Opioid Overdose
administering_ic: NIDA
award_notice_date: 2023-07-14
opportunity_number: PAR-19-039
application_type: 5
activity_code: U01
ic: DA
serial_number: 051377
program_official: VEMURI, KIRAN R V
project_start_date: 2021-09-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-MDCN-B(50)R]
contact_pi_person_id: 7842243
contact_pi: PRISINZANO, THOMAS EDWARD
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine and is used for thetreatment of pain as well as an adjuvant for anesthesia. It is also considered an incapacitating agent a chemicalthat produces a disabling condition that persists for hours to days after exposure has occurred such as in anunexpected chemical attack. As an opioid fentanyl depresses the central nervous system and respiratoryfunctions and can be lethal by respiratory depression. Due to its high potency ingestion of just a few milligramsof fentanyl or other synthetic opioid can be deadly to an opioid nave individual. Furthermore first responders ata chemical attack site who come in contact with free base fentanyl analogues are at significant risk for life-threatening toxicities.Currently there are three opioid antagonists available on the market that have potential to reverse the effects offentanyl namely naloxone naltrexone and nalmefene. The most commonly used is naloxone which is approvedfor administration by a variety of routes including intravenous intramuscular subcutaneous and intranasal.However recent reports suggest that higher doses or repeated dosing of naloxone (due to recurrence ofrespiratory depression) may be required to reverse fentanyl-induced respiratory depression. This highlights thepressing need for a more potent and longer acting opioid antagonist to combat fentanyl-induced respiratorydepression.Previous studies and our own preliminary results indicate that structural modification of naltrexone can increaseits potency and duration of action. Our central hypothesis is that structural modification of naltrexone will lead tonovel opioid receptor antagonists with the potential to treat overdose by fentanyl and related analogues inindividuals at high risk of exposure. The specific aims of this proposal are (1) identify opioid antagonists withenhanced pharmacodynamic and pharmacokinetic properties; (2) determine and optimize the in vivo activity ofopioid antagonists in mice and for their effectiveness in reversing the effects of fentanyl in preclinical models ofantinociception iteratively with Aim 1; and (3) determine and optimize the in vivo activity of opioid antagonists inrats and for their effectiveness in reversing the effects of fentanyl and selected analogues in preclinical modelsof opioid-induced locomotor and respiratory depression iteratively with Aim 1. The design synthesis evaluationof these molecules will have a broad impact on development of new pharmacologic probes that are designed tointeract with high potency and long duration at opioid receptors. This information will facilitate the identificationof safe and effective therapeutics that would rescue individuals after an acute and unexpected exposure tofentanyl and related analogues.

project_terms:
Acute;Adjuvant;Anesthesia procedures;Antidotes;Centers for Disease Control and Prevention (U.S.);Central Nervous System;Cessation of life;Chemical Warfare;Chemicals;Chemistry;Country;Development;Dose;Effectiveness;Evaluation;Event;Exposure to;FDA approved;Fentanyl;Gases;Generations;Goals;Half-Life;Hospitalization;Hostage;Hour;In Vitro;Individual;Ingestion;Inhalation Anesthetics;Intramuscular;Intravenous;Laboratories;Lead;Life;Marketing;Metabolic;Military Personnel;Modification;Morphine;Moscow;Mus;Naloxone;Naltrexone;Neuropharmacology;Opioid;Opioid Antagonist;Opioid Receptor;Pain management;Persons;Pharmaceutical Preparations;Pre-Clinical Model;Property;Rapid screening;Rattus;Recurrence;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Route;Safety;Series;Serum;Site;Survivors;Testing;Therapeutic;Toxic effect;Ventilatory Depression;Work;aerosolized;analog;antagonist;antinociception;base;carfentanil;combat;design;experience;experimental study;fentanyl analog;fentanyl exposure;fentanyl overdose;first responder;follow-up;high risk;improved;in vivo;incapacitating agents;mass casualty;milligram;mouse model;nalmefene;noradrenergic;novel;opioid overdose;overdose death;pharmacokinetics and pharmacodynamics;pharmacologic;skills;subcutaneous;success;synthetic opioid;therapeutically effective;water solubility

public_health_relevance:
Project NarrativeOur central hypothesis is that structural modification of naltrexone will lead to novel opioid receptor antagonistswith the potential to treat overdose by fentanyl and related analogues in individuals at high risk of exposure. Thedesign synthesis evaluation of these molecules will have a broad impact on development of new pharmacologicprobes that are designed to interact with high potency and long duration at opioid receptors. This information willfacilitate the identification of safe and effective therapeutics that would rescue individuals after an acute andunexpected exposure to fentanyl and related analogues.


application_id: 10672201
project_number: 5F31DE031948-02
administering_ic: NIDCR
award_notice_date: 2023-06-14
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: DE
serial_number: 031948
program_official: SARE, RACHEL
project_start_date: 2022-08-15
project_end_date: 2024-08-14
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 15957875
contact_pi: COOPER, KELLEY N
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
arra_indicator: N
budget_start_date: 2023-08-15
project_title:
Mechanisms and Immune consequences of atypical efferocytosis of neutrophils during Porphyromonas gingivalis infection.

project_abstract:
PROJECT SUMMARY/ABSTRACTNeutrophils recruited to the sites of bacterial infection or inflammation eventually undergo apoptosis and arecleared in situ by phagocytic cells such as macrophages. Efferocytosis or the phagocytic uptake of apoptoticcells (AC) is a highly selective process that relies upon the recognition of apoptosis associated ligands suchas phosphatidylserine (PS) by efferocytic receptors on the engulfing cells. These interactions initiatedownstream signaling that shuts down inflammatory pathways and orchestrates the hydrolytic breakdown ofACs within phagosomes/efferosomes for their eventual clearance. Several pathogens can manipulateefferocytosis in order to subvert immune clearance. We found that the periodontal pathogen Porphyromonasgingivalis uses a novel mechanism to dysregulate efferocytosis by causing the uptake of live neutrophils in aPS independent manner possibly bypassing engagement and/or activation of PS binding efferocytic receptors.Our preliminary data show that this atypical efferocytosis of live cells resulted in sustained production of pro-inflammatory cytokines and a profound failure of macrophages to activate pro-resolution pathways. Wehypothesize that P. gingivalis mediated atypical efferocytosis perpetuates inflammation in periodontal diseaseand breakdown of immune tolerance. In Aim 1 of this proposal we will delineate specific signaling pathwaysthat mechanistically link ingestion of live neutrophils to the generation of proinflammatory cytokines. In Aim 2of this proposal we will determine whether ingestion of live neutrophils results in degradation delays due toincomplete maturation of the efferosomes resulting in diminished hydrolytic capacity. Defects in clearance ofACs within efferosomes is increasingly linked to chronic inflammation and autoinflammatory sequalae in alarge number of diseases. Overall the data generated from this grant will not only shed mechanistic insightsatypical efferocytosis caused by a P. gingivalis but will also be useful in designing new therapeutic approachesto abate chronic inflammation associated with periodontitis. Furthermore this application includes acomprehensive training plan that will enable me to strengthen my ability to define scientific questions andanswer them using the strong technical skillset and conceptual understanding. I will continue to expand myexpertise in areas of host-pathogen interactions innate immune responses and cellular signaling pathwaysand the knowledge and skill sets gained from the proposed training will be invaluable moving forward as Ipursue a career as an independent investigator.

project_terms:
Abate;Anti-Inflammatory Agents;Apoptosis;Apoptotic;Area;Autoimmune Diseases;Bacterial Infections;Binding;Bypass;CREB1 gene;Cell physiology;Cells;Chronic;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Defect;Degradation Pathway;Digestion;Disease;Excision;Failure;Generations;Goals;Grant;Homeostasis;Immune;Immune Evasion;Immune Tolerance;In Situ;In Vitro;Infection;Inflammation;Inflammatory;Ingestion;Innate Immune Response;Kinetics;Knowledge;Left;Ligands;Link;Macrophage;Mediating;NF-kappa B;Necrosis;Neutrophil Infiltration;Oral;PTPN6 gene;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Periodontium;Phagocytes;Phagosomes;Phenotype;Phosphatidylserines;Physiological;Porphyromonas gingivalis;Predisposition;Process;Production;Research Personnel;Resolution;Secondary Prevention;Signal Pathway;Signal Transduction;Site;Surface;Technical Expertise;Training;Trypsin;autoinflammatory;career;chronic infection;cytokine;design;gingipain;immune clearance;in vivo;insight;neutrophil;new therapeutic target;novel;novel therapeutic intervention;oral pathogen;pathogen;pathogenic bacteria;periodontopathogen;receptor;receptor binding;response;skills;uptake

public_health_relevance:
NARRATIVEPeriodontal diseases are highly prevalent oral inflammatory diseases that cause the destruction of tooth-supporting structures and enhance susceptibility to several chronic inflammatory and autoimmune disorders. Inthe proposed studies we will determine how the oral pathogen Porphyromonas gingivalis dysregulatesclearance of dying cells leading to persistent inflammation. Understanding these mechanisms will provideopportunities for designing novel therapeutic targets in the treatment of periodontal diseases.


application_id: 10672174
project_number: 5F31HL162463-02
project_title: Targeting The GLP-1 Receptor As New Chronotherapy Against Nondipping Blood Pressure In Diabetes
administering_ic: NHLBI
award_notice_date: 2022-11-18
opportunity_number: PA-21-052
application_type: 5
activity_code: F31
ic: HL
serial_number: 162463
program_official: NEILSON, KAREN MARY
project_start_date: 2022-01-02
project_end_date: 2024-01-01
study_section: Special Emphasis Panel[ZRG1-F10C-C(20)L]
contact_pi_person_id: 16551080
contact_pi: CHACON, AARON
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTIn healthy individuals blood pressure (BP) is 10-20% lower during the sleep period than daytime levels.Chronic disruption in this day-night pattern has shown to be an independent risk factor for type 2 diabetes(T2DM) atherosclerosis stroke kidney disease retinopathy and more. These risks increase the less BP dipswith the most severe phenotype being reverse dipping  a pattern characterized by increased BP during thesleep period over daytime levels. Vascular complications are invariably associated with T2DM with prevalencerates of nondipping BP observed as high as 73%. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)have emerged as effective glucose-lowering therapy with a diverse range of half-lives for type 2 diabetics. Butbecause the GLP-1 receptor (GLP-1R) is widespread GLP-1 RAs have shown to have a multitude of beneficialeffects independent of their glucose-lowering properties. Inhibition of food intake anti-inflammatory propertiesand reduction in BP are among them. My preliminary data demonstrates a clear restoration in BP's rhythm in adiabetic mouse model when the short half-life GLP-1 RA exenatide is administered at the onset of the lightphase and its rhythm exacerbated when administered at the onset of the dark. Coinciding with this is arestoration or worsening in food intake's diurnal rhythm. Currently FDA guidelines consider exenatide'sadministration timing only in the context of glucose-lowering. The goal of this proposal is to investigate if andhow restoration of BP rhythm lends to improvement in vascular contractility and structure. Additionally thelong half-life GLP-1 RA semaglutide will be explored on these parameters. Moreover a novel smooth muscle-specific GLP-1R knockout mouse model will be generated to determine the GLP-1R's role in vascular smoothmuscle hyper-reactivity characteristic in type 2 diabetes. I hypothesize that timed administration of GLP-1 RAswill correct disruptions in circadian rhythm of BP which will lead to healthier vascular functioning in diabeticmice. With a rich history in circadian and vascular research my lab is uniquely positioned to carry out and testeverything proposed. Funding of this proposal will not only provide me with exceptional training in biochemicalmolecular physiological and pharmacological experimentation but also potentially offer a novelchronotherapeutic approach to improve these and other GLP-1 RA's usage in the treatment of T2DM.

project_terms:
Agonist;Anti-Inflammatory Agents;Atherosclerosis;Biochemical;Blood Glucose;Blood Pressure;Blood Vessels;Characteristics;Chronic;Chronotherapy;Circadian Rhythms;Clinical Trials;Darkness;Data;Diabetes Mellitus;Diabetic mouse;Disease;Diurnal Rhythm;Eating;Food;Functional disorder;Funding;Future;GLP-I receptor;Genes;Glucose;Glycosylated hemoglobin A;Goals;Guidelines;Half-Life;Health;Hour;Impairment;In Situ;Individual;Ingestion;Insulin;Kidney Diseases;Knockout Mice;Light;Measurement;Measures;Metabolic;Metabolism;Molecular;Monitor;Mus;Muscle Contraction;Non-Insulin-Dependent Diabetes Mellitus;Organ;Outcome;Pancreas;Pattern;Phase;Phenotype;Physiological;Positioning Attribute;Prevalence;Property;Proteins;Recording of previous events;Reporting;Research;Resistance;Rest;Retinal Diseases;Reverse Transcriptase Polymerase Chain Reaction;Risk;Risk Factors;Role;Satiation;Series;Signal Pathway;Signal Transduction;Sleep;Smooth Muscle;Stroke;Structure;Testing;Time;Training;Type 2 diabetic;Vascular Diseases;Vascular Smooth Muscle;Western Blotting;blood glucose regulation;blood pressure elevation;blood pressure reduction;blood pressure regulation;carbohydrate metabolism;cardioprotection;circadian;db/db mouse;design;diabetic;diabetic patient;exenatide;experimental study;glucagon-like peptide 1;improved;in vivo;indexing;mortality;mouse Cre recombinase;mouse model;novel;pharmacologic;pleiotropism;response;restoration

public_health_relevance:
PROJECT NARRATIVENondipping blood pressure (BP) describes a dysfunction in BP's natural healthy day-to-night rhythm and isprevalent in type 2 diabetes (T2DM). GLP-1 receptor agonists (RAs) are effective at lowering blood glucose inT2DM and have also shown to have BP-lowering effects. This proposal seeks to investigate the time-of-administration and half-life differences of GLP-1RAs to correct nondipping BP thereby improving vascularfunction and mortality outcomes in T2DM.


application_id: 10671750
project_number: 5R01AI142841-06
project_title: Maternal obesity and neonatal innate immunity
administering_ic: NIAID
award_notice_date: 2023-08-18
opportunity_number: PAR-20-298
application_type: 5
activity_code: R01
ic: AI
serial_number: 142841
program_official: PRABHUDAS, MERCY R
project_start_date: 2018-09-24
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-V(56)R]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: VARLAMOV, OLEG
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:
The developing fetal immune system is exquisitely sensitive to signals from the maternalenvironment. Maternal pre-pregnancy (pregravid) obesity has emerged as one of the mostconsequential regulators of fetal health. Data from clinical and animal model studiesdemonstrated increased susceptibility to microbial infection as well as a higher incidence ofinflammatory disorders and auto-immune diseases with maternal obesity. This dichotomy isillustrated by splenocytes generating dampened inflammatory responses to LPS stimulation whilegut resident immune cells generate exaggerated ones. Similarly pregravid obesity resulted inlower expression of inflammatory genes in umbilical cord blood monocytes at rest but followingdifferentiation into macrophages expression of inflammatory genes was significantly increased.These observations strongly suggest that pregravid obesity disrupts the development andmaturation of the fetal immune system and differentially impacts circulating monocytesand tissue resident macrophages (TRMs). However the molecular underpinnings of thisdysregulation by maternal obesity remain poorly understood due to the difficulty of obtaining termfetal tissues and of controlling for multiple maternal variables that modulate fetal immunity. Thusin this application we will leverage the rhesus macaque model to interrogate multiple fetalcompartments within the same subject to address this knowledge gap. Immune ontogeny occursvia 3 different waves starting with yolk sac transitioning to fetal liver and finally the bone marrow.TRMs are derived primarily from yolk sac and fetal liver while circulating monocytes are derivedfrom bone marrow. We recently reported that pregravid obesity is associated with low gradeinflammation that is further compounded by pregnancy. Thus we postulate that exposure to lowgrade maternal inflammation leads to training of TRMs while heightened maternal inflammatoryenvironment in late gestation leads to tolerance of bone marrow derived monocytes. Thereforethis application will test the central hypothesis that pregravid obesity results in differentialrewiring of TRMs and circulating monocytes wherein TRMs are poised to generate aheightened inflammatory response while circulating monocytes display a stuntedresponse. The novelty of this application lies in the systems biology approach integratingmaternal clinical metadata with genomic and functional readouts obtained in multiple immunecompartments in the same animal. Completion of the proposed experiments will reveal themolecular mechanisms that result in altered fetal macrophage and monocyte functions thusinforming the potential development of early interventions.

project_terms:
Adaptive Immune System;Address;Adipose tissue;Animal Model;Animals;Asthma;Autoimmune Diseases;Biological Assay;Bone Marrow;Breeding;CD14 gene;CD34 gene;Cardiovascular Diseases;Cells;Cesarean section;Chronic Disease;Classification;Clinical;Clinical Data;Clinical Research;Confounding Factors (Epidemiology);Data;Development;Disease;Early Intervention;Endocrinologist;Enterocolitis;Environment;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Escherichia coli;Exposure to;Female of child bearing age;Fetal Development;Fetal Liver;Fetal Tissues;Fetal health;Flow Cytometry;Genes;Genetic Transcription;Genomics;Gravid;Growth;Health;Hematopoiesis;Hematopoietic stem cells;Homeostasis;Host Defense;Immune;Immune system;Immunity;Immunologist;Incidence;Infection;Inflammation;Inflammatory;Inflammatory Response;Intervention;Intestines;Investigation;Knowledge;Laboratories;Ligands;Liquid substance;Lung;Macaca mulatta;Macrophage;Maternal-Fetal Exchange;Measures;Mediating;Metabolic;Metadata;Modeling;Molecular;Mothers;Mus;Myelopoiesis;Natural Immunity;Necrotizing Enterocolitis;Neonatal;Newborn Infant;Obesity;Outcome;Partner in relationship;Phagocytes;Phenotype;Population;Predisposition;Pregnancy;Reporting;Respiratory Syncytial Virus Infections;Respiratory syncytial virus;Rest;Risk;Sepsis;Signal Transduction;Site;Skeletal Muscle;Spleen;Splenocyte;Study models;Systems Biology;Systems Development;Techniques;Technology;Testing;Thinness;Third Pregnancy Trimester;Tissues;Training;Umbilical Cord Blood;United States;Wheezing;Yolk Sac;antimicrobial;chronic inflammatory disease;experimental study;fetal;fetal blood;fetal immunity;health of the mother;inflammatory milieu;innovation;insight;maternal condition;maternal obesity;microbial;monocyte;neonatal infection;neonate;nonhuman primate;obese mothers;offspring;pathogen;pathogenic bacteria;pathogenic virus;peripheral blood;prepregnancy;prepregnancy obesity;progenitor;response;single-cell RNA sequencing;success;time use

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 umbilical cord blood immune cells from babies born to obese mothers but the impact of maternalobesity on fetal immune cells remains poorly defined/understood. This application will carry out an in-depthinvestigation of maternal pre-pregnancy obesity-driven changes to the fetal immune cell populations andfunctions to contribute to the fundamental knowledge of the immune system development and identify potentialinterventions to address fetal immune dysregulations.


application_id: 10671703
project_number: 5R01DA047952-05
administering_ic: NIDA
award_notice_date: 2023-08-01
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: DA
serial_number: 047952
program_official: WEBB, CANDACE KARONDELETTE
project_start_date: 2018-09-30
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-AARR-K(92)S]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
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: 2023-08-01
project_title:
Increasing Access to Hepatitis C Treatment in Opioid Endemic Rural Areas: the  Kentucky Viral Hepatitis Treatment (KeY Treat) Study

project_abstract:
ABSTRACTThe overarching goal of the Kentucky Viral Hepatitis Treatment Project (KeY Treat) is to increase access totreatment for the hepatitis C virus (HCV) in a rural Appalachian community in the midst of the opioid/HCVsyndemic. This study seeks to examine whether removing barriers associated with accessing direct-actingantivirals (DAAs) for the treatment of HCV (high out-of-pocket costs insurance restrictions requiring aspecialist abstinence and significant liver damage) will significantly reduce the burden of HCV in PerryCounty Kentucky. The proposed study is made possible by a significant drug donation from Gilead Sciencesfor sofosbuvir/velpatasvir a 12-week once per day pan-genotypic DAA. KeY Treat proposes a multi-prongedapproach to treating HCV using a mid-level provider model. In addition to DAA treatment participants will beoffered access to subsidized medication-assisted treatment syringe services and case management. We willleverage existing resources in the target community (public health jail hospital) as well as ongoing projectsdedicated to increasing access to HCV care in affected communities (ECHO FOCUS) to answer whetherremoving the major barriers to HCV treatment affect access and what barriers remain. All RNA-positiveresidents of Perry County Kentucky will be eligible/recruited for study participation (N900) and the followingspecific aims will be addressed: 1) determination of HCV treatment uptake among rural residents with chronicHCV; 2) examination of the predictors of treatment completion among those enrolled in KeY Treat; 3)examination of the characteristics of participants achieving sustained virologic response (SVR or cure); 4)establishment of long-term re-infection rates among those achieving SVR; 5) examination of 5-year reductionsin incidence and prevalence of HCV in the intervention community compared with a control county in ruralKentucky; and 6) evaluate the impact and cost-effectiveness of KeY Treat using mathematical modeling. Theproposed research has tremendous potential to impact public health in the rural United States. The majority ofcounties identified in CDCs recent HCV/HIV hotspot analysis were rural and there is a real need to improveaccess to DAAs in order to prevent further HCV transmission reduce the burden of advanced liver diseaseand hepatocellular carcinoma in generations to come. Data from KeY Treat will inform policies aroundMedicaid/insurance restrictions for DAAs and will deliver a much needed blueprint for the provision of HCVtreatment in resource-deprived rural areas.

project_terms:
Abstinence;Address;Affect;Aftercare;Age;Antiviral Agents;Appalachian Region;Blood;Caring;Case Management;Characteristics;Chronic;Chronic Hepatitis C;Clinical Research;Communities;Community Health;Complement;County;Data;Dedications;Drug user;Eligibility Determination;Enrollment;Generations;Genotype;Goals;Guidelines;HIV;Health;Health Services Accessibility;Hepatitis C;Hepatitis C Prevalence;Hepatitis C Therapy;Hepatitis C Transmission;Hepatitis C virus;Hepatology;Hospitals;Housing;Improve Access;Incidence;Individual;Infection;Insurance;Intervention;Jail;Kentucky;Letters;Liver diseases;Measures;Medicaid;Modeling;Needle-Exchange Programs;Nurse Practitioners;Opioid;Outcome;Participant;Pharmaceutical Preparations;Pike fish;Policies;Prediction of Response to Therapy;Prevalence;Primary carcinoma of the liver cells;Provider;Public Health;RNA;Research;Research Personnel;Resources;Rural;Rural Appalachia;Sampling;Science;Secure;Services;Specialist;Syringes;Tablets;Text;United States;Universities;Viral hepatitis;community intervention;cost;cost effective;cost effectiveness;follow-up;infection rate;liver injury;marginalized population;mathematical model;medication compliance;medication-assisted treatment;opioid abuse;opioid use disorder;portability;prevent;recruit;research study;response;rural area;rural dwellers;rural setting;side effect;syndemic;telehealth;treatment services;uptake;viral RNA

public_health_relevance:
PROJECT NARRATIVEThe hepatitis C virus (HCV) is endemic in rural Appalachia primarily due to abuse of opioids. Direct-actingantivirals (DAAs) are exceedingly effective at curing hepatitis C but access and uptake of DAA treatment islacking in rural areas largely due to high cost and Medicaid restrictions. The Kentucky Viral Hepatitis CTreatment (KeY Treat) project will provide treatment with a DAA to any RNA-positive resident of Perry CountyKentucky to determine whether removing these major barriers will improve access to care and data from KeYTreat will inform policies around Medicaid/insurance restrictions for DAAs and will deliver a much neededblueprint for the provision of HCV treatment in resource-deprived rural areas.


application_id: 10671079
project_number: 5R21CA263107-02
project_title: Mechanisms underlying radiation-induced dysphagia
administering_ic: NCI
award_notice_date: 2023-08-01
opportunity_number: PAR-20-292
application_type: 5
activity_code: R21
ic: CA
serial_number: 263107
program_official: EMENAKER, NANCY J
project_start_date: 2022-08-01
project_end_date: 2025-07-31
study_section: ZCA1-TCRB-9(M1)S
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
arra_indicator: N
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;Malnutrition;Measurement;Measures;Modality;Modeling;Motor;Motor output;Movement;Muscle;Neurons;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;Therapeutic;Time;Tissues;Tongue;Trigeminal System;United States;Work;activating transcription factor 3;afferent nerve;aspirate;axon injury;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;neural patterning;neuromechanism;neuroregulation;novel;peripheral nerve damage;predictive modeling;preservation;prevent;response;screening;sensory input;sensory integration;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: 10670941
project_number: 5TL1TR001997-07
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2023-06-23
opportunity_number: PAR-18-940
application_type: 5
activity_code: TL1
ic: TR
serial_number: 001997
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2026-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Contact PD/PI: Kern Philip A. NRSA-Training-001 (003)PROJECT SUMMARY  TL1 TRAINING PROGRAM The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to sustainand enhance the current pre-doctoral and post-doctoral TL1 program currently in its ninth year of NationalInstitutes of Health (NIH) support. By providing a multidisciplinary training program that integrates traineesacross diverse fields and offers rigorous and solid translational research education the TL1 program haseffectively prepared clinicians- and scientists-in-training for careers as leaders in clinical and translationalscience. The UK TL1 program features substantial collaborations across a robust cohort of productiveinvestigators a talented pool of qualified applicants solid infrastructure and strong institutional support. Theprogram takes advantage of the physical juxtaposition of UKs six health care colleges (Medicine NursingPharmacy Public Health Health Sciences Dentistry) and key disciplines on the main campus (e.g.Engineering Social Work Biology Psychology Education) to train scholars across wide-ranging fieldsnecessary for successful clinical and translational research (CTR). The program supports career developmentof scholars with research interests that cross the lifespan (prenatal through elderly) and the full spectrum ofclinical and translational science including translational clinical community/policy studies and CTRmethods/processes (e.g. biomedical informatics) focusing on a broad array of health topics. The TL1 traineesare making important contributions to science through published work and all of the program graduates areactively engaged in CTR. This program and other CCTS-sponsored efforts are engaging underserved studentsin projects focused on health disparities of Kentucky and the Central Appalachian area. We are requestingrenewed NIH support for eight TL1 scholars. The foundation of the proposed program will continue to bepractical research experiences within multidisciplinary teams guided by experienced mentors along witheducational and training offerings such as certificate Masters and PhD degrees to ensure successful careerdevelopment of these future CTR leaders. Scholar competency assessments based on the Clinical ResearchAppraisal Inventory serve to guide new program offerings with the theory that trainees who have highconfidence in their skills are more likely to pursue a career in CTR. UK CCTS-developed pipeline programstargeting professional and graduate students including new initiatives to support health equities researchersand trainees from under-represented groups will ensure the availability of a strong pool of candidates for theTL1 program. In sum the TL1 program is designed to accelerate career development of future leaders in thetranslational science workforce who will be prepared to address todays complex research challenges andspearhead advances in human health.Project Summary/Abstract Page 1236Contact PD/PI: Kern Philip A. NRSA-Training-001 (003)BIBLIOGRAPHY AND REFERENCES CITED1. Fowler BJ Gelfand BD Kim Y Kerur N Tarallo V Hirano Y Amarnath S Fowler DH Radwan M Young MT Pittman K Kubes P Agarwal HK Parang K Hinton DR Bastos-Carvalho A Li S Yasuma T Mizutani T Yasuma R Wright C and Ambati J. Nucleoside reverse transcriptase inhibitors possess intrinsic anti- inflammatory activity. Science 346:1000-3 2014. PMCID:PMC4274127.2. Ambati J Fowler B and Ambati K inventors; Compositions and Methods for Treating Retinal Degradation patent 20180044327. 2018 Feb 15 2018.3. Sherwood AR Johnson MB Delgado-Escueta AV and Gentry MS. A bioassay for Lafora disease and laforin glucan phosphatase activity. Clin Biochem 46:1869-76 2013. PMCID:PMC3864130.4. Albuquerque R Vora P and Bell N inventors; Provision Patent: System and Method for Assessment of Choroidal Blood Flow Noninvasively Using Color Amplification patent 13177N/2191US5. The CTSA Program at NIH: Opportunities for Advancing Clinical and Translational Research. Available at http://www.nationalacademies.org/hmd/Activities/Research/CTSAreview.aspx. Accessed 20196. Brown CA Jiang Y Smith CD and Gold BT. Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities. Cortex 104:58-74 2018.PMCID:PMC6008234.7. Gupta VA Sousa M Kraitman N Annabathula R Vsevolozhskaya O Leung SW and Sorrell VL. Coronary artery calcification predicts cardiovascular complications after sepsis. J Crit Care 44:261-6 2018.8. Areephanthu CJ Bole R Stratton T Kelly TH Starnes CP and Sawaya BP. Impact of Professional Student Mentored Research Fellowship on Medical Education and Academic Medicine Career Path. Clin Transl Sci 8:479-83 2015. PMCID:PMC4626384.9. Bandura A. Self-efficacy: toward a unifying theory of behavioral change. Psychol Rev 84:191-215 1977.10. Mullikin EA Bakken LL and Betz NE. Assessing Research Self-Efficacy in Physician-Scientists: The Clinical Research APPraisal Inventory. Journal of Career Assessment 15:367-87 2007.11. Robinson GF Switzer GE Cohen ED Primack BA Kapoor WN Seltzer DL Bakken LL and Rubio DM. A shortened version of the Clinical Research Appraisal Inventory: CRAI-12. Acad Med 88:1340-5 2013.PMCID:PMC3758379.12. Pusek S Knudson B and Tsevat J. Personalized training pathways for translational science trainees: building on a framework of knowledge skills and abilities across the translational science spectrum. J Clin Transl Sci 2020 (in press).References Cited Page 1237

project_terms:
Acceleration;Address;Age;Alzheimer's disease pathology;Anti-Inflammatory Agents;Appalachian Region;Area;Behavioral;Bibliography;Biological Assay;Biology;Blood flow;Cardiovascular system;Career Choice;Caring;Clinical;Clinical Research;Clinical Sciences;Collaborations;Color;Communities;Competence;Complex;Dentistry;Discipline;Discipline of Nursing;Doctor of Philosophy;Education;Elderly;Engineering;Ensure;Equipment and supply inventories;Fellowship;Foundations;Future;Glucans;Gold;Health;Health Sciences;Healthcare;Human;Humpback Dolphins;Infrastructure;Institution;Journals;Kentucky;Knowledge;Lafora Disease;Legal patent;Longevity;Medical Education;Medicine;Mentors;Methods;National Research Service Awards;Nucleosides;Pathway interactions;Pharmacy facility;Phosphoric Monoester Hydrolases;Physicians;Policies;Postdoctoral Fellow;Process;Productivity;Psychology;Public Health;Publishing;Qualifying;Research;Research Methodology;Research Personnel;Retina;Reverse Transcriptase Inhibitors;Science;Scientist;Self Efficacy;Sepsis;Social Work;Solid;Structure;System;TNFSF15 gene;Talents;Training;Training Programs;Training and Education;Translational Research;Underrepresented Populations;United States National Institutes of Health;Universities;Work;biomedical informatics;career;career development;clinical center;cohort;college;coronary artery calcification;design;education research;experience;graduate student;health disparity;health equity;interest;multidisciplinary;pre-doctoral;prenatal;professional students;programs;skills;student mentoring;theories;underserved students;white matter


application_id: 10670122
project_number: 5R34DA053140-03
project_title: Integrated PrEP Interventions for People Who Inject Drugs in Rural Kentucky
administering_ic: NIDA
award_notice_date: 2023-06-30
opportunity_number: PA-18-780
application_type: 5
activity_code: R34
ic: DA
serial_number: 053140
program_official: JENKINS, RICHARD A
project_start_date: 2021-08-01
project_end_date: 2025-07-31
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
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:
ABSTRACTRural areas in the United States are increasingly impacted by HIV tied to the ongoing opioid epidemicgrowing stimulant use and widespread drug injection. Kentucky (KY) is among seven states identified withheavy rural HIV burden and increasing rates of new HIV diagnoses attributable to injection drug use. RuralHIV outbreaks among people who inject drugs (PWID) have occurred recently in KYs neighboring stateshighlighting the urgent need to implement proven HIV prevention and harm reduction strategies for PWID inKYs rural areas. A key pillar of Ending the HIV Epidemic (EHE): A Plan for America is the prevention of newHIV infections through scale up of evidence-based interventions including syringe service programs (SSPs)and Pre-exposure prophylaxis (PrEP). Our R21 in KYs Appalachian region demonstrated consistent utilizationof rurally located SSPs by high-risk PWID making SSPs a critical venue to scale delivery of comprehensiveHIV prevention services in rural areas. In a prior RCT conducted by the PI of this application strengths-basedcase management (SBCM) interventions were shown to be effective in increasing HIV testing and overcomingbarriers to medical care among people who use drugs. Building on this prior work and ongoing collaborationwith rural SSPs in KY this R34 will adapt and integrate a novel PrEP initiation intervention at point ofcare in rural SSPs in two KY counties that are among the nations top 10 most vulnerable to HIVamong PWID and conduct a preliminary test of its efficacy. The Specific Aims are to: 1) Assess clientprovider organization and structural-level facilitators and barriers to integration of a PrEP focusedSBCM (SBCM-PrEP) intervention into routine SSP practice. Guided by the PRISM model we will conductsemi-structured key informant interviews with PWID clinical care and harm reduction service providers andfacility administrators in our targeted SSP implementation locations to identify individual organizational andstructural challenges and opportunities to adapt the SBCM-PrEP to enhance client acceptability accessibilityand compatibility with clinical workflow; 2) Adapt an evidence-based SBCM protocol to provide PrEPintervention services for PWID in SSP sites. Using in-depth interview data from Aim 1 we will adapt refineand incorporate HIV prevention content most salient to PrEP care into the SBCM-PrEP following the ADAPTITT framework; and 3) Examine feasibility acceptability and preliminary efficacy of the adapted SBCM-PrEP. 80 participants will be randomized into: CDC-PrEP (an in-use PrEP intervention based on CDCguidelines) or SBCM-PrEP. Primary outcomes include feasibility and acceptability (measured by interventionattendance engagement and satisfaction) during the active intervention period and preliminary efficacy onPrEP initiation (measured by dispensed PrEP prescription) 3- and 6- months post-baseline. The proposedstudy fills a gap in evidence for PrEP studies among rural PWID by testing brief interventions that address bothindividual and structural challenges to PrEP uptake through an integrated point of care service delivery model.

project_terms:
AIDS prevention;Address;Administrator;Appalachian Region;Caring;Case Management;Client;Clinical;Collaborations;County;Data;Disease Outbreaks;Drug user;Education;Environment;Epidemic;Equipment;Evidence based intervention;Guidelines;HIV;HIV Infections;HIV diagnosis;Harm Reduction;Human immunodeficiency virus test;Incidence;Indiana;Individual;Infrastructure;Injecting drug user;Injections;Intervention;Interview;Kentucky;Knowledge;Literature;Location;Measures;Medical;Monitor;Needle-Exchange Programs;North Carolina;Participant;Pharmaceutical Preparations;Practical Robust Implementation and Sustainability Model;Prevention;Protocols documentation;Provider;Randomized;Risk;Rural;Rural Community;Rural Population;Service delivery model;Services;Site;Sterility;Structure;Syringes;Testing;United States;West Virginia;Woman;Work;acceptability and feasibility;barrier to care;brief intervention;clinical care;drug testing;evidence base;health care availability;high risk;high risk population;informant;injection drug use;men;new epidemic;novel;opioid epidemic;point of care;pre-exposure prophylaxis;prevention service;preventive intervention;primary outcome;risk perception;rural area;satisfaction;scale up;screening;service intervention;service providers;social stigma;stimulant use;tool;transmission process;uptake

public_health_relevance:
PROJECT NARRATIVEKentucky (KY) is among seven states identified with heavy rural HIV burden and increasing rates of new HIVdiagnoses attributable to injection drug use. The expansion of PrEP has been strongly endorsed as a keystrategy for impacting the course of the HIV epidemic however PrEP trials among people who inject drugs arelargely absent in rural areas. This R34 application will adapt and integrate a novel PrEP initiation interventionat point of care in rural syringe service programs in two KY counties that are among the nations top 10 mostvulnerable to HIV among PWID and fills a gap in evidence by testing brief interventions that address bothindividual and structural challenges to PrEP uptake.


application_id: 10669480
project_number: 4R33DA049130-03
project_title: Glutamergic Mechanisms in Opioid and Cocaine Co-Use
administering_ic: NIDA
award_notice_date: 2022-08-25
opportunity_number: PAR-18-084
application_type: 4
activity_code: R33
ic: DA
serial_number: 049130
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2020-09-30
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-X(03)M]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: STOOPS, WILLIAM WALTON
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:
Opioid use disorder (OUD) is a leading public health crisis in the United States. Individuals with opioid usedisorder frequently use other substances including cocaine. Past year opioid withdrawal was associated with 4times greater odds of current cocaine use which may represent an attempt to ameliorate opioid withdrawaleffects but also increases overdose risk as evidenced by preclinical and clinical findings. Approved OUDpharmacotherapies are modestly effective but these medications are not indicated for treating cocaine co-usehighlighting the need for a novel intervention approach to improve outcomes in co-morbid OUD and cocaine usedisorder. Mechanistically drug-motivated behaviors are regulated by glutamate signaling within corticostriatalcircuitry. Both opioid and cocaine self-administration (SA) down-regulate the glial glutamate transporter (GLT-1) and alter synaptic plasticity measured as changes in dendritic spines and AMPA-to-NMDA current ratios(A/N) within the nucleus accumbens core (NAcore). Thus glutamatergic plasticity is a conserved neuralmechanism underlying drug motivation in both opioid and cocaine use. The combined effects of opioid andcocaine co-use on glutamatergic systems however are unknown. n-Acetylcysteine (NAC) has showntranslational promise for treating multiple drug use disorders including cocaine and opioids. NAC is capable ofrestoring glutamatergic alterations induced by either drug alone likely by increasing glutamate clearance fromthe synapse following drug use through upregulation of GLT-1. Clinically we have shown that NAC reduces theincentive salience of cocaine-related stimuli which controls drug seeking. As well others have shown that NACnormalizes glutamate function in cocaine-dependent individuals. Whether NAC reduces drug intake and reversesglutamatergic alterations induced by co-use of opioids and cocaine is unknown. The work proposed here willbegin to fill those crucial knowledge gaps. Our overarching hypotheses are that (1) persistent brain glutamatechanges induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence andwithdrawal and (2) that NAC will ameliorate glutamatergic dysregulation and thus will reduce both oxycodoneand cocaine use. We propose a two phase translational project supported by the R21/R33 mechanism. In thefirst phase (R21) we will characterize NAcore glutamatergic signaling in opioid and cocaine co-use as a neuralbiomarker for pharmacotherapeutic targeting with NAC using preclinical laboratory methods. Upon meeting themilestones set forth for the R21 we will conduct the second phase (R33) in which we will determine the influenceof NAC on glutamate function and reinforcing effects of cocaine in co-morbid opioid and cocaine use disorderusing human laboratory methods. The milestones completed during this translational project will elucidateglutamatergic dysregulation underlying opioid and cocaine co-use laying the groundwork for effectivepharmacotherapeutic treatment for this pattern of polysubstance abuse through targeting glutamate signaling.

project_terms:
Acetylcysteine;Animals;Attenuated;Biological Markers;Brain;Chemosensitization;Chronic;Clinical;Cocaine;Cocaine use disorder;Cocaine withdrawal;Cues;Dendritic Spines;Dependence;Development;Dose;Drug Controls;Drug Use Disorder;Drug usage;Food;Glutamate Transporter;Glutamates;Heroin;Homosynaptic Depression;Human;Individual;Intake;Intervention;Intravenous;Knowledge;Laboratories;Magnetic Resonance Spectroscopy;Maintenance;Measures;Methods;Modeling;Motivation;N-Methylaspartate;Neurons;Nucleus Accumbens;Opioid;Opioid agonist;Oral;Oxycodone;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phased Innovation Awards;Physical Dependence;Physiological;Placebos;Proteins;Protocols documentation;Proxy;Public Health;Randomized;Reporting;Self Administration;Specific qualifier value;Stimulus;Synapses;Synaptic plasticity;System;Time;United States;Up-Regulation;Withdrawal;Work;cocaine exposure;cocaine self-administration;cocaine use;comorbidity;comparison group;experience;glutamatergic signaling;improved outcome;incentive salience;meetings;motivated behavior;multiple drug use;neurobiological mechanism;neuromechanism;novel;novel therapeutics;opioid use;opioid use disorder;opioid withdrawal;overdose risk;polysubstance abuse;pre-clinical;protein expression;relating to nervous system;sex

public_health_relevance:
Project NarrativeProblems posed by opioid use disorder are often compounded by comorbid cocaine use. This proposal will use sophisticated preclinical and clinical laboratory models to determine neurobiological mechanisms thatcontribute to this significant and growing public health concern and could contribute to the development ofnovel therapeutic options aimed at reversing opioid and cocaine co-use-induced alterations in the brain.


application_id: 10668987
project_number: 5R01DA049333-04
administering_ic: NIDA
award_notice_date: 2023-07-06
opportunity_number: PAR-18-747
application_type: 5
activity_code: R01
ic: DA
serial_number: 049333
program_official: DUNSTON, SHEBA KING
project_start_date: 2020-09-30
project_end_date: 2025-07-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-01
project_title:
Research Examining Factors Associated with the Opioid Crisis among Underserved African Americans (REFOCUS)

project_abstract:
ABSTRACTOpioid-related overdose rates among African Americans have increased exponentially. Given AfricanAmerican opioid users have the lowest treatment completion rates when compared to other races/ethnicitiesthere is increased risk for mortality and morbidity. As a result there is a dire need to better understand thisfatal epidemic among this historically underserved group. Using the theory of Subcultural Evolution and DrugUse which suggests cultural and generational influences are linked to drug use patterns and risks amongAfrican Americans the Research Examining Factors Associated with the Opioid Crisis among UnderservedAfrican Americans (REFOCUS) project will employ a within-racial group mixed-methods design among AfricanAmerican adults in the community. The overall objective is to better understand the complex structural socialand cultural factors that differentially influence NMPOU other nonmedical prescription drug use and treatmentservice use among African Americans. Ultimately our goal is to gather data that will inform culturally-tailoredinterventions to reduce NMPOU and better facilitate initiation and completion of treatment. The REFOCUSproject has three aims: 1) To understand cultural and generational characteristics associated withNMPOU other NMPDU illicit drug use and treatment service use. We will conduct in-depth interviews withapproximately 40 African American nonmedical prescription opioid users stratified by gender and age tounderstand NMPOU across the lifespan within the context of lived experience. Using thematic analysis datawill be gathered to culturally-tailor the survey. 2) To assess structural social and cultural patterns ofNMPOU other NMPDU illicit drug use and treatment service use among 800 (400 = male and 400 =female) African American NMPO users. We will conduct cross-sectional face-to-face culturally-informedsurveys (modified by information obtained in Aim 1) and drug testing using targeted recruitment and stratifiedsampling by age and gender. 3) To pretest messaging generated from initial findings that will informtargeted interventions specific to African American nonmedical prescription opioid users. We willconduct in-depth semi-structured interviews and using health communication techniques we will develop alibrary of cultural gender and generational specific messages related to decreasing NMPOU and increasingtreatment engagement and retention. We will test these messages that will be constructed from Aim 1 and Aim2 data with approximately 40 African American nonmedical prescription opioid users stratified by gender andage. This pretesting task will prepare us to conduct a fully powered RCT as the next step in our research.This underrepresented new investigator led project directly aligns with the PAR and NIDAs priority focusarea of addressing real-world complexities. As this high-impact project focuses on a marginalized groupunderrepresented in opioid use research and it has the potential to yield insights on ways to culturally-tailorfuture interventions for African Americans.

project_terms:
Address;Adult;African American;African American population;Age;Area;Attention;Buprenorphine;Cessation of life;Characteristics;Child Rearing;Communities;Complex;Comprehension;Criminal Justice;Data;Data Sources;Dimensions;Discrimination;Disparity;Dose;Drug usage;Employment;Epidemic;Ethnic Origin;Evolution;Female;Future;Gender;Goals;Healthcare Systems;Heroin;Imprisonment;Intervention;Interview;Kentucky;Libraries;Link;Longevity;Mediating;Mental Health;Methadone;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Outcome;Overdose;Pain;Participant;Patients;Pattern;Pharmacotherapy;Policies;Population;Public Health;Race;Reporting;Research;Research Personnel;Research Project Grants;Risk;Sampling;Stress;Structure;Surveys;Techniques;Testing;Treatment outcome;Underrepresented Populations;Underserved Population;cohort;design;distrust;drug testing;evidence base;experience;health care availability;health communication;illicit drug use;improved;insight;low socioeconomic status;male;marginalized population;men;misuse of prescription only drugs;mortality risk;older women;opioid epidemic;opioid overdose;opioid use;opioid user;physical conditioning;pill;prescription opioid;prescription opioid misuse;racial population;recruit;response;social;synthetic opioid;theories;treatment services;trend;young woman

public_health_relevance:
PROJECT NARRATIVEThe REFOCUS project-Research Examining Factors Associated with the Opioid Crisis amongUnderserved African Americans has significant public health implications by examining howstructural social and cultural factors influence nonmedical prescription opioid use (NMPOU) andtreatment service use among African Americans across the adult lifespan. Overdose rates haverisen exponentially among African Americans but this group has received much less attention.The REFOCUS project will generate data directly applicable to culturally-tailor interventionstargeting African American opioid users in order to reduce NMPOU and improve treatmentoutcomes.


application_id: 10668983
project_number: 5F31DC020639-02
project_title: Mechanisms of Tip Link Tensioning in Mammalian Auditory Hair Cells
administering_ic: NIDCD
award_notice_date: 2023-06-12
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: DC
serial_number: 020639
program_official: SCHURMAN, JACLYN REBECCA
project_start_date: 2022-07-31
project_end_date: 2025-07-30
study_section: ZDC1-SRB-Y(56)
contact_pi_person_id: 78133926
contact_pi: DRAGICH, ABIGAIL
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:
Project SummaryMammalian auditory hair cells detect sound through deflections of stereocilia that are organized in precisestaircase-like bundles and interconnected by extracellular tip links. Sound-induced deflections modulate thetension of tip links and convey these forces to mechano-electrical transduction (MET) channels located atthe tips of the shorter rows of stereocilia. Even at rest there is a certain amount of tension on the tip linkswhich ensures detection of the softest sounds and results in some resting amount of MET currentcontinuously entering the cell. We and other groups demonstrated that this resting MET current regulatesthe height of transducing stereocilia thereby providing a plausible mechanism for long-term maintenance ofthe shape of stereocilia bundle. Furthermore my recent study revealed that MET-dependent retraction ofstereocilia in mammalian auditory hair cells increases the tension within MET machinery which could onlyoccur if in contrast to the classical models the upper end of the tip link is not freely moved by myosinmotors but instead somehow locked to the stereocilia core (Dragich et. al. in review). The proposed projectwill explore a potential molecular mechanism of this phenomenon. We hypothesize that G-InteractingProtein C-terminus-3 (GIPC3) is involved in locking the upper end of the tip link to the stereocilia actin core.Several mutations in GIPC3 have been linked to hearing loss in humans but the exact function of thisprotein in the mammalian cochlea is yet unknown. Data from our collaborator (Dr. Craig Vander Kooi) showthat GIPC3 interacts with myosin VI (MYO6) and the upper tip link density (UTLD) proteins cadherin-23(CDH23) and potentially myosin VIIa (MYO7a). My preliminary data also show that GIPC3 deficiency resultsin the loss of resting MET current and slipping adaptation of the MET responses in cochlear outer haircells of mice carrying the p.W301X mutation in Gipc3 recapitulating a known human deafness. In thisproject we will use this Gipc3W301X mouse strain as well as a Gipc3 knockout strain to determine: (a) therole of GIPC3 in regulating the tension within the MET machinery and adaptation in mammalian auditoryhair cells; (b) the role of GIPC3 in UTLD assembly and maintenance; and (c) the potential for restoringwildtype MET responses in Gipc3-deficient mice. This project will not only identify the specific role of GIPC3in mammalian auditory hair cells but also elucidate the mechanisms behind the maintenance of stereociliabundle structure and tensioning of the MET machinery. Approaching this project using electrophysiologyadvanced electron microscopy and cell biology techniques will help me to develop a unique set of scientificskills in preparation for a career as a future principal investigator in basic auditory research.

project_terms:
Actins;Auditory;Biochemical;CDH23 gene;Cell Survival;Cells;Cellular biology;Clinical Treatment;Cochlea;Confocal Microscopy;Data;Detection;Development;Electron Microscopy;Electrophysiology (science);Ensure;Environment;Future;Genes;Hair;Hair Cells;Hearing;Height;Human;Image;In Vitro;Knock-out;Laboratories;Link;Liquid substance;MYO7A gene;Maintenance;Mechanics;Methods;Microscopy;Modeling;Molecular;Motor;Mouse Strains;Mus;Mutation;Myosin ATPase;Outer Hair Cells;Patients;Phenotype;Physiological;Play;Preparation;Principal Investigator;Proteins;Research;Rest;Role;Shapes;Slide;Speed;Structure;Techniques;Traction;career;deaf;deafness;density;experimental study;extracellular;hearing impairment;inhibitor;mechanotransduction;mutant;myosin VI;patch clamp;protein function;response;skills;sound

public_health_relevance:
Project NarrativeMutations in the gene encoding G-Interacting Protein C-terminus 3 (GIPC3) are known to cause profoundhearing loss in humans. This project explores the role of GIPC3 in mechanoelectrical transduction ofmammalian cochlear hair cells. Therefore the study may identify mechanistic causes of hearing loss inpatients carrying specific GIPC3 mutations potentially contributing to new clinical treatments.


application_id: 10668525
project_number: 5R01AT008617-07
project_title: Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation
administering_ic: NCCIH
award_notice_date: 2023-05-10
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AT
serial_number: 008617
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
arra_indicator: N
project_abstract:
Brain chronic inflammation is a hallmark of the aging process and promotes the progression of many braindiseases. Compelling evidence shows that healthy edible plants have important physiological roles for normalbrain function and can prevent neuroinflammatory processes. However mechanistic studies in the brain haveprimarily focused on single or individual factors from edible plants which most likely do not represent the resultsgenerated from multiple factors that are provided in a healthy diet consumed daily.Recently a tiny nanoparticle called an exosome-like nanoparticle (ELN) has been isolated from a number ofedible plants. ELNs consists of lipids proteins and RNAs. We have demonstrated that ELNs like prebioticsare taken up by intestinal bacteria resulting in inhibition of mouse colitis. However whether these edible plant-derived nanoparticles have a direct effect on the brain is not clear.In this study we will provide cellular and molecular insight into how ELNs modulate neuroimmune function via agut-brain axis by targeting microglial cells that benefits the brain. Indispensable to this proposal is the use of amouse aging model to investigate mechanistic details that will facilitate developing ELNs as a potential new classof prebiotic to target specific components involved in brain inflammation. Based on these findings it is temptingto speculate that the clinical profile of at least some brain anti-inflammation therapeutics can be improved byinterventions relying on one or more edible plant-derived ELNs. This finding urgently awaits experimentalconfirmation which is what we proposed to investigate in this proposal. From a clinical application standpointand as proof-of-concept in this study our hypothesis is that multiple factors carried by garlic ELNs (GaELN)target to microglial cells simultaneously to inhibit brain inflammation in aged mice. This will be tested ina mouse aging model that mimics human aging process. The plan to test our hypothesis is outlined in threespecific aims. Our proposed studies will determine: (1) Determine and evaluate if garlic ELN (GaELN)phosphatidic acid (PA) stimulated BASP1 domain(s) that binds to calmodulin (CaM) prevents c-MYC mediatedbrain inflammation in aged mice; (2) Evaluate whether GaELN nc-sRNA21 contributes to inhibition of braininflammation by enhancing the transporting of c-MYC-nick into exosomes in a Rab11a dependent manner; and(3) Evaluate whether GaELN induces a switch to secretion of CYLD+exosomes with immune tolerant cargos.Upon accomplishing this proposed study the study will lead to identification of new therapeutic targets andpotential ELN based interventions for treating brain inflammation. In addition findings will provide a foundationto further study whether oral administration of customized ELNs isolated from different plants will have asynergistic/additive effect on prevention or treatment of chronic inflammatory brain related diseases. Thereforethis study is a highly translational study aimed at finding new therapeutic targets for brain inflammation.

project_terms:
Acids;Affect;Aging;Bacteria;Binding;Biological;Brain;Brain Diseases;CD11 Antigens;Calmodulin;Cell Separation;Cells;Chronic;Clinical;Consumption;Data;Development;Diet;Disease;Edible Plants;Encephalitis;Foundations;Garlic;Health Status;Human;Immune Tolerance;In Vitro;Individual;Inflammation;Inflammatory;Interleukin-1 beta;Interleukin-10;Interleukin-6;Intervention;Intestines;Knock-out;Knowledge;Lipids;Macrophage;Mediating;Microglia;Modeling;Molecular;Mus;Neuroimmune;Oral;Oral Administration;Pathway interactions;Phosphatidic Acid;Physiological;Physiology;Plants;Prevention;Prevention strategy;Probiotics;Process;Production;Protein Analysis;Proteins;Publishing;RNA;Role;Small RNA;Sorting;Structure of thyroid parafollicular cell;TNF gene;Testing;Therapeutic;Untranslated RNA;aged;aging brain;blood-brain barrier crossing;brain tissue;c-myc Genes;clinical application;cytokine;design;exosome;good diet;gut-brain axis;improved;in vivo;insight;murine colitis;nanoparticle;neuroinflammation;new therapeutic target;prebiotics;prevent;protective effect;protein expression;transcriptome sequencing;translational study;v-myc Gene

public_health_relevance:
Brain chronic inflammation is a hallmark of the aging process and promotes the progression ofmany brain diseases and there is currently no approved therapy for preventing brain chronicinflammation. The focus of this application is to determine the molecular mechanism throughwhich tiny nanoparticles derived from diet can interact with brain macrophages to inhibit braininflammation. Defining these underlying mechanisms will provide a strategy forprevention/treatment of brain aging and thus improve the health status.


application_id: 10668336
project_number: 5KL2TR001996-07
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2023-06-23
opportunity_number: PAR-18-940
application_type: 5
activity_code: KL2
ic: TR
serial_number: 001996
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2026-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  KL2 INSTITUTIONAL CAREER DEVELOPMENT The University of Kentucky Center for Clinical and Translational Science (CCTS) proposes to sustain andenhance the current KL2 program currently in its ninth year of National Institutes of Health (NIH) support. Byproviding two to three years of release time (75% effort) and research funding support for mentored careerdevelopment the program is designed to accelerate the academic growth for the next generation of leaders inclinical and translational research (CTR). The program has four programmatic objectives: 1) to provide acurriculum that meets core training needs of CTR scholars 2) to support a mentored program of researchtraining that expedites development of research careers 3) to support personalized training programs thatexpedite CTR career development and 4) to provide continuous assessment and quality improvement of bothindividual scholar career development and overall KL2 program. The program has garnered strong institutionalsupport; across the nine years the initial two NIH-supported training slots have been expanded to seven slots(four NIH-supported three institutionally supported). The program supports career development of scholarswith research interests that cross the lifespan (prenatal through elderly) and the full spectrum of clinical andtranslational science including translational clinical community/policy studies and clinical and translationalresearch (CTR) methods/processes (e.g. biomedical informatics) focusing on a broad array of health topics.Scholars and mentors represent a wide range of disciplines and colleges including Medicine NursingDentistry Pharmacy Health Sciences Public Health Education Engineering and Arts and Sciences. Allprogram graduates (n=18) remain actively engaged in CTR have made important contributions to sciencethrough published research and have successfully competed for extramural funding with 14 as principalinvestigators. We are requesting renewed NIH support of four KL2 scholar training slots. The training of aminimum of three additional institutionally sponsored early-career scholars will continue to be fully integratedwith these NIH-supported scholars to sustain a cohort of at least seven scholars. The foundation of theproposed program will continue to be practical research experiences within multidisciplinary teams guided byexperienced mentors with a Faculty Oversight Committee monitoring the successful career development ofthese future CTR leaders. Educational technology promotes vigorous yet efficient competency trainingprograms. Further our enhanced team science training programs will focus specifically on developingleadership skills. Institutionally sponsored pipeline programs targeting undergraduates medical studentsresidents fellows and clinical instructors several focused on underrepresented minorities will support theavailability of a strong and diverse pool of candidates for the KL2 program. In sum the KL2 program isaccelerating the career development of future leaders of the biomedical research workforce who are wellprepared to address todays complex research challenges and spearhead future advances in human health.

project_terms:
Acceleration;Address;Arts;Biomedical Research;Clinical;Clinical Research;Clinical Sciences;Communities;Competence;Complex;Dentistry;Discipline;Discipline of Nursing;Education;Educational Curriculum;Educational Technology;Elderly;Engineering;Extramural Activities;Faculty;Foundations;Funding;Future;Growth;Health;Health Sciences;Human;Individual;Institution;Kentucky;Leadership;Longevity;Medical Students;Medicine;Mentors;Monitor;Pharmacy facility;Policies;Principal Investigator;Process;Public Health;Publishing;Research;Research Methodology;Research Training;Science;Time;Training;Training Programs;Training Support;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;biomedical informatics;career;career development;clinical center;cohort;college;design;experience;improved;instructor;interest;multidisciplinary;next generation;prenatal;programs;research and development;skills;undergraduate student


application_id: 10667426
project_number: 5K01AG073698-02
administering_ic: NIA
award_notice_date: 2023-06-22
opportunity_number: PA-20-190
application_type: 5
activity_code: K01
ic: AG
serial_number: 073698
program_official: JOSEPH, LYNDON
project_start_date: 2022-08-01
project_end_date: 2027-06-30
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 12504171
contact_pi: SAMAAN, MICHAEL A
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Quantifying the Mechanism and Impact of Hip Extensor Muscle Dysfunction During Aerobic Exercise in Hip Osteoarthritis

project_abstract:
Project Summary/AbstractHip osteoarthritis (OA) impacts approximately 25% of the population over the age of 45 years. Currentconservative treatments include exercise-based programs yet these interventions are ineffective in reducinghip OA-related clinical and functional abnormalities. One limitation of these exercise programs is the lack ofevidence used to establish these treatment paradigms which leads to the ineffectiveness of these programs intreating hip OA. Current experimental protocols used to inform exercise programs for the hip OA populationlack precision in measuring hip joint muscular dysfunction. Therefore there is a need to establish anexperimental platform that can precisely measure hip joint muscular dysfunction. The novel experimentalplatform proposed in this application will be able to precisely assess hip muscle dysfunction and will provideclinicians with the evidence needed to develop effective multi-disciplinary exercise programs for conservativetreatment of symptomatic hip OA. The principal investigator (PI) of this K01 award will develop a novel multi-modal experimental platformthat will precisely measure the effects of hip extensor muscle dysfunction in patients with symptomatic hip OA.The PI will utilize novel imaging techniques and assessment of muscle torque development to assess thepathomechanism of hip extensor dysfunction in patients with symptomatic hip OA. The corresponding effectsof hip extensor dysfunction during aerobic exercise (mechanical stress test) will be assessed in patients withsymptomatic hip OA. Musculoskeletal simulations and serum-based biomarkers of cartilage health will be usedto quantify the changes that occur in hip joint contact forces and systemic cartilage turnover/synthesisrespectively during the mechanical stress test. These study results will be used to determine the relationshipof gluteus maximus muscle fibrosis and hip extensor rate of torque development with changes in hip loadingcartilage health and self-reported hip pain in the symptomatic hip OA population. Upon completion of this K01project the applicant will possess the knowledge needed to implement this novel experimental platform on alarge scale basis to assess the longitudinal relationship between hip extensor dysfunction with hip OA diseaseprogression in the subsequent R01 application. The PI has developed a strong training plan in aging muscle-imaging muscle-physiology andbiochemical biomarkers. The PI has established a diverse advisory committee with expertise in aging physicaltherapy biomechanics muscle-physiology exercise for OA biomarkers of OA and biostatistics. This K01-award will provide the PI with the training and resources needed to accomplish the goals of this project and willlead the PI towards a successful career as an independent investigator in aging-related research.

project_terms:
Advisory Committees;Aerobic Exercise;Age;Aging;Area;Biochemical;Biological Markers;Biomechanics;Biometry;Cartilage;Cartilage Matrix;Chronic;Clinical;Data;Degenerative polyarthritis;Development;Disease;Disease Progression;Elderly;Exercise;Exhibits;Extensor;Fibrosis;Functional disorder;Goals;Health;Hip Joint;Hip Osteoarthritis;Hip Pain;Hip region structure;Image;Intervention;Knee Osteoarthritis;Knowledge;Literature;Magnetic Resonance Imaging;Measures;Mechanical Stress;Mechanics;Mentored Research Scientist Development Award;Muscle;Muscle function;Musculoskeletal;Pain;Patient Self-Report;Patients;Physical therapy;Population;Principal Investigator;Protocols documentation;Recommendation;Research;Research Personnel;Resources;Serum;Stress Tests;Techniques;Therapeutic;Torque;Total Hip Replacement;Training;United States;Work;age related;aging population;career;chronic pain patient;comparison control;exercise intervention;exercise program;gait rehabilitation;improved;innovation;insight;joint loading;mammalian COMP;multidisciplinary;multimodality;muscle physiology;novel;novel imaging technique;preservation;programs;prospective;simulation;skills;symptom treatment

public_health_relevance:
Project NarrativeExercise-based programs for hip osteoarthritis (OA) lack scientific evidence and are ineffective inconservatively treating hip OA. Current experimental protocols are unable to precisely assess the underlyingpathomechanism of hip extensor dysfunction that is associated with abnormal hip joint mechanics hip pain andcartilage breakdown during exercise in hip OA. This study will lead to the development of a novel multi-modalexperimental platform consisting of magnetic resonance imaging muscle-function assessmentmusculoskeletal simulations and biochemical biomarkers which will be used to assess the pathomechanismand corresponding effects of hip extensor dysfunction during aerobic exercise in patients with symptomatic hipOA.


application_id: 10667157
project_number: 1R01AG082142-01
administering_ic: NIA
award_notice_date: 2023-04-10
opportunity_number: RFA-AG-23-010
application_type: 1
activity_code: R01
ic: AG
serial_number: 082142
program_official: YAO, ALISON Q
project_start_date: 2023-04-15
project_end_date: 2027-12-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (J1)]
contact_pi_person_id: 12467458
contact_pi: WANG, WANG-XIA
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
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: 2023-04-15
project_title:
MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulation in Alzheimers disease

project_abstract:
Project Title: MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulationin Alzheimers diseaseAbstractMicroRNAs (miRNA) are small non-coding regulatory RNA that have large impacts in health and disease.While prior studies have implicated miRNA in Alzheimers disease and associated dementias (ADRD) theyhave not been used yet in a successful therapeutic strategy. We discovered that microRNA-223 (miR-223) amiRNA residing on the X-chromosome which is enriched in microglia/macrophage cells regulates a sexuallydimorphic ApoE pathway via targeting CCAAT-enhancer-binding protein beta (CEBP). CEBP is an importantregulator of neuroinflammatory response and acts as a transcription factor mediating ApoE expression. Our recent data showed that deficiency of miR-223 resulted in a substantial female-biased elevation ofCEBP ApoE and a heightened inflammatory state in macrophages and in aged mouse brain following abrain injury. Thus miR-223 appears to regulate a sexually dimorphic microglia/macrophages-dependentincrease in inflammation and ApoE as brain cells become activated in parallel with age injury and/orAlzheimers disease-related pathology. We further demonstrated that miR-223 can be targeted using a novelmiRNA-liposome delivery system. Based on these exciting preliminary results the main goals of this proposalare to test the miR-223-CEBP pathway in regulating inflammation-triggered ApoE dysregulation in thebiological context of age sex and Alzheimers disease-relevant brain injury event; and to test the efficacy of anovel liposome-miRNA delivery method as a potential therapeutic strategy. To complete these objectives we will 1) confirm that miR-223 directly targets the CEBP-ApoE pathway inmyeloid cells and test whether liposome-miR-223 delivery affects this pathway; 2) test the miR-223-CEBP-ApoE pathway using a brain injury mouse model and target the pathway using the liposome miRNA deliverysystem in a novel miR-223 knockout mouse; 3) evaluate the miR-223-CEBP-ApoE pathway in human cells inparallel with neuropathological changes of Alzheimers disease. These studies will include assessments ofbrain tissue from the world-class University of Kentucky Alzheimers Disease Center biobank. Completion of the funded studies will extend our understanding of mechanisms regulatinginflammation/ApoE pathways in the context of sex aging and brain injury ultimately advancing treatments forAlzheimers disease. Filling these knowledge gaps could have a lasting impact on public health. Moreover ourinnovative miRNA-based therapeutic strategy targeting miR-223 provides a proof of efficacy for a new drugtarget particularly in females who are vulnerable for diseases associated with neuroinflammation and ApoEdysregulation including Alzheimers disease and other brain injury.

project_terms:
Acute;Affect;Age;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Apolipoprotein E;Behavioral Assay;Biochemical;Biological;Bone Marrow;Brain;Brain Injuries;CCAAT-Enhancer-Binding Protein-beta;Cell Separation;Cells;Data;Dementia;Disease;Event;Female;Funding;Genotype;Goals;Health;Histologic;Human;Human X Chromosome;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Injury;Intravenous;Kentucky;Knockout Mice;Knowledge;Late Onset Alzheimer Disease;Link;Liposomes;Macrophage;Mediating;Methods;MicroRNAs;Microglia;Modeling;Molecular;Mus;Myeloid Cells;Nerve Degeneration;Nervous System Physiology;Pathology;Pathway interactions;Proteins;Public Health;RNA;Regulation;Role;Sampling;Senile Plaques;Signal Transduction;System;Testing;Therapeutic;Therapeutically Targetable;Universities;Untranslated RNA;X Chromosome;aged;biobank;brain cell;brain tissue;efficacy testing;improved;in vivo;innovation;lipid nanoparticle;liposomal delivery;male;microRNA delivery;mouse model;neuroinflammation;neuropathology;new therapeutic target;novel;novel therapeutics;protein biomarkers;response;sex;sexual dimorphism;systemic inflammatory response;targeted treatment;therapeutic miRNA;transcription factor

public_health_relevance:
Project NarrativeThis project will reveal a novel mechanism regulating a female-biased neuroinflammation-trigged ApoEdysregulation pathway in the context of sex aging and brain injury. Furthermore this study will provide a proofof efficacy for a new drug target particularly in females who are vulnerable for diseases associated withneuroinflammation and ApoE dysregulation including Alzheimers disease and brain injury.


application_id: 10667102
project_number: 1R01AA030308-01A1
project_title: Sex and Sex Hormone Factors Influencing Acute Alcohol Effects on Sleep Physiology
administering_ic: NIAAA
award_notice_date: 2023-08-28
opportunity_number: PA-20-184
application_type: 1
activity_code: R01
ic: AA
serial_number: 030308
suffix: A1
program_official: KUMAR, SHAILESH
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS]
contact_pi_person_id: 12510124
contact_pi: WHITEHURST, LAUREN
other_pis: WEAFER, JESSICA J
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
project_abstract:
Rates of heavy drinking and Alcohol Use Disorder (AUD) are increasing in women at an alarming pace. Suchdrastic increases in drinking will have a significant negative impact on womens health. Unfortunately untilrecently heavy drinking has been considered a male-oriented problem and consequently research on alcohol-related harms in women has been minimal. One specific aspect of womens health that may be negativelyaffected by alcohol is sleep. Numerous studies in men show that although alcohol has an initial sedative effectit leads to frequent awakenings and impaired rapid eye movement sleep in the second half of the night.Preliminary evidence suggests that women experience similar impairment and that they may be even moresensitive to alcohol-disrupted sleep than men. Further in the general population women are at greater risk forinsomnia and sleep disturbances than men in part because womens sleep is sensitive to fluctuations inovarian hormones. Hormonal influences on sleep are especially pronounced in older women of latereproductive age. However the influence of sex and sex hormones on alcohol-disrupted sleep across thereproductive lifespan in women is unknown. Here we will determine the influence of sex menstrual cyclephase and sex hormones on alcohol-disrupted sleep in adults across the reproductive age range for women.Healthy women and men (age 21-45) will complete two pairs of experimental sessions in which they receive adose of alcohol (target BrAC = 100mg% intravenous) or placebo (saline) one hour prior to eight hours ofpolysomnographically-monitored sleep in the lab. Women will complete one alcohol-placebo session pairduring the mid-follicular phase of the menstrual cycle and one pair during the late luteal phase. Men willcomplete two session pairs at matched intervals. Participants will also complete two 5-day at-home monitoringperiods of naturalistic sleep and alcohol consumption patterns during the mid-follicular and late luteal phases.Sleep and alcohol use will be assessed with actigraphy daily sleep and wake diaries and alcohol wristsensors. We hypothesize that women will show greater disruption of sleep following alcohol than men and thatalcohol-disrupted sleep measured in lab with polysomnography and at-home with actigraphy will be morepronounced in the late luteal phase compared to the mid-follicular phase. We also expect that estradiol will benegatively associated with alcohol-disrupted sleep whereas progesterone will be positively associated withalcohol-disrupted sleep. This study will provide essential information regarding alcohol effects on sleep acrossthe reproductive age span in women and critically how these effects are moderated by sex menstrual cycleand fluctuations in sex hormones. Findings will directly inform future interventions aimed at reducing alcoholconsumption and the negative impacts of alcohol on sleep in women. Given the wide-ranging impact of sleepon other areas of function including cognition stress and well-being such interventions will have a substantialpositive impact on womens health.

project_terms:
21 year old;Acute;Adult;Age;Alcohol consumption;Alcohols;Area;Biosensor;Blood specimen;Cognition;Data;Dose;Estradiol;Future;General Population;Goals;Gonadal Steroid Hormones;Heavy Drinking;Home;Hormonal;Hormones;Hour;Impairment;Individual;Infusion procedures;Intervention;Intravenous;Laboratories;Longevity;Luteal Phase;Measures;Mediating;Menstrual cycle;Menstruation;Monitor;Ovarian hormone;Ovulation;Participant;Patient Self-Report;Pattern;Personal Satisfaction;Pharmaceutical Preparations;Phase;Placebos;Polysomnography;Prevention;Progesterone;REM Sleep;Reporting;Research;Research Personnel;Risk;Saline;Sex Differences;Sleep;Sleep disturbances;Sleeplessness;Stress;Wakefulness;Woman;Women's Health;Wrist;actigraphy;age effect;alcohol consequences;alcohol effect;alcohol monitoring;alcohol use disorder;behavioral pharmacology;breath alcohol measurement;design;diaries;drinking;experience;innovation;male;men;negative affect;older women;poor sleep;proliferative phase Menstrual cycle;rapid eye movement;reproductive;sedative;sensor;sex;sex cycle;sleep behavior;sleep physiology;sleep quality;sobriety

public_health_relevance:
The findings from this project will determine the degree to which sex and sex hormones influence alcoholeffects on sleep physiology. The results will inform future interventions aimed at reducing alcohol consumptionand the negative impacts of alcohol on sleep in women. Given the wide-ranging impact of sleep on other areasof function including cognition stress and well-being such an intervention will have a substantial positiveimpact on womens health.


application_id: 10666769
project_number: 1R01NS126228-01A1
project_title: The role of macrophage metabolism and age in recovery from spinal cord injury
administering_ic: NINDS
award_notice_date: 2023-05-26
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 126228
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2023-06-01
project_end_date: 2028-05-31
study_section: Special Emphasis Panel[ZRG1 CN-T (90)]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: PATEL, SAMIRKUMAR
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
project_abstract:
PROJECT SUMMARY/ABSTRACTThe average age at the time of spinal cord injury (SCI) has increased to 50.5 years old in the US. Observationsfrom several independent laboratories demonstrate that inflammation specifically sustained pro-inflammatorymacrophage activation contributes to age-related SCI deficits. In addition it was recently discovered that theefficacy of immunomodulatory SCI therapies is age-dependent. There is an urgent need to understand theage-dependent mechanisms of sustained pro-inflammatory macrophage activation in SCI. The purpose of thisproposal is to investigate the role of macrophage bioenergetics in age-dependent inflammation and SCIpathophysiology. The central hypothesis is that age-dependent impairments in macrophage metabolism drivepro-inflammatory macrophage activation and contribute to secondary injury after SCI. The premise is that thepyruvate dehydrogenase (PDH) pathway is a key regulator of pro- or anti-inflammatory macrophage activationas a connecting link between glycolysis (pro-inflammatory) or oxidative phosphorylation (OXPHOS i.e. TCA orKrebs cycle activity; anti-inflammatory). PDH kinase (PDK) regulates PDH thereby serving as the gatekeeperfor OXPHOS. The hypothesis to be tested is that PDK inhibition will drive metabolic processes (i.e. increasedOXPHOS) required for reparative macrophage activation and improved SCI recovery by PDK. Accordinglythree independent Aims are designed to selectively target macrophage metabolism mechanistically usingchimerization with PDK knockout mice and therapeutically using a newly generated liposomal drugformulation of dichloroacetate (DCA) a PDK inhibitor. 4 and 14-month-old mice will undergo T9 contusion SCIto model the current SCI demographic. Aim 1 will identify PDH as a bottleneck for SCI macrophagemetabolism using a newly optimized purification approach that allows for isolation of macrophages after SCIand assessment of extracellular acidification (ECAR i.e. glycolysis) and oxygen consumption (OCR i.e.OXPHOS) rates using the Seahorse bioanalyzer. Aim 2 will identify metabolic targets for macrophagedysfunction after SCI using state-of-the-art techniques including single-cell RNA-sequencing and in vivo StableIsotope-Resolved Metabolomics to determine the metabolic profiles of resident microglia and peripherallyderived macrophages. Aim 3 will identify PDK inhibition as a therapeutic target to treat SCI through evaluationof anatomic and functional recovery. Completion of the proposed work will identify ways to harness thereparative functions of CNS macrophages and improve clinical practice by refining translational treatmentstrategies including age as a potential influence in SCI treatment and recovery. Understanding the extent towhich metabolic activity regulates macrophage function will provide insight into age-dependent CNSinflammation thereby advancing the fields of neurotrauma neuroscience and aging. Macrophage metabolismis a contributing factor in a host of inflammatory conditions including cardiovascular disease diabetes canceretc. and the completion of the proposed aims will advance the study of human health on multiple fronts.

project_terms:
5 year old;Acetyl Coenzyme A;Age;Aging;Anatomy;Animal Model;Anti-Inflammatory Agents;Automobile Driving;Bioenergetics;Cardiovascular Diseases;Catalogs;Chronic;Citric Acid Cycle;Clinical;Data;Diabetes Mellitus;Dichloroacetate;Disease Progression;Dose;Drug Formulations;Evaluation;Fostering;Functional disorder;Gatekeeping;Genetic;Genetic Transcription;Genus Hippocampus;Gliosis;Glucose;Glycolysis;Health;Health Care Costs;Human;Impairment;In Vitro;Incidence;Individual;Inflammation;Inflammatory;Injury;Knockout Mice;Knowledge;Label;Laboratories;Link;Liposomes;Locomotor Recovery;Macrophage;Macrophage Activation;Malignant Neoplasms;Measures;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Microglia;Mission;Modeling;Mus;Myeloid Cells;Nervous System Trauma;Neurosciences;Outcome;Oxidative Phosphorylation;Oxygen Consumption;PDH kinase;Paralysed;Pathologic;Pathology;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Population;Public Health;Publishing;Pyruvate;Reaction;Recovery;Recovery of Function;Reporting;Research;Role;Secondary to;Sensory;Spinal Cord Contusions;Spinal cord injury;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Translating;United States National Institutes of Health;Work;age related;aged;axonal sprouting;clinical practice;clinically relevant;design;disability;experimental study;extracellular;immunomodulatory therapies;immunoregulation;improved;in vivo;inhibitor;injury recovery;innovation;insight;juvenile animal;kinase inhibitor;liposomal formulation;metabolic profile;metabolomics;neuroinflammation;neuronal survival;novel;pharmacologic;pyruvate dehydrogenase;repair function;response;single-cell RNA sequencing;stable isotope;therapeutic evaluation;therapeutic target;tissue repair;tool;translational impact;treatment strategy

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because the injured spinal cord does not heal properlyresulting in chronic paralysis and expensive health care costs for patients with spinal cord injuries. There arefew therapies for treating spinal cord injury and although there are increased incidences of injury in olderindividuals age is not considered in most research. The proposed research will examine age-relatedinflammatory mechanisms of spinal cord injury progression using a clinically relevant drug and is thereforerelevant to the part of the NIH mission that pertains to developing fundamental knowledge and applying thatknowledge to foster innovative research strategies to reduce the burden of human disabilities.


application_id: 10666485
project_number: 5R01MD016864-02
project_title: K-VAC: Kentucky Vaccinating Appalachian Communities
administering_ic: NIMHD
award_notice_date: 2023-07-07
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: MD
serial_number: 016864
program_official: JONES, NANCY LYNNE
project_start_date: 2022-07-15
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-HDM-V(90)]
contact_pi_person_id: 6914381
contact_pi: KIVINIEMI, MARC T
other_pis: CARDARELLI, KATHRYN MARIE
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTVaccination of adults is central to control of SARS-CoV-2/COVID-19 and multiple other infectious diseases.Failure to engage in vaccine uptake is a complex multilevel systems problem--individual factors such asfatalism lack of factual information medical and government mistrust and political affiliation are all knowninhibitors to vaccine uptake as are community factors such as lack of access limited delivery mechanismsand messages from untrusted communicators. Thus addressing vaccine hesitancy requires a multilevelintervention that aligns and addresses individual relational and structural elements to incorporate all of thenecessary and sufficient components to increase uptake. COVID-19 vaccine uptake among Appalachianresidents has been unacceptably low with rates plateauing months ago. Appalachian Kentucky encompassesa number of population characteristics that add up to a "perfect storm" for a vaccine hesitant population.Structurally the region is rural with many communities geographically isolated and lacking access to healthcare. This in addition to poverty low education and high levels of chronic disease place this population atsignificant risk of complications and mortality due to COVID-19 infection. In a population that historically hasdistrusted institutions vaccination interventions must leverage culturally appropriate community partnershipsand strategies. The purpose of this community-engaged study is to optimize SARS-CoV-2 vaccine uptake bythis highly vulnerable Appalachian Kentucky population. We will achieve three specific aims: Aim 1: Using acommunity-engaged approach elucidate: a) key themes for message content and framing that addressindividual-level factors b) trusted communicators to deliver culturally-sensitive messages and c) structuralbarriers to effective vaccine delivery as well determining to what degree such factors are community-specificversus more generalizable. Aim 2: Using a cluster randomized trial design assess the efficacy of a multilevelintervention that delivers individual-level target messaging tailored for theme and presentation by trusted localcommunicators AND that provides structural components to facilitate easy and acceptable access tovaccination delivery. Aim 3: Determine the process factors that affect reach acceptance and implementationfidelity for the intervention components as well as necessary adaptation components for broadertransferability dissemination and delivery of the intervention. Our long-term goal as a research team is todevelop effective multilevel intervention strategies that can be used to address vaccine hesitancy inAppalachian and similar rural populations for existing vaccination concerns.

project_terms:
2019-nCoV;Achievement;Address;Adult;Affect;Appalachian Region;Behavior;COVID-19;COVID-19 mortality;COVID-19 prevention;COVID-19 vaccine;Chronic Disease;Cluster randomized trial;Communicable Diseases;Communities;Community Health Aides;Community Relations;Complex;Education;Educational Status;Elements;Emerging Communicable Diseases;Epidemic;Face;Failure;Future;Geography;Goals;Government;Health Personnel;Health protection;Individual;Influenza;Infrastructure;Institution;Intervention;Kentucky;Medical;Obesity;Obstructive Lung Diseases;Persons;Politics;Population;Population Characteristics;Poverty;Preparation;Prevalence;Process;Public Health;Research;Research Personnel;Respiratory Disease;Risk;Rural;Rural Population;SARS-CoV-2 infection;Safety;Series;Source;System;Trust;Unemployment;Vaccinated;Vaccination;Vaccines;community based participatory research;community organizations;community partnership;community-level factor;distrust;effectiveness measure;efficacy evaluation;experience;falls;health care availability;health care delivery;health goals;implementation fidelity;indexing;inhibitor;intervention delivery;prevent;smoking prevalence;tailored messaging;transmission process;trial design;uptake;vaccination strategy;vaccine acceptance;vaccine access;vaccine delivery;vaccine efficacy;vaccine hesitancy;vaccine safety;vulnerable community;willingness

public_health_relevance:
NARRATIVESuccessful vaccination to prevent COVID-19 requires that people be willing to be vaccinated and thatthe vaccine be easy and accessible for them to obtain. Appalachian Kentucky is a regionexperiencing high vaccine hesitancy an important challenge that need to be addressed to reduceCOVID-19 rates. We will study ways of simultaneously addressing willingness to be vaccinated andvaccine accessibility and see if addressing those problems increases vaccine uptake.


application_id: 10666355
project_number: 5R21EB032515-02
administering_ic: NIBIB
award_notice_date: 2023-04-06
opportunity_number: PAR-20-084
application_type: 5
activity_code: R21
ic: EB
serial_number: 032515
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2022-08-01
project_end_date: 2025-04-30
study_section: Emerging Imaging Technologies and Applications Study Section[EITA]
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Non-destructive optical spectroscopic assay for high-throughput metabolic characterization of in vitro cell models  and patient-derived organoids

project_abstract:
AbstractTo maximize cancer patients survival rate post-therapy in vitro immortal cancer cell models and newlydeveloped patient-derived organoids are widely used to study the role of tumor metabolism reprogramming intumor growth and survival under therapeutics stresses. Although conducting longitudinal metabolicmeasurements on the same tumor sample during a course of therapy is critical for therapeutic studies thereare surprisingly few techniques that can provide a systems-level view of tumor metabolism on in vitro cancermodels or organoids non-destructively. Several metabolic tools such as Seahorse Assay and Metabolomicsprovide standardized metabolic measurements but often require destructive sample preparation. Relying onthe non-invasive nature of optical technique this proposal seeks to fill the critical technical gap by developingan optical spectroscopic assay that will enable non-destructive high-throughput metabolism measurement on invitro cancer models and organoids for cancer research. Specifically we will develop a novel multi-channelfluorescence spectroscopic assay and a machine learning de-convolution algorithm to quantify the keymetabolic parameters of in vitro cancer models (Aim 1). As there is a significant unmet clinical need for breastcancer (BC) radiotherapy (RT) sensitivity evaluation prior to treatment we will demonstrate our non-destructiveassay for early prediction of BC radiation responses within the decision-making window via longitudinalmetabolic characterization of patient-derived organoids under radiation stresses (Aim 2). Our technology fillsan important gap that exists between Seahorse Assay (in vitro cells) and Metabolomics (in vitro cells and exvivo tissue) by providing a novel approach for non-destructive metabolism measurement on in vitro cancermodels and patient-derived organoids. Our innovative RT sensitivity prediction model will directly impact BCpatients by providing a novel paradigm for patients RT sensitivity prediction during the decision-makingwindow. Once we demonstrate the proof-of-concept of our optical technique and the RT sensitivity predictionmodel we will move our study to a large-scale trail in clinics with a goal of providing individualized RT for BCpatients in our future R01 plan.

project_terms:
4T1;Algorithms;Biological Assay;Biological Markers;Biomedical Research;Breast Cancer Model;Breast Cancer Patient;Cancer Model;Cancer Patient;Cell Line;Cell model;Cells;Clinic;Clinical;Control Groups;Convulsions;Decision Making;Evaluation;Fatty Acids;Fiber;Fluorescence;Future;Genus Hippocampus;Goals;In Vitro;Incubated;Light;Machine Learning;Matrix Metalloproteinases;Measurement;Measures;Membrane Potentials;Metabolic;Metabolism;Modeling;Nature;Optics;Organoids;Outcome;Patients;Performance;Preparation;Radiation;Radiation Tolerance;Radiation therapy;Reader;Regimen;Role;Sampling;Siblings;Source;Specimen;Spectrum Analysis;Standardization;Stress;Survival Rate;System;Techniques;Technology;Testing;Therapeutic;Therapeutic Studies;Time;Tissues;Update;Work;anticancer research;cancer cell;cancer radiation therapy;cancer therapy;experience;experimental group;fluorophore;glucose uptake;high throughput screening;improved;in vivo;indexing;innovation;machine learning algorithm;malignant breast neoplasm;metabolomics;mitochondrial membrane;new technology;novel;novel strategies;pilot test;pre-clinical;preclinical study;predictive modeling;programs;radiation response;radioresistant;tool;tumor;tumor growth;tumor metabolism;uptake

public_health_relevance:
PROJECT NARRATIVEThe goal of this program is to develop a high-throughput optical assay that enables non-destructive metaboliccharacterization of in vitro cell models and organoids for biomedical applications. We will demonstrate ourassay for early prediction of breast cancer radiation sensitivity within the decision-making window vialongitudinal metabolic characterization of patient-derived organoids under radiation stresses. The proposedwork will impact the biomedical research by providing a novel tool for non-destructive metabolic measurementof cell and organoid models and a novel paradigm for cancer patients radiotherapy sensitivity prediction.


application_id: 10665862
project_number: 1R21NS128749-01A1
project_title: Development of a Novel Animal Model for Spinal Cord Injury with Sepsis
administering_ic: NINDS
award_notice_date: 2023-04-14
opportunity_number: PA-21-219
application_type: 1
activity_code: R21
ic: NS
serial_number: 128749
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2023-04-15
project_end_date: 2025-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11775081
contact_pi: PATEL, SAMIRKUMAR
other_pis: SAITO, HIROSHI
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
project_abstract:
Summary AbstractSepsis is a predominant life-threatening secondary complication following traumatic spinal cord injury (SCI).Several predisposing factors such as polytrauma prolonged/repeated hospital stay pressure ulcer andindwelling catheters make SCI patients more susceptible to microbial infections that can lead to sepsis. Sepsisis a leading cause of death after spinal trauma and is associated with poor functional outcomes among survivors.Depending on the time of onset there are two sepsis types. Sepsis diagnosed within 48hr of initial injury istermed primary sepsis and when its onset occurs after 48hr it is known as secondary sepsis. Though sepsiswith SCI is a serious condition leading to diminished life expectancy and quality of life this combined medicalissue has not been well studied. This is mainly due to lack of an appropriate animal model. Accordingly the goalof proposed study is to develop and validate a novel clinically relevant rodent model that closely mimics the long-term dysfunction of survivors of sepsis after SCI. This model will be validated with six parameters: 1) survivalrate 2) infection severity 3) inflammatory cytokines 4) locomotor score 5) muscle force and 6) histopathology.Our team has developed a clinically relevant rodent sepsis model consisting of polymicrobial abdominal sepsisby cecal slurry (CS) injection followed by a delayed but repeated ICU-like resuscitation procedure with fluids andantibiotics; this refined model allows us to investigate long-term physical dysfunction among sepsis survivors.Our main approach is to combine this long-term sepsis survivor model with rat spinal contusion model to mimiceither primary (Aim 1) or secondary (Aim 2) sepsis after SCI. Our central hypothesis is that the cumulativeeffects of sepsis plus SCI will impair spontaneous motor recovery limit spinal cord tissue sparing exacerbateskeletal muscle weakness and increase mortality. Two specific Aims are designed to test this hypothesis. InAim 1 we will induce sepsis immediately after SCI to mimic primary sepsis by CS injection followed by ICU-like resuscitation initiated at 8 hrs. To mimic secondary sepsis in Aim 2 we will induce sepsis at 6 weeks afterSCI by CS injection and resuscitation initiated at 8hrs after sepsis induction. SCI animals in Aim 1 will undergoweekly locomotor testing for 6 weeks and in Aim 2 for a total of 12 weeks (6 weeks before sepsis induction and6 weeks after) to assess spontaneous recovery. After final locomotor assessments survivors will be subjectedto ex vivo muscle force testing histological examination and mitochondrial function analyses to assess muscleweakness. Spinal cord tissue will be used for quantitative histology of spared gray and white matter as well aslesion volume that will be correlated with locomotor recovery. Successful development of this model will allowus to investigate detailed molecular/physiological mechanisms of sepsis following SCI with a long-term goal ofdeveloping therapeutic strategies to improve quality of life in the afflicted population. Success of this project isassured by our strong multi-disciplinary team including Drs. Patel (MPI SCI researcher) Saito (MPI sepsisresearcher) Butterfield (Co-I muscle researcher) and Stromberg (Co-I biostatistician).

project_terms:
Abdomen;Acute;Address;Affect;Animal Model;Animals;Antibiotics;Biochemical;Blood;Cause of Death;Clinical;Complication;Contusions;Development;Diagnosis;Functional disorder;Goals;Histologic;Histology;Histopathology;Hospitalization;Impairment;Individual;Indwelling Catheter;Infection;Inflammatory;Injections;Injury;Left;Length of Stay;Lesion;Life;Life Expectancy;Liquid substance;Locomotor Recovery;Medical;Mitochondria;Modeling;Molecular;Multiple Trauma;Muscle;Muscle Weakness;Outcome Measure;Phase;Physiological;Population;Predisposing Factor;Predisposition;Procedures;Quality of life;Rattus;Recovery;Recovery of Function;Research Personnel;Research Proposals;Resuscitation;Rodent;Rodent Model;Secondary to;Sensory;Sepsis;Severities;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Spleen;Sports;Survival Rate;Survivors;Testing;Therapeutic;Time;Tissues;Trauma;Vertebral column;Violence;body system;catheter associated UTI;clinically relevant;cytokine;decubitus ulcer;design;falls;functional outcomes;gray matter;improved;inflammatory marker;innovation;microbial;model development;mortality;motor recovery;multidisciplinary;novel;skeletal muscle weakness;success;vehicular accident;white matter;young adult

public_health_relevance:
NARRATIVESepsis is a predominant secondary complication that affects quality of life and reduces life expectancy in spinalcord injury (SCI) populations. Although sepsis after SCI is an existing clinical condition this medical issueunfortunately is understudied due to lack of good animal models. Accordingly the current innovative proposal isdesigned to develop for the first time a novel rat model of sepsis survivors following SCI to study compromisedfunctional recovery as well as damage to various tissue/organ system(s) due to the compounding effects of SCI-sepsis.


