# projects

application_id: 11534265
project_number: 6U01DP006632-05M002
administering_ic: NCCDPHP
award_notice_date: 2026-04-21
opportunity_number: RFA-DP-21-001
application_type: 6
activity_code: U01
ic: DP
serial_number: 006632
suffix: M002
project_start_date: 2021-05-01
project_end_date: 2027-04-30
study_section: ZDP1-KVA(02)
contact_pi_person_id: 10799084
contact_pi: JEWELL, TRACEY DANIELLE
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_title:
DP21-001 Kentucky Pregnancy Risk Assessment Monitoring SystemApplication for Core PRAMS funding RFA-DP-21-001

project_abstract:
Project SummaryThe Kentucky Department for Public Health (KDPH) is applying for Component A CoreSurveillance for the Pregnancy Risk Assessment Monitoring System. This application is inresponse to Notice of Funding Opportunity RFA-DP-21-001.

public_health_relevance:
Project NarrativeThe Kentucky Department for Public Health (KDPH) is seeking to conduct on-going corePRAMS surveillance among women with a recent live birth. The KDPH will conduct PRAMSsurveillance according to the CDC approved PRAMS protocols and implement surveysupplements to respond to emerging issues when needed.


application_id: 11513763
project_number: 1P20GM156679-01
project_title: Novel role of PAQR4 in Pancreatic Beta Cell Function and Type 2 Diabetes
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
program_official: BASKIR, RUBIN SAM
project_start_date: 2026-03-12
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 6272
contact_pi_person_id: 12157122
contact_pi: ZHU, QINGZHANG
other_pis: NIKOLAJCZYK, BARBARA
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Insulin secretion from pancreatic -cells is essential for maintaining glucose homeostasis a process frequently disrupted in obesity-related type 2 diabetes (T2DM). Despite ongoing therapeutic advances the prevalence of diabetes among U.S. adults rose to 15.8% in 2023 and current treatments including GLP-1- based therapies remain limited by side effects and inconsistent responsiveness. PAQR4 is an orphan receptor in the progestin and adiponectin receptor family (PAQR1-11) with a poorly defined role in metabolic diseases. We recently uncovered a novel role of PAQR4 in metabolic regulation by mediating ceramide homeostasis. PAQR4 promotes ceramide accumulation by regulating ceramide synthases. In adipocytes PAQR4 overactivation impairs adipose tissue function and causes insulin resistance whereas its deficiency lowers ceramide levels and improves insulin sensitivity in obesity. Elevated ceramides a class of bioactive sphingolipids promote lipotoxicity and drive -cell dysfunction in T2DM. Our preliminary data show that PAQR4 expression in human islets increases with hyperglycemia and correlates negatively with INS (insulin) and GLP1R (GLP-1 receptor) but correlates positively with HbA1c levels. Supporting this our pilot data in mice show that Paqr4 overexpression specifically in -cells induces hyperglycemia and reduces insulin secretion and GLP-1 action. Based on these data we hypothesize that PAQR4 is a key regulator of -cell function by mediating ceramide metabolism while chronic metabolic stress disrupts PAQR4-mediated ceramide balance and drives -cell dysfunction. In Aim1 we will determine the impact of PAQR4 on -cell function and systemic glucose homeostasis during metabolic stress. We will use human islets alongside our newly developed inducible -cell-specific gain- and loss-of-function mouse models to temporally investigate the role of PAQR4 in -cell function islet remodeling and systemic metabolism. In Aim2 we will investigate how PAQR4 influences ceramide homeostasis and GLP-1 signaling in -cell function. We will examine how PAQR4-mediated ceramide imbalance drives -cell dysfunction by regulating cellular stress insulin secretion and cell survival in mouse and human islets and how activation the PAQR4-ceramide axis affects GLP-1R signaling and whether combining GLP-1R agonists with ceramide-targeting interventions improves -cell function. Successful results in these studies will provide considerable mechanistic insights into ceramide homeostasis and -cell function and establish PAQR4 as a valuable therapeutic target for improving metabolic disorders associated with ceramide dysregulation.


application_id: 11472160
project_number: 7R13FD008332-02
administering_ic: FDA
award_notice_date: 2026-03-20
opportunity_number: PAR-23-072
application_type: 7
activity_code: R13
ic: FD
serial_number: 008332
program_official: HEAD, DANIELLE
project_start_date: 2024-09-20
project_end_date: 2025-08-31
study_section: ZFD1-ORA-T(06)
contact_pi_person_id: 14385418
contact_pi: SCHAUER, GILLIAN L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 047905955
primary_uei: MRJ5C114CPT4
duns_number: 047905955
uei: MRJ5C114CPT4
fips: US
organization_id: 1360301
organization_name: COUNCIL OF STATE GOVERNMENTS
organization_city: LEXINGTON
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 405118536
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-01-15
project_title:
Cannabis Regulators Association 2024 Annual Member Meeting: Furthering Regulatory Exchange and Collaboration

project_abstract:
PROJECT SUMMARY / ABSTRACTCannabis-related policy changes in the US and abroad have outpaced science and research about the impactsdifferent potential regulatory approaches have on consumer safety public health equity and other outcomes.Convening regulators from different government jurisdictions to discuss lessons learned and emergingchallenges in cannabis policy and regulation has never been more important. The Cannabis RegulatorsAssociation (CANNRA) is a nonpartisan nonprofit 501(c)(4) association of government agencies engaged incannabis cannabinoid and hemp regulation and policy implementation across 45 states and U.S. territoriesCanada and the Netherlands. The current proposal requests funding to support CANNRAs 2024 AnnualMember Meeting a unique event that brings together government officials to discuss different regulatory issuesshare new approaches being taken in their jurisdictions troubleshoot challenges and build new skills andconnections to support their ongoing government regulatory work. The meeting is restricted to governmentofficials only to ensure open sharing and exchange across government jurisdictions. The meeting has twospecific aims: Aim 1 is to improve regulatory science by identifying discussing and debating emerging researchand practice-based outcomes in cannabinoid policy and regulation and Aim 2 is to develop and foster skills thatgovernment regulators can use to implement policies that protect public health and consumer safety. Meetingcontent is guided by CANNRAs Executive Director and PI Dr. Gillian Schauer and a Meeting OrganizingCommittee comprised of the lead cannabis and/or hemp regulators from seven diverse states (CA CO GA ILMD MO OK). They work closely with CANNRA Voting Members (key designees from each CANNRA-memberjurisdiction) and co-chairs from CANNRAs twelve different standing committees to develop and facilitate themeeting content. Session and workshop moderators are all CANNRA member government officials and the PIand Organizing Committee work with moderators to identify panelists who represent diverse perspectives.Agenda topics are selected using input from past year Member Meeting participants and CANNRA Membersand include skill-based workshops to improve and enhance the skillset regulators can apply to their work. Paneldiscussions and workshops are directly relevant to FDAs mission and the mission of the FDA Office ofRegulation and will cover topics that include: cannabinoid hemp products and policies; cannabinoid productsafety and lab testing; product standards; packaging and labeling regulations; technology and cannabis; datamonitoring; using science to inform policy; public health and youth prevention; and more. CANNRA directlyinvites over 900 government staff who participate in CANNRA through our online collaboration platform andSpecial Committees. Following the Meeting CANNRA will disseminate findings and take-aways to governmentofficials by recording key sessions and making them available to government regulators who cannot attend inperson and by conducting meeting report outs through CANNRA committees.

public_health_relevance:
PROJECT NARRATIVELaws legalizing cannabis use for adults have increased exponentially across the U.S. since 2010 with 38 statesthe District of Columbia (D.C.) and four U.S. territories legalizing cannabis for medicinal use and 24 of thosestates D.C. and three U.S. territories also legalizing cannabis for non-medical (recreational) use. Policy changehas outpaced scientific research and in the absence of federal legalization of cannabis states have takendifferent policy approaches providing a natural experiment that can lend insight into how policies impactconsumer safety public health and equity. The Cannabis Regulators Association is a nonpartisan associationof government agencies regulating cannabis and/or hemp. CANNRAs 2024 Annual Member Meeting bringstogether over 200 agency officials and their staff to share emerging practices and develop skills to advanceregulatory science.


application_id: 11446855
project_number: 7R01NS121191-06
project_title: Hemodynamic basis for secondary cervical grey matter tissue loss after spinal cord injury
administering_ic: NINDS
award_notice_date: 2026-02-26
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: NS
serial_number: 121191
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-05-15
project_end_date: 2027-03-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 8201225
contact_pi: KHAING, ZIN Z
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Currently there is no known treatment to limit and/or protect the injured spinal cord from secondarydamage in patients with spinal cord injury (SCI). More than 60% of SCIs occur at the cervical spine resulting inrespiratory dysfunction and quadriplegia which is the paralysis of all four limbs severely affecting patients'quality of life. A therapeutic strategy that can reduce grey matter tissue loss could have dramatic andmeaningful functional outcomes for patients with cervical SCI. The overall objective of this proposal is toexamine and evaluate critical blood flow parameters that can reduce grey matter loss for improved functionalrecovery after cervical SCI in a rodent model. Acutely after traumatic SCI a complete loss of blood flow occurs at the injury center and is thought tobe a major contributor of the injury expansion during the secondary phase. Improving blood flow to the lesioncenter and adjacent tissue has long been considered desirable to mitigate the loss of neural tissue. Howeveruntil recently there were no techniques available to monitor spinal cord blood flow in vivo in real-time.Recently we have developed a novel intravital ultrafast ultrasound imaging technique to visualize spinalblood flow in real-time with unprecedented spatial and temporal resolution. This new technology has createda unique opportunity to evaluate local spinal hemodynamic changes in real-time. Recent work from our grouphas shown that ultrafast ultrasound can 1) detect distinct areas of perfusion loss in both the grey and whitematter 2) evaluate quality of peri-lesional blood flow and 3) visualize patent spinal vessel morphology (down to~ 50 micrometer) in a rat thoracic SCI model. Excitingly we have now extended this work to include non-invasive 3D image acquisitions allowing us to monitor blood flow changes within the injured spinal cordin 4D (3D imaging with time). In addition to the loss of blood flow at the lesion center injury areas oftenexperience progressive hemorrhaging resulting in an expanding hematoma. We hypothesize that reducingthe propagation of intraparenchymal hemorrhage and reducing elevated intraspinal pressure after SCIcan improve spinal tissue perfusion and mitigate secondary grey matter loss for improved functionaloutcomes. Importantly because there are known sex differences in cerebral blood flow and response to spinalcord injury we will examine the hemodynamic changes after cervical SCI in both males and females. Byapplying this innovative ultrasound imaging we aim to (1) discover critical perfusion thresholds for grey mattertissue at risk (2) monitor spatial and temporal development of the intraparenchymal hematoma and (3)evaluate treatment effects of reducing raised intraspinal pressure in real-time. Overall these studies willprovide direct insights into the critical hemodynamic changes within the microcirculation of the spinal cord aswell as effective ways of limiting secondary grey matter damage for improved functional recovery after SCI.

public_health_relevance:
PROJECT NARRATIVEThe major goal of this project is to gain better insights into blood flow changes that underlie grey matter lossduring the secondary damage after cervical spinal cord injury. Limiting hemorrhage and surgicaldecompression are considered as strategies for improving grey matter damage and functional recovery.


application_id: 11412383
project_number: 5P20GM125504-08
administering_ic: NIGMS
award_notice_date: 2025-02-24
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
program_official: CUPIT, PAULINE
project_start_date: 2025-09-09
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3(C2)
subproject_number: 8361
contact_pi_person_id: 79184346
contact_pi: GHODS, SHIRIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Cobalamin serves as a key redox-active mediator protecting Porphyromonas gingivalis from oxidative stress.

project_abstract:
Cobalamin (vitamin B12) is critical for bacterial adaptation and pathogenesis aiding redox management during host defenses including reactive oxygen species (ROS). Periodontal pathogens such as Porphyromonas gingivalis (Pg) rely on homologs of the Btu transporter for cobalamin uptake but the mechanisms and impact remain largely unexplored. This study investigates how cobalamin uptake via the Pg Btu transporter regulates stress responses and pathogenesis. Preliminary data demonstrate that cobalamin enhances Pg's survival under oxidative stress promotes biofilm formation and upregulates virulence factors like gingipains. we hypothesize that cobalamin can provide a powerful tier of stress response regulation during Pg pathogenesis through a homolog of the Btu (cobalamin) transporter by which Pg uptakes cobalamin and utilizes it to resist oxidative stress and promote pathogenesis. This grant proposal aims to reveal the mechanisms underlying cobalamin uptake by the Pg Btu transporter and its role in resistance to oxidative stress and pathogenesis. This hypothesis will be investigated through two specific aims.  Aim 1. The impact of the Pg Btu cobalamin transporter on resistance to oxidative stress. Investigate the role of the PGN_0704 (btu) gene in cobalamin uptake under H2O2 stress using gene expression analysis and knockout mutants.  Aim 2. Understanding the impact of cobalamin uptake on Pg pathogenesis and virulence potential. Examine how cobalamin uptake via the Btu transporter influences gingipain activity and the colonization and invasion potential of Pg using an in vitro cell model.  The results will yield essential insights into the molecular mechanisms of cobalamin-mediated pathoadaptations in strictly anaerobic pathogens.

project_terms:
Applications Grants;Cell model;Cobalamin;Data;Gene Expression Profiling;Genes;Homologous Gene;Host Defense;In Vitro;Inflammation;Invaded;Knock-out;Mediating;Mediator;Microbial Biofilms;Molecular;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathogenicity;Porphyromonas gingivalis;Reactive Oxygen Species;Regulation;Resistance;Role;Stress;Virulence;Virulence Factors;Vitamin B 12;biological adaptation to stress;gingipain;insight;microbiome research;mutant;pathogen;periodontopathogen;uptake


application_id: 11412333
project_number: 75N93025C00020-0-9999-1
project_title: A more durable and universal adjuvanted influenza vaccine through synthetic biology
administering_ic: NIAID
project_start_date: 2025-06-01
project_end_date: 2027-05-31
contact_pi_person_id: 80314300
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:
Technology to develop and produce vaccines that offer broader protection against constantly mutating pathogens has been a continuing challenge. Formulating adjuvants with new antigens can result in elevated immune responses leading to better and longer protection. Yet despite  the advantages of delivering vaccines with adjuvants such deployment has been hindered. This is because of limited availability of cGMP adjuvants for clinical trials and overarching intellectual property (IP) and freedom-to-operate (FTO) constraints. Now that the IP/FTO landscape for proven adjuvants has opened innovations in adjuvant formulations and antigen design have emerged as important strategies in addressing worldwide seasonal influenza outbreaks. Enepret Inc. has developed mimics of widely used oil-in-water emulsion adjuvants (EVAX emulsions) which can be manufactured sustainably and limitlessly under cGMP conditions. These emulsions will be preclinically evaluated with innovative toll-like receptor agonists (TLR4: BECC470 and TLR9: CpG55.2) and novel universal and commercially available seasonal influenza antigens for immune response breadth and efficacy. These evaluations will lead to selection of the most promising combination of adjuvants/influenza antigen to take forward which can proceed without impediments from FTO constraints. Critically these adjuvants combination can be available as cGMP-grade products advanced in clinical trials and deployed for more efficacious and durable vaccinations.

project_terms:
Address;Adjuvant;Agonist;Animal Model;Antigens;Biological Assay;Clinical Trials;Cyclic GMP;Data;Emulsions;Evaluation;Formulation;Freedom;Ha antigen;Histocompatibility Antigens Class II;Immune response;Immunoglobulins;Influenza;Intellectual Property;Measures;Mus;Mutate;Oils;Particle Size;Phase;Phase I Clinical Trials;Property;Recommendation;Seasons;Technology;Toll-like receptors;Vaccinated;Vaccination;Vaccine Production;Viral;Virus;Water;cross immunity;design;dosage;influenza outbreak;influenza virus vaccine;innovation;manufacture;novel;particle;pathogen;pre-clinical;pre-clinical assessment;safety study;seasonal influenza;synthetic biology;vaccine candidate;vaccine delivery;vaccine development;zeta potential


application_id: 11408075
project_number: 3R01HL163818-04S1
project_title: Systematic identification of cardiotoxic e-cigarette flavorants
administering_ic: NHLBI
award_notice_date: 2025-09-11
opportunity_number: RFA-OD-21-002
application_type: 3
activity_code: R01
ic: HL
serial_number: 163818
suffix: S1
program_official: POSTOW, LISA
project_start_date: 2022-04-22
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-E(56)R]
contact_pi_person_id: 11702638
contact_pi: CARLL, ALEX PERROW
other_pis: NYSTORIAK, MATTHEW A
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
AbstractThe use of e-cigarettes (e-cigs) has increased substantially since they were first introduced in 2003. E-cigdevices aerosolize e-liquids that typically consist of humectants with variable levels of nicotine and flavoringchemicals. Although there are thousands of commercially available flavor mixtures they routinely overlap inindividual flavor chemicals (flavorants) which are far fewer in number. Many of these flavorants belong tocommon chemical classes and are generally recognized as safe for ingestion. However their direct and indirectcardiac effects following heating and inhalation particularly in combination with nicotine remain mostly unknown.Direct exposure to nicotine alone distinctly affects the cardiac action potential waveform potentially contributingto the high incidence of arrhythmias and sudden cardiac death among smokers. Recent evidence also suggeststhat nicotine in e-cigs may similarly promote adverse cardiac outcomes. Yet the influence of flavorants on thecardiac effects of e-cig aerosols remains untested. In our ongoing work we found that exposure to nicotine-containing e-cig aerosols of various flavors acutely and differentially altered the electrocardiogram (ECG) in micevariably inducing QT interval prolongation increasing heart rate and evoking arrhythmia. As well two separatee-liquids with the same characterizing flavorant consistently increased ventricular arrhythmias. Furthermore weobserved in cardiomyocytes that treatment with several flavorants common to e-cigs directly altered contractilityrhythmicity and action potential duration. Nonetheless it remains unknown how individual flavorants in e-cigaerosols exert direct or indirect cardiac effects in vivo. Considering the growing popularity of e-cigarettes andthe urgent need for studying the in vivo toxicological profile of constituents in these products we propose to testthe hypothesis that e-cigarette flavorants modify the effects of e-cig aerosol exposures on cardiacelectrophysiology leading to arrhythmias and functional remodeling of the heart. To test this we willsystematically identify both acute and long-term effects of flavorant exposure on cardiac electrophysiology usinga combination of state-of-the-art in vivo in vitro and ex vivo approaches. Specifically we will: 1) Identify theacute effects of flavored e-cig aerosol inhalation on cardiac electrophysiology in vivo 2) Examine thedirect impact of flavorants on cardiac electrophysiology in vitro and ex vivo and 3) Elucidate deleteriousimpacts of acute and chronic flavorant aerosol exposure on cardiac electrophysiology structure andfunction. These studies which are responsive to the research priorities of the FDA/CTP will provide new datashowing how different flavor chemicals affect cardiac excitability and potentially promote arrhythmogenesis.Such results would aid in formulating policies regulating the manufacture distribution and marketing of flavorede-cigarettes.

project_terms:
Action Potentials;Acute;Adult;Adverse effects;Aerosols;Affect;Aldehydes;Arrhythmia;Biological;Biological Assay;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac Myocytes;Cardiotoxicity;Cardiovascular Physiology;Cardiovascular system;Cessation of life;Chemicals;Chronic;Circulation;Conscious;Consumption;Data;Dependence;Devices;Dose;Electrocardiogram;Electronic cigarette;Electrophysiology (science);Emerging Tobacco Products;Equilibrium;Evaluation;Exposure to;Female;Flavoring;Food Additives;Functional disorder;Future;Heart;Heart Rate;Heating;Human;In Vitro;Incidence;Individual;Ingestion;Inhalation;Knowledge;Link;Long-Term Effects;Lung;Malignant Neoplasms;Marketing;Modeling;Monitor;Mus;Negative Finding;Nicotine;Oral Ingestion;Outcome;Pathologic;Pathway interactions;Performance;Periodicity;Policies;Prevalence;Propylene Glycols;Regulation;Research Priority;Risk;Safety;Serum;Smoker;Smoking;Solvents;Structure;Sum;Testing;Tissues;Toxic effect;Toxicology;Toxin;Ventricular;Ventricular Arrhythmia;Work;Youth;aerosolized;air filter;clinical predictors;e-cigarette aerosols;electronic cigarette use;electronic cigarette user;electronic liquid;experimental study;heart cell;heart function;high risk;in vivo;male;manufacture;nicotine exposure;respiratory;response;stem;sudden cardiac death;tobacco products;tobacco regulatory science;vegetable glycerin

public_health_relevance:
Project NarrativeElectronic cigarettes (e-cigs) aerosolize a mixture of chemical solvents flavor additives and nicotine andinhalation of the resultant aerosol by e-cigarette users has unknown effects on the heart. In this project we willexamine how specific flavoring chemicals that are inhaled during e-cigarette use impact the function of mouseand human heart cells and tissues. Ultimately this study will advance knowledge of the toxicity of e-cigaretteswhich will direct new regulation of e-liquid constituents based on their potential for adverse effects on the heart.


application_id: 11407509
project_number: 6T42OH010278-12M010
project_title: OCCUPATIONAL SAFETY AND HEALTH EDUCATION AND RESEARCH CENTERS (T42)
administering_ic: NIOSH
award_notice_date: 2025-08-28
opportunity_number: PAR-15-303
application_type: 6
activity_code: T42
ic: OH
serial_number: 010278
suffix: M010
program_official: MAPLES, ELIZABETH
project_start_date: 2019-07-01
project_end_date: 2026-06-30
study_section: ZOH1-EHG(02)
contact_pi_person_id: 8433958
contact_pi: SANDERSON, WAYNE T.
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
project_abstract:
DESCRIPTION (provided by applicant): The Central Appalachian Regional Education and Research Center (CARERC) provides graduate and continuing education for occupational safety and health professionals for the 5-year period July 2014-June 2019. Specifically we (1) provide interdisciplinary occupational safety and health education for graduate students; (2) enhance the research skills of students and faculty in the targeted disciplines; (3) encourage and conduct interdisciplinary research on a variety of occupational diseases and injuries; (4) deliver continuing education consultation and outreach to address environmental and occupational safety and health concerns; and (5) translate research into prevention practice. CARERC's scope includes counties in eastern Kentucky western North Carolina eastern Tennessee western Virginia and southern West Virginia where elevated rates of occupational Injuries and fatalities persist particularly in production agriculture forestry mining and transportation. CARERC combines the resources of the University of Kentucky College of Public Health (MPH and PhD in Occupational Epidemiology and Injury and MPH in Agricultural Safety and Health); the UK College of Nursing (PhD in Occupational Nursing); the UK College of Engineering (MS and PhD in Mine Safety & Health) and the Eastern Kentucky University College of Justice & Safety (MS in Occupational Safety). CARERC collaborates with other regional institutions as well as industry labor and government in its Pilot Research Program (PRP) Outreach and Continuing Education (CE) programs to enhance research capacity and catalyze the translation of research to practice. We plan to support the following number of trainees each year: 9 doctoral students 7 MPH and BMS students across the core programs. Building on our strengths and stature after only one year of NIOSH funding CARERC will continue to serve as a catalyst for interdisciplinary research in occupational safety and health and a centralized resource center for innovative education and training.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Building on the strengths of our education and research programs and responding to the need for innovative coordinated occupational safety and health training in central Appalachia the Central Appalachian Regional Education and Research Center (CARERC) provides targeted instruction training and applied research while serving as a recognized source of knowledge and expertise.


application_id: 11400562
project_number: 3R01AI187483-01A1S1
project_title: Development of novel antivirals for arthritogenic alphaviruses
administering_ic: NIAID
award_notice_date: 2025-09-26
opportunity_number: PA-20-185
application_type: 3
activity_code: R01
ic: AI
serial_number: 187483
suffix: A1S1
program_official: DAVIS, MINDY I
project_start_date: 2025-09-24
project_end_date: 2030-08-31
study_section: Special Emphasis Panel[ZRG1-DCAI-K(81)]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
other_pis: BANNISTER, THOMAS D;LUO, DAHAI
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project summary: Development of Antivirals for Arthritogenic Alphaviruses This NIH grant proposal aims at the optimization of a New World (NW) alphavirus-specific quinazolinescaffold for the development of an anti-Old World (OW) arthritogenic alphavirus therapeutic candidate. With aparticular focus on Chikungunya virus and other alphaviruses with a pandemic potential this project respondsto an urgent public health need for effective antiviral treatments for OW alphaviruses given the recent increasein global prevalence of OW alphavirus infections. Dr. Chung's research group has made significant advancements in developing a quinazolinone-basedantiviral specifically targeting NW alphaviruses like Venezuelan Equine Encephalitis Virus exhibitingremarkable efficacy in preclinical models. This success coupled with the compound's unique mechanism ofaction targeting the viral replicase complex positions the quinazoline scaffold as a valid starting point fordeveloping effective antivirals for other alphaviruses. However the compound series necessitates significantenhancement in potency against OW alphaviruses. The team has identified a key residue that contributes tothe NW alphavirus-specific antiviral spectrum. Here by elucidating the molecular interactions and clashesbetween the quinazolinone scaffold and OW alphavirus replicase complexes the team aims to develop next-generation inhibitors with enhanced efficacy toward OW arthritogenic alphaviruses. Recognizing the need to enhance the potency of the quinazoline series against OW alphaviruses theproject proposes three Specific Aims undertaking a comprehensive and systemic approach integratingstructural insights medicinal chemistry and preclinical evaluations. Dr. Luo's work in Specific Aim 1 focuses onmapping molecular interactions and clashes between the current quinazolinone scaffold and the OWalphavirus replicase complex providing critical structural insights that will inform the design of new inhibitors inSpecific Aim 2 led by Dr. Bannister. Specific Aim 2 efforts are directed towards identifying chemical groupsleading to resistance in OW alphaviruses designing and synthesizing new compounds tailored for OWalphaviruses and ultimately developing lead candidates with optimized pharmacological profiles. Dr. Chung inSpecific Aim 3 will assess these novel antivirals in vitro and in vivo supporting the structure-activity study forAim2. Aim 3 will also study the mechanisms of action and resistance of the series. The overarching goal of the project is to deliver novel potent therapeutic candidates for OW arthritogenicalphaviruses. With a highly integrated team of experts and a meticulous approach spanning molecularstructural biology medicinal chemistry and virology this project holds the promise of advancing preclinicaldevelopment ultimately addressing a critical gap in public health preparedness against OW alphavirusinfections. Upon successful completion the project will deliver promising therapeutic candidates ready foradvanced preclinical development to address the critical needs for arthritogenic alphaviruses therapeutics.

project_terms:
Acceleration;Address;Alpha Virus;Alphavirus Infections;Amino Acids;Anti-viral Agents;Applications Grants;Arthritogenic;Binding;Binding Sites;Biological Assay;Cells;Chikungunya virus;Complex;Coupled;Cryoelectron Microscopy;Deforestation;Development;Exhibits;Family;Future;Global Warming;Goals;In Vitro;Individual;Infection;Lead;Ligands;Lysine;Maps;Methodology;Modeling;Molecular;Mus;Mutation;Nonstructural Protein;Pharmaceutical Chemistry;Pharmaceutical Preparations;Polyarthritides;Positioning Attribute;Pre-Clinical Model;Prevalence;Property;Public Health;Quinazolines;RNA chemical synthesis;Readiness;Research;Resistance;Seminal;Series;Site;Structure;Structure-Activity Relationship;Therapeutic;Togaviridae;Toxic effect;Tyrosine;United States National Institutes of Health;Vaccines;Venezuelan Equine Encephalitis Virus;Viral;Viral Physiology;Virus;Work;anti-viral efficacy;antiviral drug development;chemical group;design;drug discovery;effective therapy;emerging virus;experience;genetic approach;helicase;in vivo;inhibitor;insight;lead candidate;meter;mosquito-borne;mouse model;next generation;novel;pandemic potential;pandemic preparedness;pharmacologic;preclinical development;preclinical evaluation;programs;replicase;resistance mutation;restoration;scaffold;structural biology;success;therapeutic candidate;viral RNA;virology

public_health_relevance:
PROJECT NARRATIVE: Development of Antivirals for Arthritogenic Alphaviruses This NIH grant proposal is to advance antiviral drug discovery against Old World arthritogenic alphaviruseswith a pandemic potential. By utilizing state-of-the-art methodologies and leveraging our deep understanding ofthe mechanism of action of a previously developed potent anti-encephalitic New World alphavirus candidateour research aims to develop robust antiviral compounds and facilitate the development of effective therapiesagainst arthritogenic Old World alphaviral infections. This project addresses a critical gap in public health andcontributes to the NIH pandemic preparedness program.


application_id: 11394129
project_number: 4R00HD108801-03
administering_ic: NICHD
award_notice_date: 2025-09-04
opportunity_number: RFA-NS-19-043
application_type: 4
activity_code: R00
ic: HD
serial_number: 108801
program_official: MILLER, BRETT
project_start_date: 2025-09-05
project_end_date: 2028-08-31
study_section: NSS
contact_pi_person_id: 11782641
contact_pi: LOGEMAN, BRANDON
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-09-05
project_title:
Sex and physiological State dependent molecular characterization of circuits governing parental behavior

project_abstract:
PROJECT SUMMARY/ABSTRACTParental care is essential for offspring well-being and survival yet requires a significant invest from adultswithout immediate benefit suggesting the existence of hard-wired mechanisms governing its control. Despitethe importance of this evolutionarily controlled behavior parental behaviors vary greatly between animals ofdifferent sex physiological state and genetic background. Previous studies examining sex- and state-dependent influences on parental behavior have lacked the cell-type resolution critical to understanding howspecific circuit components are modulated. The long timescale (hours to days) of changes affecting parentingbehaviors suggests that neural circuits respond through dynamic gene expression changes. Through the useof intersectional genetics and single cell analysis I have established exquisitely specific access to two keyneuronal hubs controlling parenting behavior. Preliminary results comparing Mothers Fathers and Virginanimals suggest potential transcriptional epigenetic and biophysical differences that are dependent on theanimals sex and physiological state. During the K99 phase of the work proposed here I will rigorously assesssex- and state-dependent transcriptional changes as well as their biophysical and behavioral implicationsusing the latest tools for cell-type specific recording and manipulation. I will uncover gene regulatory networksthat give rise to observed transcriptional changes and will develop new intersectional tools to modulate geneexpression in a cell-type specific manner. The successful completion of these Aims will reveal the molecularmechanisms though which sex and state mediate transcriptional reprograming to affect the function of thisconserved behavioral circuit. Genetic variation also contributes to differences in the display of parental care.Preliminary results utilizing genetically distinct mouse strains show dramatic differences in parenting behaviorand suggest a genetic contribution to behavioral variation. In the independent R00 phase of this proposal I willperform a forward-genetic screen utilizing a well-characterized panel of genetically diverse mice to findgenomic variants that contribute to parental behavior. The cell-type specific gene regulatory networks revealedin the previous Aims will then be used to assess the causal role of individual variants providing a level ofmolecular explanation unobtainable with previous genetic mapping experiments. Furthermore the successfulcompletion of this project will provide a platform for future experiments aimed at understanding how geneticvariants contribute to gene expression that ultimately affects animal behavior.The training phase of the award will be conducted in the laboratory of Dr. Catherine Dulac at HarvardUniversity. In addition I will be mentored by the outstanding team of scientists on my advisory committee thatwill assist with specific training goals as well as career guidance. In my application I have outlined acomprehensive plan for the acquisition of conceptual technical and professional skills that will enable mytransition to an independent research position.

project_terms:
ATAC-seq;Address;Adult;Advisory Committees;Affect;Alleles;Animal Behavior;Animals;Award;Behavior;Behavioral;Biophysics;Calcitonin Receptor;Caregivers;Caring;Cell Nucleus;Child Rearing;Chromatin;Chromosome Mapping;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Electrophysiology (science);Environment;Epigenetic Process;Exhibits;Fathers;Female;Future;Gene Expression;Genes;Genetic;Genetic Screening;Genetic Transcription;Genetic Variation;Genomics;Goals;Hormones;Hour;Hypothalamic structure;Individual;Infant;Infant Care;Investments;Knowledge;Laboratories;Lactation;Maps;Measures;Mediating;Mentors;Molecular;Mothers;Mouse Strains;Mus;Neurons;Parents;Pathologic;Personal Satisfaction;Phase;Physiological;Population;Population Control;Positioning Attribute;Preoptic Areas;Prolactin;Quantitative Trait Loci;Research;Resolution;Role;Scientist;Sex Differences;Signal Pathway;Signal Transduction;Slice;Stimulus;Testing;Testosterone;Training;Transcriptional Regulation;Universities;Variant;Ventricular;Vocational Guidance;Work;behavior influence;behavioral outcome;biophysical properties;biophysical techniques;bombesin receptor subtype 3;causal variant;cell type;differential expression;epigenomics;experimental study;galanin receptor;gene regulatory network;genetic approach;genetic variant;genomic locus;male;neural circuit;neuronal circuitry;offspring;parental influence;pharmacologic;sex;sexual dimorphism;single cell analysis;single nucleus RNA-sequencing;skills;tool;trait;vesicular glutamate transporter 2

public_health_relevance:
PROJECT NARRATIVEParental care is an evolutionarily conserved behavior that is highly modulated by the sex physiological stateand genetic background of the caregiver. An inability to properly display parental behaviors can lead to long-lasting detrimental effects in the infant. Thus understanding the molecular basis for sex- state- and genetic-dependent expression of parental behavior is critical to understanding this essential behavior in normal andpathological contexts.


application_id: 11392061
project_number: 3U01DE031223-04S1
project_title: Susceptibility Patterns for Grade C Periodontitis in Young Individuals
administering_ic: NIDCR
award_notice_date: 2025-08-21
opportunity_number: PAR-20-060
application_type: 3
activity_code: U01
ic: DE
serial_number: 031223
suffix: S1
program_official: CHOU, ALICIA YESIU
project_start_date: 2022-09-22
project_end_date: 2027-08-31
study_section: ZDE1-YM(12)
contact_pi_person_id: 8964577
contact_pi: SHADDOX, LUCIANA MACCHION
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The American Academy of Periodontology and European Federation of Periodontology have recently adoptedthe new terminology Grade C Periodontitis to identify individuals with a high risk for disease progression. Thelocalized form of this disease now termed Stage 3-4 Grade C molar-incisor pattern periodontitis (C/MIP)exhibits a very well-defined clinical presentation. Although less common than other periodontitis C/MIP has asignificant public health impact as it affects systemically healthy young individuals of low social economicstatus who usually cannot afford its expensive and complex treatment as their affected teeth are often lost dueto its rapid progression and delayed diagnosis. This leads to early function and aesthetics issues and life-longdifficulties for functional and aesthetic rehabilitation. Due its common aggregation in families several studieshave searched for genetic associations with grade C disease but not in large cohorts of C/MIP. Thus geneticcontributions for C/MIP are not yet identified. The team put together for this proposal have conducted ground-breaking work in this field over the last 3 decades including the identification of candidate genetic susceptibilityvariants hyper-inflammatory response and strong association with Aa and Aa JP2 clone. However differentpopulations have different genetic predispositions environmental exposures and microbial colonization whichfurther complicates unveiling the true etiology and pathogenesis of this disease. Thus there is a critical need toexamine a large well-defined cohort of C/MIP families from different world regions to systematically andcomprehensively determine the genetic host response and microbial determinants of this disease. The goal ofthis proposal is to characterize the genetic host and microbial factors of the early onset well-defined localizedform of periodontitis in populations worldwide. We propose to do this by gathering large cohort of C/MIP familiesin 4 different continents to 1)identify genetic susceptibility variants within C/MIP families via WES; 2)Identify theinflammatory networks associated with C/MIP 2 via transcriptome and network analysis and inflammatorymediator profile in the oral environment of these affected families; and 3) Determine common microbiome profilesvia metagenomic analysis and unique Aa strains in C/MIP families from different regions of the world associatedwith this disease. Our hypotheses are that 1-C/MIP will be associated with identifiable genetic variants whichmay vary in different regions of the globe 2-a specific transcriptome is linked to pro-inflammatory pathways inC/MIP and 3-genotypically and phenotypically different strains of Aa will differ among regions of the globe andwill correlate with microbiome communities of distinct functionality and virulence potential. The impact of the proposed work is the development of an integrative series of interaction network andfunctional analyses which will lead to the characterization of susceptibility molecular and microbial phenotypesof C/MIP in different populations around the world which will provide criteria for early disease diagnosis anddevelopment of targeted and individualized therapies for these highly susceptible families.

project_terms:
Academy;Actinobacillus actinomycetemcomitans;Adopted;Affect;African ancestry;Age;American;Bacteria;Characteristics;Clinical;Complex;DNA;DNA sequencing;Development;Diagnosis;Dideoxy Chain Termination DNA Sequencing;Disease;Disease Progression;Economics;Environment;Environmental Exposure;Epithelial Cells;Esthetics;Etiology;European;Exhibits;Family;Genes;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Gingival Crevicular Fluid;Goals;Immune response;Incisor;Individual;Inflammation Mediators;Inflammatory;Inflammatory Response;Link;Metagenomics;Molecular;Multicenter Studies;Names;Oral;Pathogenesis;Pathway Analysis;Pathway interactions;Pattern;Periodontitis;Phenotype;Population;Predisposition;Property;Public Health;Rehabilitation therapy;Saliva;Sampling;Series;Shotguns;Siblings;Site;Susceptibility Gene;Taxonomy;Terminology;Testing;Tooth structure;Variant;Virulence;Virulent;Work;candidate identification;case control;cohort;data integration;disease diagnosis;early onset;exome sequencing;gene interaction;genetic association;genetic variant;genome-wide analysis;high risk;individualized medicine;metagenome;microbial;microbial colonization;microbial community;microbiome;microbiome community;neutrophil;older adult;oral cavity epithelium;oral microbiome;peripheral blood;social;targeted treatment;transcriptome;transcriptome sequencing

public_health_relevance:
NarrativeAggressive periodontitis now named Grade C periodontitis (C/MIP) is a group of less frequently often severeand rapidly progressive form of periodontitis affecting young individuals at an early age usually aggregating infamilies of lower social economic background. The factors that render affected individuals to C/MIP diseaseare yet to be clearly identified which affects the proper control of this aggressive disease. This multi-centerstudy will gather clearly-defined cases of C/MIP from different regions of the globe and within families toevaluate genetic susceptibility variants using whole exome sequencing host response via epithelial celltranscriptome to pinpoint mechanistic pathways associated with C/MIP and with genetic variants and microbialcommunity profile via metagenomics as well as specific species strains associated with this disease.


application_id: 11390849
project_number: 1U01FD008732-01
administering_ic: FDA
award_notice_date: 2025-09-19
opportunity_number: PAR-25-014
application_type: 1
activity_code: U01
ic: FD
serial_number: 008732
program_official: KABERA, CLAUDINE
project_start_date: 2025-09-20
project_end_date: 2030-08-31
study_section: Special Emphasis Panel[ZFD1 CVM-J (04)]
contact_pi_person_id: 78775561
contact_pi: HELMY, YOSRA A.
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-09-20
project_title:
Strengthening Antimicrobial Resistance Surveillance in Retail Food Commodities in Kentucky as a Part of the National Antimicrobial Resistance Monitoring System (NARMS)

project_abstract:
SUMMARY:Antimicrobial-resistant (AMR) infections represent a growing public health concern with foodborne pathogenssuch as Salmonella Campylobacter Escherichia coli and Enterococcus playing a significant role. Currentlythere is limited data on the prevalence of antibiotic-resistant bacteria isolated from raw meat sold in retail storesacross the state of Kentucky. To strengthen the antibiotic resistance surveillance data generated through theNational Antimicrobial Resistance Monitoring System (NARMS) we propose a collaborative effort with the U.S.Food and Drug Administration (FDA) to monitor antimicrobial resistance in bacteria isolated from retail meat inseveral regions of the Commonwealth. This objective will be achieved through three specific aims: First retailmeat samples including chicken breast ground turkey ground beef pork and seafood will be collected twicemonthly from grocery stores located in six geographically and socioeconomically distinct regions acrossKentucky. These regions will include urban areas such as Lexington Louisville and Northern Kentucky as wellas underserved rural and Appalachian communities including Hazard Morehead and Paducah. Samples willbe transported under refrigeration to the laboratory where bacterial isolation of Salmonella CampylobacterEscherichia coli Enterococcus Vibrio and Aeromonas will be conducted in accordance with the NARMSSurveillance Laboratory Protocols. Confirmed isolates will be shipped monthly to the FDA Center for VeterinaryMedicine (CVM) for further analysis.Second we will develop a statewide database on antibiotic resistance in retail meat products using antimicrobialsusceptibility testing and whole-genome sequencing (WGS). This database will catalog the prevalence of targetpathogens by commodity type serotypes of Salmonella antimicrobial resistance profiles and detailed samplemetadata including retail location zip code meat brand processor packaging type and production claims (e.g.organic raised without antibiotics). This resource will not only enhance Kentuckys contribution to NARMS butwill also enable high-dimensional analyses linking retail surveillance data with upstream sources such as on-farm AMR monitoring and environmental exposures.Third this initiative will foster greater collaboration among federal state and academic stakeholders involved infoodborne disease surveillance and outbreak response. Key partners in this effort include the FDA-CVM theKentucky Department for Public Health the Colorado Department of Public Health& Environment and theUniversity of Kentuckys College of Agriculture Food and Environment. By achieving these aims this project willexpand the reach of NARMS into Kentucky improve the detection and characterization of antimicrobial-resistantfoodborne pathogens and strengthen cross-sector collaboration for AMR surveillance and food safetypreparedness at the state and national levels.

public_health_relevance:
PROJECT NARRATIVEAntimicrobial resistance (AMR) in foodborne pathogens poses a serious threat to public health by compromisingthe effectiveness of antibiotics used to treat human infections. This project will enhance AMR surveillance acrossKentucky in retail food commodities by implementing FDA-standardized sampling microbiological testing andwhole genome sequencing protocols. The data collected will be shared with NARMS and support national effortsto monitor resistance trends inform regulatory decisions and guide public health interventions aimed at reducingthe burden of resistant infections transmitted through the food supply.


application_id: 11390525
project_number: 7K01DA056692-02
administering_ic: NIDA
award_notice_date: 2025-08-21
opportunity_number: PA-24-254
application_type: 7
activity_code: K01
ic: DA
serial_number: 056692
program_official: FEDOTA, JOHN RAPHAEL
project_start_date: 2025-08-11
project_end_date: 2029-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 14148307
contact_pi: HARRIS, HANNAH MARIE
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
budget_start_date: 2025-08-11
project_title:
Effects of Repeated CBD Administration on Cannabis Abuse-Liability and Analgesia: A Human Laboratory Study

project_abstract:
Project SummaryOver 50 million Americans suffer from chronic pain and many use cannabis and cannabidiol (CBD) aconstituent of cannabis to treat their pain. Despite state-wide cannabis legalization and mainstream promotionof the medical benefits of these products there are few carefully controlled empirical studies assessing theeffects of cannabis and CBD when used repeatedly or used in combination. Pre-clinical studies show CBDenhances the analgesic efficacy of cannabis while attenuating its abuse-related properties but the effect ofrepeated CBD use on cannabis-induced analgesia and abuse liability in humans is not known. In the proposedrandomized counterbalanced human laboratory study healthy adult cannabis smokers (N=72; 36M 36F) willbe randomized to receive one of four CBD doses (0 50 100 300 mg/day) for 15 days. On days 1 8 and 15they will participate in a laboratory session where they will smoke 75% of a cannabis cigarette (7% THC) andwe will measure the time-course of abuse-related subjective effects (good drug effect high) and experimentalpain using two mechanistically distinct paradigms (Cold Pressor Test Quantitative Sensory Testing) over 3hours. We will then assess whether CBD alters cannabiss reinforcing effects by providing participants theopportunity to self-administer up to 4 additional puffs of cannabis (7% THC). This study will answer two criticalquestions: Does daily oral CBD administration alter: 1) the abuse-related and reinforcing effects of smokedcannabis; 2) the analgesic effects of smoked cannabis. In addition to contributing novel data regarding theinteraction between CBD and cannabis this proposal will provide critical training needed to achieve my goal ofbecoming an independently funded researcher. Specifically this mentored research scientist developmentapplication will advance my career by providing essential: (1) experience in human laboratory model studydesign and methodology specifically to evaluate cannabinoids on abuse-and pain-related endpoints and (2)training in statistics and grantsmanship. My past pre-clinical research experience combined with the goals Ihave set forth within this application will allow me to gain the skills and experiences to become an independentresearch scientist translating findings from pre-clinical animal models into human laboratory studies.

project_terms:
Absence of pain sensation;Acute;Adult;American;Analgesics;Animal Model;Attenuated;Cannabidiol;Cannabinoids;Cannabis;Cannabis Abuse;Cigarette;Clinical;Data;Development;Dose;Funding;Goals;Hour;Human;Individual;Laboratories;Laboratory Study;Mainstreaming;Measures;Medical;Mentors;Methodology;Modality;Modeling;Neurobiology;Oral;Oral Administration;Pain;Pain management;Participant;Pathway interactions;Pharmaceutical Preparations;Placebos;Preclinical data;Process;Property;Randomized;Research;Research Design;Research Personnel;Research Proposals;Scientist;Self Administration;Sensory;Smoke;Spinal Cord;Study models;Techniques;Testing;Therapeutic Effect;Therapeutic Uses;Time;Training;Translating;abuse liability;antinociception;attenuation;career;central sensitization;chronic pain;consumer demand;experience;healthy volunteer;innovation;marijuana legalization;marijuana smoker;marijuana use;non-opioid analgesic;novel;pain perception;pre-clinical;pre-clinical research;preclinical study;response;skills;statistics;substance use

public_health_relevance:
Project NarrativeMany individuals use cannabis and cannabidiol (CBD) a constituent of cannabis to treat their pain despite fewempirical studies assessing their effects when used repeatedly or in combination. Pre-clinical studies show thatCBD can attenuate the abuse-related effects of cannabis and enhance its analgesic efficacy but the effect ofrepeated CBD use on cannabis-induced analgesia and abuse liability in humans is not known. The primarygoal of this mentored research proposal is to determine if daily CBD administration across a range of dosesand time alters the abuse-related reinforcing and analgesic effects of smoked cannabis.


application_id: 11379346
project_number: 1U2FFD008699-01
administering_ic: FDA
award_notice_date: 2025-09-18
opportunity_number: PAR-25-003
application_type: 1
activity_code: U2F
ic: FD
serial_number: 008699
program_official: ISAKSON, ISAIAH
project_start_date: 2025-09-20
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZFD1 HFP-D (07)]
contact_pi_person_id: 14147267
contact_pi: HARRISON, GLEN ALAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-09-20
project_title:
University of Kentucky Animal Food Regulatory Program Standards Implementation Development and Maintenance with Mutual Reliance Initiatives

project_abstract:
Project Summary/Abstract:The University of Kentucky Division of Regulatory Services (UKDRS) is committed toadvancing its Animal Feed Regulatory Program in full alignment with the Animal FeedRegulatory Program Standards (AFRPS). Through this cooperative agreement UKDRS willstrengthen its regulatory infrastructure and support the goals of the Integrated Food SafetySystem (IFSS) in partnership with the U.S. Food and Drug Administration (FDA).This initiative focuses on four strategic components: A. Sustaining full AFRPS implementation through continuous quality improvement annual reviews and FDA assessments; B. Leading and participating in AFRPS-related activities and national collaborations including the AAFCO Standards Committee and emergency preparednessexercises; C. Applying AFRPS protocols to conduct follow-up inspections investigations and enforcement actions based on robust sampling and compliance frameworks; and D. Advancing to Phase 3 of the SMG-8076 audit program by training additional auditors to ensure long-term program sustainability.UKDRSs longstanding leadership technological integration and commitment toregulatory excellence position it as a key contributor to national food safety efforts. Thisproposal seeks continued support to enhance program effectiveness promote mutualreliance and protect public and animal health.

public_health_relevance:
Project NarrativeThe University of Kentucky Division of Regulatory Services (UKDRS) is fully committed tomaintaining and continuously improving its Animal Feed Regulatory Program in alignmentwith the Animal Feed Regulatory Program Standards (AFRPS). With a long-standing history ofcollaboration with the U.S. Food and Drug Administration (FDA) UKDRS will continue tostrengthen its regulatory infrastructure promote mutual reliance and support the goals of theIntegrated Food Safety System (IFSS).


application_id: 11379343
project_number: 3R01AA029798-05S1
project_title: Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
administering_ic: NIAAA
award_notice_date: 2025-08-14
opportunity_number: PA-20-185
application_type: 3
activity_code: R01
ic: AA
serial_number: 029798
suffix: S1
program_official: PERRUCCIO, ELIZABETH M
project_start_date: 2021-09-22
project_end_date: 2027-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
2.5% of United States population is affected by alcohol-associated liver disease (ALD) which represents theeighth most common cause of mortality. Despite significant progress in the field the complex mechanismsdriving the onset and progression of ALD are still not fully understood. cAMP is a second messenger that playsa critical role in regulating multiple cellular functions via its effectors (e.g. protein kinase A). Amplitude andduration of cAMP signaling is fine-tuned by phosphodiesterases (PDEs) via cAMP hydrolysis and degradation.Our work has shown that ethanol increases expression of hepatic PDE4 in experimental ALD as well as inalcohol-associated hepatitis (AH) patients livers. However their role in ALD pathogenesis is not clear. Westarted elucidating the role of PDE4s in ALD by demonstrating that Pde4b plays a critical role in ethanol-mediated impairment of fatty acid -oxidation and steatosis. We also showed that inhibition of PDE4 activityattenuates liver injury in in vivo and in vitro models of ALD. However underlying mechanisms of ethanolmediated induction of PDE4 enzymes have not been determined. Moreover how PDE4 inhibition exerts itsbeneficial effect on dysregulated lipid metabolism and hepatocytes survival is not fully understood. Ourpreliminary studies using animal and cell models of ALD identified novel pathways of ethanol and PDE4-mediated regulation of hepatic lipid metabolism and cell injury which have never been examined before. Basedon our previous work and preliminary data our central hypothesis is that ethanol via cytochrome p450(CYP2E1) mediated increase in hypoxia inducible factor 1 (HIF1) induces hepatic PDE4 whichcontributes to dysregulation of hepatic lipid metabolism and injury.The specific objectives of these mechanistic studies are to:Aim 1: Determine the underlying mechanisms of PDE4 upregulation by ethanol in hepatocytes.Aim 2: Determine mechanisms underlying ethanol/PDE4-mediated de novo lipogenesis and hepaticsteatosis.Aim 3: Determine the role of MKP1 in ethanol/PDE4-mediated toxicity in hepatocytes.The ultimate goal of this application is to identify not only the mechanisms of PDE4 upregulation but also therole of PDE4s in the development of ALD. Importantly we predict that these preclinical studies will providestrong rationale using PDE4 specific inhibitors in the treatment of ALD. Importantly there are potent PDE4inhibitors that are already FDA-approved for the treatment of other inflammatory disease processes and theseinhibitors could potentially be repurposed for ALD.

project_terms:
ADD-1 protein;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Apoptosis;Attenuated;Automobile Driving;CYP2E1 gene;Cell Physiology;Cell model;Cessation of life;Complex;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cytochrome P450;Data;Development;Disease;Enzymes;Ethanol;FDA approved;Fatty Acids;Fatty Liver;Genes;Goals;H19 gene;HIF1A gene;Heavy Drinking;Hepatic;Hepatocyte;Hydrolysis;Impairment;In Vitro;Inflammatory;Injury;Knockout Mice;Liver;Liver diseases;MAPK8 gene;Mediating;Metabolic;Mitogen-Activated Protein Kinases;PDE4B;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Population;Process;Regulation;Role;Second Messenger Systems;Signal Transduction;Specificity;Toxic effect;Transcriptional Regulation;United States;Untranslated RNA;Upregulation;Work;alcohol effect;cell injury;genetic manipulation;hypoxia inducible factor 1;in vitro Model;in vivo;inhibitor;lipid biosynthesis;lipid metabolism;liver injury;member;mortality;new therapeutic target;novel;oxidation;phosphatase-1 kinase;phosphodiesterase IV;phosphoric diester hydrolase;preclinical study;response;transcription factor

public_health_relevance:
Project NarrativeAbout 2.5% of the US population is affected by alcohol-associated liver disease (ALD) which represents the8th most common cause of mortality. Currently there is no FDA approved therapy available for the treatment ofALD. This project will examine phosphodiesterase 4 (PDE4)-mediated pathogenic pathways in ALD. Thefindings of this project will lead to the development of novel therapies targeting PDE4 for treatment of ALD.


application_id: 11376705
project_number: 1OT2ES038696-01
project_title: The East Palestine Train Derailment Health Research Program
administering_ic: NIEHS
award_notice_date: 2025-09-22
opportunity_number: OTA-25-007
application_type: 1
activity_code: OT2
ic: ES
serial_number: 038696
program_official: QUINN, ASHLINN KO
project_start_date: 2025-09-25
project_end_date: 2026-08-31
study_section: ZES1-SRC(99)
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:
On February 3 2023 a 150-car freight train derailed and caught fire in East Palestine Ohio. Eleven of the 52 derailed rail cars contained hazardous materials including vinyl chloride and butyl acrylate which were released into the air water and soil. A controlled release and burn of five cars containing over 880000 pounds of vinyl chloride was conducted on February 6th and residents were told it was safe to return to their homes on February 8th. However they soon reported numerous symptoms following the derailment. Leveraging our more-than-10-year collaboration on environmental health research with community partners in Columbiana County Ohio our team launched the East Palestine Health Tracking Study on April 11 with and for the residents to assess health symptoms markers of exposure and indoor air quality. From these efforts we have identified an alarmingly high rate of post-traumatic stress which has persisted over time elevated rates of respiratory symptoms and an immune profile indicating immune dysfunction among the residents of these communities. To address these ongoing concerns and gaps in knowledge we will conduct a community-engaged longitudinal epidemiological study to better understand the health impacts of these exposures. We will build on our existing robust community partnerships to accomplish the following goals: Goal 1: Conduct a comprehensive community health needs assessment through the involvement of key stakeholders. Using structured and unstructured strategies we will identify health needs from our study participants through serial surveys and journaling; our Community Advisory Board (CAB); and the experiences of our Clinical and Public Health (CPH) Taskforce. We will synthesize the concerns of the community to inform project direction with insight from our Scientific Advisory Board (SAB). Goal 2: Conduct longitudinal high-impact research studies. We will expand our cohort to include children and residents impacted by the disaster who lived within 50 miles of the derailment and engage a comparison community to further examine the effect of the disaster. Using serial surveys as well as biological and clinical assessments our team will investigate the impact of the disaster on mental health including stress; respiratory function; immune function; cardiovascular health; and reproductive health. Hair will be analyzed for biomarkers of stress and alternations in the hypothalamic-pituitary-adrenal (HPA). We will examine medical diagnoses pre- and post-derailment and identify trends and geographic hot spots. These results will then be used to inform the education strategies we create for the community. We will also curate a biorepository for future research that includes hair toenails blood/plasma DNA and naturally deciduous teeth. Goal 3: Develop and implement a health research tracking system with data management infrastructure. Partnering with the Kentucky Center for Clinical and Translational Science and the Center for Applied Artificial Intelligence (AI) we will design and deploy a secure health research tracking system to integrate the health tracking survey data with electronic medical records of study participants. We will innovatively deploy HIPPA complaint-AI and the journaling data to help devise actionable insights that will be shared with community members. Goal 4: Provide training and educational materials as well as report-back of research findings to the community. Study findings will be co-developed with our CAB and CPH Taskforce with input from our SAB. Residents will join a Community Data Analyses Team and assist in creating graphics that convey our findings for broad sharing. Community partners will identify and implement strategies including newsletters town hall meetings website updates podcasts and open houses to disseminate our findings. The proposed East Palestine Health Tracking Study will provide critical actionable insights into the short- and long-term health impacts of chemical exposures from the East Palestine train derailment. Ultimately this work will empower affected communities with evidence-based information and tools to improve health outcomes inform disaster response strategies and advance environmental health science in vulnerable populations

project_terms:
Acrylates;Address;Adrenal Glands;Advisory Committees;Affect;Air;Artificial Intelligence;Back;Biological;Biological Markers;Blood;Chemical Exposure;Child;Clinic Visits;Clinical;Clinical Sciences;Clinical assessments;Collaborations;Collection;Communication;Communities;Community Health;Computerized Medical Record;County;Custom;DNA;Data;Data Analyses;Data Set;Databases;Diagnosis;Disasters;Education;Educational Materials;Ensure;Environmental Health;Event;Fire - disasters;Geography;Goals;Hair;Hazardous Substances;Health;Home;Hot Spot;Hypothalamic structure;Immune;Immune System Diseases;Indoor Air Quality;Infrastructure;Kentucky;Knowledge;Medical Records;Mental Health;Multimedia;Needs Assessment;Newsletter;Ohio;Ontology;Outcome;Participant;Physiological;Pituitary Gland;Plasma;Public Health;Reporting;Reproductive Health;Research;Research Priority;Respiratory Signs and Symptoms;Respiratory physiology;Sampling;Secure;Soil;Stress;Structure;Structure of nail of toe;Surveys;Symptoms;System;Time;Training;Training and Education;Translational Research;Update;Vinyl Chloride;Vulnerable Populations;Water;Work;artificial intelligence method;biobank;cardiovascular health;clinical center;cohort;community advisory board;community partners;community partnership;controlled release;data access;data management;deciduous tooth;design;digital platform;empowerment;epidemiology study;evidence base;experience;health assessment;immune function;improved;innovation;insight;medical examination;meetings;member;podcast;post-traumatic stress;programs;research study;response;tool;trend;web site


application_id: 11373832
project_number: 3R01DA055872-04S1
administering_ic: NIDA
award_notice_date: 2025-07-28
opportunity_number: PA-20-183
application_type: 3
activity_code: R01
ic: DA
serial_number: 055872
suffix: S1
program_official: LEE-WINN, ANGELA EUNJI
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
project_title:
Kentucky Outreach Service Kiosk (KyOSK): Reducing Overdose Hepatitis C and Other Drug-related Risks in Rural Appalachia through Health Kiosks

project_abstract:
The proposed project will test and evaluate the effectiveness of an innovative approach to reducing harms related to the epidemics of injection drug use overdoses hepatitis C (HCV) and to imminent HIV outbreaks in rural Appalachian Kentucky which has long been an epicenter of these intertwined crises. Our research has shown that the region has high rates of HCV overdose injection drug use and dense risk networks that could kindle an HIV outbreak. Following a 2014 HIV outbreak in neighboring Indiana and a national analysis of HIV/HCV outbreak vulnerability among people who inject drugs (PWID) revealing that 54 of Kentuckys 120 counties ranked in the top 5% nationally Kentucky passed landmark legislation permitting counties to operate substance abuse treatment outreach programs that provide syringe services alongside other healthcare resources (hereafter SSPs). Despite an arduous county-level approval process Kentucky has succeeded in opening 80 SSPs more than any other U.S.state. Unfortunately this robust infrastructure remains under-utilized in rural settings. Data from our research funded by NIDAs National Rural Opioid Initiative revealed that nearly half of PWID had never used the existing staffed SSPs and over 24 months of follow-up SSP uptake remained low and program drop-out was not uncommon. The most frequent reasons cited for having never used an SSP were related to fear of being outed as a person who uses drugs. Evidence suggests that PWID in the region want a range of service models and among those who report fear of social and legal consequences as a reason for not using the staffed SSPs the most desired model is a vending machine or kiosk. Kiosks have been operating globally for more than 30 years and research has demonstrated that they can expand syringe access. Yet very few kiosks operate in the U.S. and none operate in rural areas where they might be especially beneficial. Research suggests that kiosks might be a cost-effective way to expand syringe access when coupled with staffed SSPs but their implementation impact and cost-effectiveness have not been rigorously evaluated. In response we propose a type 1 hybrid effectiveness trial to test the effectiveness implementation outcomes and cost effectiveness of a locally-tailored kiosk in reducing overdose hepatitis C and HIV risk behavior in rural Appalachia. Our kiosk or KyOSK (KY Outreach Service Kiosk) will feature first-of-its-kind technology and will be supplied with injection equipment naloxone fentanyl testing kits hygiene kits and other supplies as well as an innovative call-back feature for facilitated referral to needed services (e.g. employment education treatment) by trained recovery coaches. The KyOSK will be tailored to the local context under the leadership of a Kiosk Design Team involving people who use drugs and local and state leaders. Interest in kiosks is soaring nationwide and the proposed project would provide critical and timely data to inform scale-up of this potentially cost effectivemodel especially in rural areas of the country that have been severely impacted by substance use related harms.

project_terms:
Appalachian Region;Callback;Country;County;Coupled;Data;Diagnostic Reagent Kits;Disease Outbreaks;Dropout;Drug user;Education;Effectiveness;Employment;Epidemic;Equipment;Fright;Funding;HIV;HIV/HCV;Harm Reduction;Health;Hepatitis C;Hepatitis C Transmission;Hybrids;Hygiene;Indiana;Infrastructure;Injecting drug user;Injections;Kentucky;Leadership;Legal;Modeling;Naloxone;National Institute of Drug Abuse;Needle-Exchange Programs;Opioid;Overdose;Overdose reduction;Pharmaceutical Preparations;Process;Quasi-experiment;Recovery;Reporting;Research;Risk;Risk Behaviors;Risk Reduction Behavior;Rural;Rural Appalachia;Service delivery model;Services;Statutes and Laws;Syringes;Technology;Testing;Training;cost effective;cost effectiveness;design;effectiveness evaluation;effectiveness testing;effectiveness trial;fentanyl test;follow-up;health care resources;implementation outcomes;injection drug use;innovation;interest;outreach program;outreach services;programs;response;rural area;rural setting;scale up;social;substance abuse treatment;substance use;uptake

public_health_relevance:
The proposed study will test the effectiveness implementation outcomes and cost effectiveness of a locally-tailored health kiosk to reduce overdose hepatitis C and HIV risk behavior in rural Appalachia. The proposed project will take place in two counties in Appalachian Kentucky an epicenter for the intertwined national crises of injection drug use overdoses and hepatitis C.


application_id: 11364674
project_number: 4R01DA056646-02
project_title: Ghrelin Deacylase as a Treatment for Opioid Polysubstance Abuse
administering_ic: NIDA
award_notice_date: 2025-08-14
opportunity_number: RFA-DA-22-031
application_type: 4
activity_code: R01
ic: DA
serial_number: 056646
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: ZDA1-IXR-Q(09)R
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: ZHENG, FANG
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
With currently available medications for opioid use disorder (OUD) the relapse rate is very high. Further co-use of an opioid and a stimulant such as methamphetamine (METH) undermines success in treatment for OUD.It is highly desired to develop novel therapeutic options for treatment of OUDs including polysubstance usedisorders (PSUDs). Recently reported studies have revealed an interesting role of ghrelin in drug abuse andreward-relevant behaviors. Ghrelin is known as a growth-hormone-releasing acylated peptide from stomach a28 amino-acid peptide with the third residue (Ser3) acylated by n-octanoic acid. Ghrelin is produced in thestomach travels to the brain through blood circulation and acts on ghrelin (or growth hormone secretagogue)receptor (GHSR) to stimulate the mesolimbic dopamine reward pathway and increase rewarding behaviors inrodents. GHSR antagonism has been shown to attenuate rewarding effects induced by various substancesincluding METH amphetamine fentanyl morphine heroin cocaine nicotine and alcohol. For exampleadministration of a selective GHSR antagonist significantly reduced the fentanylseeking/relapselike behaviorin rats. On the other hand GHSR has diverse regulatory roles associated with its constitutive activity (the activityin the absence of ghrelin ligand) and hence GHSR antagonism could also result in unwanted adverse effects.Thus alternative strategies targeting ghrelin itself could be more interesting. However whether targeting ghrelinitself would be effective to attenuate the drug rewarding effects remains controversial in literature as ghrelinlevels before and after treatment were not measured in previous animal studies targeting ghrelin itself. It isunclear whether any of the previously used approaches was able to decrease the ghrelin level significantlyenough to attenuate the substance reward. We propose to use our recently identified ghrelin deacylase (a mutantof human butyrylcholinesterase or BChE) as a safe and effective ghrelin modulator to attenuate substancerewarding effects. Such a ghrelin modulator is expected to be as effective as a GHSR antagonist in treatment ofsubstance use disorders (SUDs) including PSUDs but without interacting with any brain receptors/transporters.Specifically in this investigation we will first evaluate the BChE mutant for its in vivo potency in modulatingghrelin and attenuating the rewarding and reinforcing effects of representative opioids (fentanyl and heroin) andtheir combinations with METH in various rodent models. Then we will design and discover a new BChE mutantas a more potent ghrelin deacylase with further improved catalytic activity for ghrelin diacylation develop itslong-acting fusion protein form and examine the long-term in vivo effects of the long-acting ghrelin deacylase.Accomplishment of this investigation will determine whether ghrelin itself is a truly effective target and whethera potent ghrelin deacylase as a ghrelin modulator is truly effective for treatment of PSUDs. If the answers are allpositive the most effective long-acting ghrelin deacylase (recombinant protein) to be tested and developed mayalso serve as a promising therapeutic candidate for treatment of PSUDs.

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

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


application_id: 11364662
project_number: 4R01DA057605-02
project_title: Rapid Actionable Data for Opioid Response in Kentucky (RADOR-KY)
administering_ic: NIDA
award_notice_date: 2025-08-08
opportunity_number: RFA-DA-22-044
application_type: 4
activity_code: R01
ic: DA
serial_number: 057605
program_official: KURAMOTO-CRAWFORD, SATOKO JANET
project_start_date: 2022-09-30
project_end_date: 2027-08-31
study_section: ZDA1-JRB-A(12)R
contact_pi_person_id: 12111311
contact_pi: SLAVOVA, SVETLA STEFANOVA
other_pis: TALBERT, JEFFERY C
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
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:
AbstractOpioid use disorder (OUD) remains a persistent public health crisis and epidemic. In spite of robust nationalstate and local public health responses to the epidemic opioid overdose deaths continue to increase; of the91799 drug overdose deaths in 2020 reported by the Centers for Disease Control and Prevention (CDC) themajority 68630 (75%) involved opioids a 38% increase from 2019. The opioid overdose death burden inKentucky is even higher with a 63% increase from 2019 (n=1036) to 2020 (n=1688). In the context of thedynamically changing opioid epidemic complicated by the challenges presented by the COVID-19 pandemicagencies and organizations responsible for monitoring and improving the health of the population need timelystate and local data to make critical decisions on resource allocation and targeted responses. Such decisionsare typically related to a set of evidence-based practices (EBPs) aimed at preventing opioid overdose mortality.We will harness the infrastructure and methodological expertise at the University of Kentucky (UK) researchcenters (incl. the Kentucky Injury Prevention and Research Center the Center on Drug and Alcohol Researchand the Institute for Biomedical Informatics) along with the experience gained from our work on the HEALingCommunities Study supported by the National Institute on Drug Abuse and the Overdose Data to Actionproject sponsored by the CDC. The specific aims of this project are to establish the Rapid Actionable Data forOpioid Response in Kentucky (RADOR-KY) an integrated population-based near-real time statewidesurveillance system that will ingest data from multiple state agencies and implement advanced informaticsalgorithms for fast data processing data linkage machine learning and predictive analytics to shorten the timebetween data capture and when analytical results are available to support opioid overdose prevention andcontrol. RADOR-KY will have mobile and web-based applications to provide immediate dissemination andaccess to near-real time community or state level data reports and visual analytics to share with agencies andcommunity end-users. RADOR-KY End-user Advisory Group including partners in state government and localcommunities will guide the development of the RADOR-KY reporting and visualization functionality. RADOR-KY will establish a longitudinal dataset accessible thru the RADOR-KY portal and also shared within the HEALData Ecosystem. Programming code for implemented algorithms and web-based dashboards will be shared ina public repository to advance the efforts to mitigate the opioid epidemic across the U.S.

project_terms:
Agreement;Algorithms;Area;COVID-19 pandemic;Centers for Disease Control and Prevention (U.S.);Code;Communities;County;Data;Data Linkages;Development;Environment;Epidemic;Evidence based practice;Evidence based treatment;Goals;Harm Reduction;Health;Heterogeneity;Informatics;Information Systems;Infrastructure;Kentucky;Link;Machine Learning;Measures;Methodology;Monitor;Morbidity - disease rate;National Institute of Drug Abuse;Opioid;Outcome;Overdose;Persons;Pharmaceutical Preparations;Policy Maker;Population Surveillance;Predictive Analytics;Prevention;Public Health;Randomized Controlled Clinical Trials;Recovery;Reporting;Research;Resource Allocation;Risk;Source;Specific qualifier value;State Government;Statistical Models;Stimulant;System;Time;Universities;Visual;Visualization;Visualization software;Waiting Lists;Work;addiction;alcohol research;biomedical informatics;community led intervention;computerized data processing;data dashboard;data ecosystem;data ingestion;data quality;experience;healing;improved;informatics infrastructure;injury prevention;longitudinal dataset;machine learning algorithm;mobile application;mortality;multiple datasets;next generation;opioid epidemic;opioid exposure;opioid mortality;opioid overdose;opioid use disorder;overdose death;overdose prevention;population based;population health;prevent;public repository;response;statistical and machine learning;trend;web app

public_health_relevance:
Project NarrativeThis project will establish the Rapid Actionable Data for Opioid Response in Kentucky (RADOR-KY) anintegrated population-based near-real time statewide surveillance system that will ingest data from multiplestate agencies and implement advanced informatics algorithms for fast data processing data linkagemachine learning and predictive analytics to shorten the time between data capture and when analyticalresults are available to support opioid overdose prevention and control. RADOR-KY End-User AdvisoryGroup including partners in state government and local communities will guide the development of thereporting and visualization functionality. RADOR-KY will establish a longitudinal dataset accessible thru theRADOR-KY portal and shared within the HEAL Data Ecosystem.


application_id: 11360424
project_number: 4R01DA057686-02
project_title: Fast and fine: NLP methods for near real-time and fine-grained overdose surveillance
administering_ic: NIDA
award_notice_date: 2025-08-07
opportunity_number: RFA-DA-22-044
application_type: 4
activity_code: R01
ic: DA
serial_number: 057686
program_official: KURAMOTO-CRAWFORD, SATOKO JANET
project_start_date: 2022-09-30
project_end_date: 2026-09-29
study_section: ZDA1-JRB-A(12)R
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
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:
This study is part of the NIHs Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction. Timely and accurate estimation of overdose (OD) event rates is an indispensable surveillance component to mit-igate the toll of the ongoing OD epidemic. Getting fast updates for nonfatal ODs is crucial in decreasing further escalations in OD deaths. Traditional approaches to OD surveillance currently rely on CDC's syndromic surveil-lance system and aggregated emergency department (ED) billing data. However national level estimates are plagued by substantial delays. Hence there is an increasing push to monitor (sub)state level datasets including ED and emergency medical service (EMS) records. Meanwhile the role of narrative data in these records is being recognized to offer complementary signal for ODs and drugs leading to them because existing diagnosis code based OD denitions are shown to have lower recall (sensitivity). Even rule-based denitions that search for terms in narratives are missing the sequential semantic context in narrative data. To address these shortcom-ings we propose to design and implement state-of-the-art natural language processing (NLP) models using deep neural networks (DNNs) for OD classication and ne-grained recognition of drug terms leading to ODs. To this end we will rst create and disseminate the rst of their kind public gold standard hand-labeled datasets for these tasks using ED and EMS narratives. Our de-identied notes will be used to build DNN models that will also beshared publicly to the wider OD surveillance community. Our models are expected to improve recall substantially and lead to better nonfatal OD surveillance in a timely manner. We will also develop domain adaption methods to enhance the application of models developed with data from a site to datasets from a different site. Overallour project will create novel public resources (data code models) for the OD surveillance community to leverage latest advances in NLP methods.

project_terms:
Accident and Emergency department;Address;Benchmarking;COVID-19 pandemic;Classification;Clinical;Code;Collaborations;Communities;Computer software;County;Data;Data Set;Death Certificates;Diagnosis;Drug usage;Emergency department visit;Emergency medical service;Epidemic;Evaluation;Event;Goals;Grain;Hand;Health;Helping to End Addiction Long-term;Human;Information Retrieval;International Statistical Classification of Diseases and Related Health Problems Tenth Revision (ICD-10);Kentucky;Label;Learning;Letters;Life;Linear Models;Logistic Regressions;Machine Learning;Manuscripts;Methods;Modeling;Monitor;Naloxone;Names;Natural Language Processing;Neural Network Simulation;Non-linear Models;Opiate Addiction;Opioid;Overdose;Performance;Pharmaceutical Preparations;Public Health;Records;Recurrence;Reporting;Research;Research Personnel;Resource Allocation;Resource-limited setting;Resources;Role;Semantics;Service delivery model;Signal Transduction;Site;Source;Speed;Spottings;Structure;Substance abuse problem;System;Time;Training;Triage;United States National Institutes of Health;Universities;Update;Work;billing data;care delivery;dashboard;data de-identification;data modeling;data reuse;deep neural network;design;disability;experimental study;improved;injury prevention;insight;learning strategy;machine learning method;machine learning model;model building;neural;neural model;novel;open source;opioid misuse;opioid use disorder;overdose death;random forest;stem;supervised learning;syndromic surveillance;tool;transfer learning

public_health_relevance:
NARRATIVEAs the overdose epidemic continues to ravage the nation high quality surveillance efforts to generate timelyand actionable insights are needed. In this project we aim to increase the quality and timeliness of overdoseestimates by leveraging textual narratives authored by emergency department (ED) clinicians and emergencymedical services (EMS) staff. We will produce reusable de-identied ED/EMS textual datasets and machinelearned models to extract overdose information from textual notes.


application_id: 11360392
project_number: 7R01CA262241-04
project_title: PTP1b Inhibition Restores the Innate Anti-tumor Response During Chemotherapy
administering_ic: NCI
award_notice_date: 2025-09-16
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: CA
serial_number: 262241
program_official: CARDONE, MARCO
project_start_date: 2025-07-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZRG1-OTC-D(08)F]
contact_pi_person_id: 12361479
contact_pi: UBIL, ERIC S
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Despite advances in diagnosis and treatment cancer is the second leading cause of death in the UnitedStates. The discovery and targeting of adaptive immune checkpoints (like PD-1 and CTLA4) has been a boonto cancer patients. Unfortunately only a subset of patients will respond and those that do often relapse. In anattempt to improve the efficacy of adaptive immune targeted therapy several clinical trials have been proposedor are underway exploring the combination of checkpoint blockade with chemotherapy. One rationale forcombination therapy is that chemotherapy induces immunogenic tumor cell death which provides robustactivation of the anti-tumor response by releasing neo-antigens and Damage Associated Molecular Patterns(DAMPs) that initiate the innate pro-inflammatory response. We discovered and characterized a novel innate immune checkpoint utilized by tumor cells to suppress theimmune response during chemotherapy. We found that tumor secreted proteins bind and activate themacrophage Mer receptor leading to a reduction in the expression of the key Toll-Like Receptor (TLR) adapterprotein MyD88. In the absence of MyD88 macrophages are no longer able to respond to DAMP/TLR signalingeffectively preventing the pro-inflammatory response during chemotherapy. This suppressive mechanism ischaracteristic of tumors of diverse origins including melanoma lung pancreas and breast cancers. Our mechanistic studies have identified that ligand-activated macrophage Mer induces ternary complexformation increasing the association of Mer Stat1 and a phosphatase known as PTP1b. This complexreduces the phosphorylation and nuclear translocation of Stat1 which leads to a decrease in MyD88expression. Treating with a PTP1b inhibitor blocks this immune suppressive process and restores DAMP-mediated activation in vitro and in vivo. Combining PTP1b inhibition with chemotherapy causes ~50%decrease in tumor growth in multiple murine cancers including chemotherapy resistant models. We hypothesize that by targeting the Mer:PTP1b axis we may be able to improve the innate andsubsequent adaptive immune response during chemotherapy. To test our hypothesis we propose to 1)determine the regulatory mechanism governing tumor secretion of Mer ligands and whether their expression inhuman tumors is predictive of chemotherapy response 2) identify which forms of chemotherapy yield the mostrobust immune activation in combination with PTP1b inhibition and 3) ascertain the effects ofchemotherapy/PTP1b inhibition combination therapy on the adaptive immune response.

project_terms:
Adaptor Signaling Protein;Advanced Malignant Neoplasm;Affect;Agonist;Antitumor Response;B16F10;Binding;Binding Proteins;CTLA4 gene;Cancer Patient;Career Transition Award;Cause of Death;Cell Communication;Cell Death;Characteristics;Chemoresistance;Clinical Trials;Combined Modality Therapy;Complex;Diagnosis;Genetic;Human;Immune;Immune Targeting;Immune response;Immunosuppression;Immunotherapy;In Vitro;Inflammatory;Inflammatory Response;Innate Immune Response;Interferon Type II;Ligands;Macrophage;Macrophage Activation;Malignant Breast Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mediating;Melanoma;Modeling;Molecular;Mus;MyD88 protein;Nuclear Translocation;Patient-Focused Outcomes;Patients;Pattern;Phosphoric Monoester Hydrolases;Phosphorylation;Pre-Clinical Model;Process;Prognosis;Protein S;Proteins;Receptor Activation;Receptor Signaling;Relapse;Signal Transduction;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Time;Toll-like receptors;Tumor-Derived;Tumor-Secreted Protein;Tumor-infiltrating immune cells;United States;adaptive immune response;anti-cancer therapeutic;anti-tumor immune response;checkpoint therapy;chemotherapy;efficacy evaluation;immune activation;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;immunogenic;improved;improved outcome;in vivo;inhibitor;innate immune checkpoint;melanoma model;mouse model;neoantigens;neoplastic cell;novel;patient response;patient subsets;pharmacologic;prevent;programmed cell death ligand 1;programmed cell death protein 1;receptor;response;screening;success;targeted treatment;therapeutic target;treatment response;tumor;tumor growth

public_health_relevance:
PROJECT NARRATIVEAnti-cancer therapeutics targeting the adaptive immune response including checkpoint blockade have been aboon for a subset of patients and are being combined with chemotherapy to further improve outcomes. Wehave identified an innate immune checkpoint utilized by tumor cells to suppress the anti-tumor response duringchemotherapy and based on our mechanistic understanding have discovered a combination therapy (PTP1binhibition/chemotherapy) that improves survival in multiple preclinical models. We propose to 1) determinewhether this immune suppressive mechanism is predictive of patient response to chemotherapy 2) identifywhich chemotherapies yield the most robust response in conjunction with PTP1b inhibition and 3) understandhow our therapeutic affects the adaptive immune response and responsiveness to checkpoint blockade.


application_id: 11357343
project_number: 4R33DA061365-02
administering_ic: NIDA
award_notice_date: 2025-07-23
opportunity_number: RFA-DA-23-053
application_type: 4
activity_code: R33
ic: DA
serial_number: 061365
program_official: HIGHSMITH, KEISHER S
project_start_date: 2024-09-30
project_end_date: 2029-08-31
study_section: ZDA1-SKP-E(M2)R
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: KNIGHT, KEVIN
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: 2025-09-30
project_title:
An innovative trauma-informed approach for reducing overdose risk among women re-entering the community from prison

project_abstract:
Overdose continues to ravage US communities with deaths at an all-time high and women aredisproportionately affected. Overdose deaths among women rose nearly 500% in the past two decades a rate considerably higher than men. Yet overdose prevention approaches that target the unique risks of women particularly those involved in the criminal legal system (CLS) are limited. Considering the complex histories of substance use and violence among justice-involved women there is a need to adapt and implement innovative and targeted intervention strategies that address violent victimization and related problems as part of the substance use disorder (SUD) treatment continuum including the need to target risks prior to prison release andduring community re-entry. This application is submitted in response to RFA-DA-053 with the overall aim of accelerating the translation of research to practice addressing overdose risk for justice-involved women during community re-entry through the adaptation and testing of an innovative trauma-informed relational intervention approach which also closely aligns with NIDAs funding priority area NOT-DA-23-007 to improve substance use outcomes for individuals with a history of violence. Guided by the ADAPT-ITT framework and previous research the R61 phase will focus on achieving 2 specific aims: 1) Adapt TBRI by focusing on two interventioncomponents: prison group sessions and re-entry recovery support. A focus group process will be used that engages key stakeholders (N=30) including administrators practitioners and women with lived experience target alignment with the unique treatment needs of the women and establish intervention feasibility; 2) Pilot test the adapted TBRI-Womens Reentry Approach (TBRI-WRA) intervention components in one group of women in KY (n=8). Final adaptations will be made to TBRI-WRA for the R33 implementation and testing across four sites. The R33 will use a Hybrid Type 1 effectiveness implementation design to achieve the following aims: Aim 3) Examine effectiveness of TBRI-WRA to reduce overdose risk among women (N=264) being released from four in-prison SUD treatment program sites using random assignment of sites to start date. Comparisons will examine (1) Treatment as Usual (TAU standard in-prison SUD treatment n=88) (2) In-prison TBRI (TAU +TBRI prison-based sessions only; n=88) and (3) TBRI + Re-entry Recovery Support (TAU + prison-based TBRI sessions + Re-entry Recovery Support; n=88). The primary outcome is overdose risk defined as any illicit substance use (self-reported and urine drug screen results; excluding alcohol and marijuana) during the 6 months after release from prison; secondary outcomes include trauma-related symptoms and connection(recovery supports emotional regulation and healthy coping) during the 6 months post-release. Aim 4) Examine implementation factors associated with study preparation launch and sustainability guided by the EPIS framework. This study and resulting adapted intervention have the potential for significant impact on overdose risk reduction among justice-involved women re-entering the community with a history of violence exposure.This study is part of the NIHs Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

project_terms:
Acceleration;Address;Administrator;Adolescent;Adult women;Alcohols;Area;Cessation of life;Collaborations;Communities;Complex;Coping Skills;Data;Death Rate;Disproportionately impacts women;Drug Screening;Effectiveness of Interventions;Exclusion;Focus Groups;Funding;Gender;General Population;Group Processes;Helping to End Addiction Long-term;High Risk Woman;Hybrids;Imprisonment;Individual;Intervention;Intervention Strategies;Justice;Kentucky;Legal system;Lived experience;Marijuana;National Institute of Drug Abuse;Opiate Addiction;Opioid;Outcome;Overdose;Overdose reduction;Patient Self-Report;Phase;Preparation;Prevention approach;Prisons;Public Health;Randomized;Recording of previous events;Recovery;Recovery Support;Reporting;Research;Research Personnel;Risk;Risk Reduction;Screening Result;Site;Speed;Substance Use Disorder;Symptoms;Testing;Texas;Time;Translational Research;Trauma;Trust;United States National Institutes of Health;United States Substance Abuse and Mental Health Services Administration;Universities;Urine;Victimization;Violence;Woman;Women's Group;Women's mortality;Youth;access to medications;community reentry;coping;early life adversity;effectiveness evaluation;effectiveness/implementation design;emotion regulation;experience;feasibility testing;implementation determinants;improved;improved outcome;individualized medicine;innovation;men;opioid misuse;overdose death;overdose prevention;overdose risk;pilot test;primary outcome;research to practice;response;secondary outcome;substance use;support network;therapy design;treatment as usual;treatment program;violence exposure;women versus men

public_health_relevance:
PROJECT NARRATIVEThis application is submitted in response to RFA-DA-053 with the overall aim of accelerating the translation ofresearch to practice reduce overdose risk for women during community re-entry following release from prisonthrough the adaptation and testing of an innovative trauma-informed relational intervention approach. Theproposed study closely aligns with NIDAs funding priority area NOT-DA-23-007 to improve substance useoutcomes for individuals with a history of violence.


application_id: 11354406
project_number: 4R01DE033318-02
project_title: Understanding the Association between Sublingual Buprenorphine and Oral Health Outcomes
administering_ic: NIDCR
award_notice_date: 2025-08-14
opportunity_number: RFA-DE-23-015
application_type: 4
activity_code: R01
ic: DE
serial_number: 033318
program_official: BACCAGLINI, LORENA
project_start_date: 2023-09-21
project_end_date: 2028-08-31
study_section: ZDE1-AC(22)
contact_pi_person_id: 15954449
contact_pi: ROJAS RAMIREZ, MARCIA VANESSA
other_pis: OYLER, DOUGLAS
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe standard treatment for opioid use disorder (OUD) involves the use of medications (MOUD) primarilysublingual (SL) buprenorphine due to its accessibility efficacy and tolerability. However recently the Food andDrug Administration (FDA) published an advisory suggesting SL buprenorphine use is linked to oral disease.While compelling this advisory is based on adverse event reports and case reports that did control for importantconfounders such as behavioral and lifestyle factors that may increase the risk in individuals with OUD. More sothese reports were cross-sectional providing limited evidence of rate of progression and incidence of newdisease. Additionally the mechanism by which SL buprenorphine may adversely impact oral health remainsunclear. The long-term goal of this project is to quantify adverse oral events associated with SL buprenorphinefacilitating implementation of interventions and practice recommendations to mitigate the burden of oralcomplications in adults taking SL buprenorphine. The objective of this proposal is to understand if and howSL buprenorphine increases the extent onset and progression of oral disease in adults with OUD. Our centralhypothesis is that SL buprenorphine causes alterations in the oral environment (e.g. reduction in salivaryflow/pH/buffer capacity and microbiome and inflammatory host response changes) that facilitate the incidenceand progression of oral disease. We will test this hypothesis with three aims: 1) characterize baseline extent oforal complication and identify risk factors in adults receiving MOUD 2) test whether SL buprenorphine is a riskfactor for oral disease onset and progression in adults taking MOUD and 3) assess whether SL buprenorphinechanges saliva quantity composition microbial profile or inflammatory host response in adults taking MOUD.To accomplish these aims we propose a prospective multisite cohort study across Kentucky and NorthCarolina leveraging a multidisciplinary team of researchers and clinicians to overcome the limitations identifiedin the literature and expand our understanding of the link between SL buprenorphine and oral disease. We willenroll 372 participants across two states that have been highly impacted by the opioid epidemic and evaluateclinical radiographic physiologic and behavioral information over an 8-month follow-up period. This study isinnovative as it is the first one to: conduct longitudinal follow-up utilize a comparison MOUD group and analyzesalivary characteristics to clarify the mechanisms of sublingual buprenorphine-induced disease and will quantifythe bacterial composition and inflammatory response and correlate to clinical findings. The proposed researchis significant because it will generate data-driven conclusions about the risks associated with oral diseaseextent onset and progression in adults taking SL buprenorphine. These findings can be used to developpreventive interventions to reduce the burden of oral disease and improve health in this population.

project_terms:
16S ribosomal RNA sequencing;Acids;Address;Adult;Adverse event;Affect;American;Anti-Cholinergics;Behavioral;Buffers;Buprenorphine;Case Study;Characteristics;Clinical;Cohort Studies;Complication;Confounding Factors (Epidemiology);Data;Decayed Missing and Filled Teeth;Dental;Dental Hygiene;Dental Plaque Index;Dental caries;Dentistry;Development;Diet;Disease;Disease Outcome;Disease Progression;Economic Burden;Enrollment;Environment;Epidemiology;Event;Fracture;Goals;Half-Life;Health;Health Services Accessibility;Hemorrhage;High Prevalence;Hour;Immune response;Immunology;Immunosuppression;Incidence;Individual;Inflammatory;Inflammatory Response;Kentucky;Link;Literature;Longitudinal Studies;Measurement;Measures;Mediator;Methadone;Mouth Diseases;Naltrexone;North Carolina;Onset of illness;Opioid;Opioid agonist;Oral;Oral health;Outcome;Participant;Patient Self-Report;Patients;Periodontal Diseases;Persons;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Physiological;Population;Property;Prospective cohort study;Publishing;Questionnaires;Recommendation;Recording of previous events;Recovery;Reporting;Research;Research Design;Research Personnel;Risk;Risk Factors;Saliva;Salivary;Sample Size;Severities;Site;Smoking;Standardization;Testing;Time;Tooth Attrition;Tooth Loss;Tooth structure;United States Food and Drug Administration;Visit;absorption;bacterial community;behavioral health;burden of illness;comparison group;cytokine;design;evidence base;follow-up;high risk;implementation facilitation;implementation intervention;improved;indexing;individual response;innovation;insight;lifestyle factors;medication for opioid use disorder;microbial;microbiome;mortality;multidisciplinary;multiple drug use;neglect;opioid epidemic;opioid overdose;opioid use disorder;oral infection;oral microbiome;overdose death;pathogenic bacteria;pharmacologic;preventive intervention;prospective;radiological imaging;standard care

public_health_relevance:
NARRATIVESublingual (SL) buprenorphine is the most common medication used to treat opioid use disorder but FDA datasuggests it may be linked to serious oral complications. While the available evidence is compelling there is aneed to develop large controlled longitudinal studies to assess if SL buprenorphine is a risk factor for oraldisease while accounting for previous history of oral disease and other risk factors. This multidisciplinaryprospective cohort study will examine if and how SL buprenorphine influences the extent onset and progressionof oral disease in patients with opioid use disorder and will produce data-driven conclusions that in will improveour understanding and the implementation of potential treatments to reduce the burden or oral disease in thosetaking SL buprenorphine.


application_id: 11330126
project_number: 4R44HL174221-02
project_title: UroMarker Test Panel for Obstructive Sleep Apnea
administering_ic: NHLBI
award_notice_date: 2025-08-13
opportunity_number: PA-23-230
application_type: 4
activity_code: R44
ic: HL
serial_number: 174221
program_official: DIXIT, SHILPY
project_start_date: 2024-09-20
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1-RCCS-B(11)]
contact_pi_person_id: 14097488
contact_pi: BURNS, CHRISTOPHER THOMAS
other_pis: VALDES, ROLAND
congressional_district: 03
department: Unavailable
primary_duns: 012986391
primary_uei: ZFN5J433DCT1
duns_number: 012986391
uei: ZFN5J433DCT1
fips: US
organization_id: 10019586
organization_name: PGXL TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40206
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY PGXL Technologies is developing a patented non-invasive urine-based assay for obstructive sleepapnea (OSA) in children. OSA occurs in up to 3% of children and as much as 10% of the pediatric orthodonticpopulation. OSA can lead to disturbed sleep neurobehavioral problems neurocognitive impairments andhypertension in children. Diagnosis is primarily limited to in-clinic sleep studies because patient history andphysical examinations are not adequately able to differentiate OSA from primary snoring (PS) i.e. snoringwithout associated sleep apnea or underlying sleep disorder. Polysomnography (PSG) tests are the goldstandard for diagnosis but they are highly expensive require an overnight stay in a supervised sleep clinic aredifficult for children and do not meet the need for screening OSA. There are several home sleep tests (HSTs)that have been cleared for use in children that use similar sensors and methods as PSG studies in the homebut the Academy of Sleep Medicine currently does not recommend the use of HSTs for diagnosis of OSA inchildren due to the lack of physician supervision and a lack of sufficient evidence of efficacy. There is an unmetneed for a rapid and sensitive test for OSA that can be used for potential diagnosis patient monitoring as theyundergo treatment and screening of broader populations. PGXL Technologies is advancing development of aurine-based multiplexed immunoassay for screening children for OSA. The four biomarkers urocortin-3(UCN3) kallikrein-1 orosomucoid-1 and uromodulin are present in urine and have previously shown highsensitivity and specificity for detection of OSA in children using ELISA assays. Prior to this project PGXL hasadapted two of the four biomarkers to the Meso Scale Discovery (MSD) platform a clinical diagnostic platformbased on a highly sensitive electrochemiluminescent detection approach. PGXL has demonstrated initialclinically relevant detection for two biomarkers and acquired a retrospective set of pediatric urine samples thatcan be used to determine reference ranges. The goal of this Fast-Track proposal will be to advancedevelopment through initial clinical validation. In Phase I of this Fast-Track project PGXL will integrateimmunoassays for the remaining biomarkers and optimize the analytical range for each of the assays in theUroMarker panel using pediatric urine specimens. In Phase II PGXL will complete analytical validationrequired to meet CLIA requirements and conduct a prospective study to establish clinical cutoffs for analgorithm that includes all four biomarkers. PGXL will also develop a prototype urine collection kit that can beused for urine collection at home and mailed to a CLIA lab for analysis. Success with these goals will alsoinform a larger multi-site clinical study that is expected in Phase IIb and will support FDA clearance of the test.These milestones provide a path toward the commercial deployment of a high-throughput multiplex test forrapid OSA screening through simple home-based sample collection to improve patient outcomes.

project_terms:
Academy;Adenoidectomy;Advanced Development;Affect;Algorithms;Antibodies;Apnea;Biological Assay;Biological Markers;CLIA certified;Child;Childhood;Clinic;Clinical;Clinical Research;Clinical Trials;Collection;Detection;Diagnosis;Diagnostic Equipment;Diagnostic Procedure;Enzyme-Linked Immunosorbent Assay;Frequencies;Future;Goals;Health;Home;Hypertension;Hypoxia;Immunoassay;Impaired cognition;Institutional Review Boards;Investments;Laboratories;Legal patent;Literature;Measures;Medicine;Methods;Multi-site clinical study;Myocardial dysfunction;Neurocognitive Deficit;Obstructive Sleep Apnea;Orosomucoid;Orthodontic;Patient Monitoring;Patient-Focused Outcomes;Patients;Phase;Physical Examination;Physicians;Polysomnography;Population;Prevalence;Prospective Studies;Proteins;Recording of previous events;Reference Values;Sampling;Sensitivity and Specificity;Severities;Shipping;Site;Sleep;Sleep Apnea Syndromes;Sleep Disorders;Sleep disturbances;Snoring;Specific qualifier value;Specificity;Specimen;Stress;Supervision;System;Technology;Testing;Time;Tonsillectomy;UMOD gene;Urinary Kallikrein;Urine;Validation;biomarker panel;clinical diagnostics;clinical validation;clinically relevant;commercialization;cost;cost effective;design;detection test;diagnosis standard;diagnostic algorithm;diagnostic development;diagnostic platform;experience;improved;improved outcome;in-vitro diagnostics;indexing;multiplex assay;neurobehavioral;novel;prospective;prototype;rapid test;sample collection;screening;sensor;standard care;success;systemic inflammatory response;urocortin

public_health_relevance:
PROJECT NARRATIVE Approximately 3% of children have obstructive sleep apnea (OSA) but many remain undiagnosed dueto limited testing capabilities. Polysomnography tests (overnight sleep studies) are the primary method fordiagnosis of OSA in children but these tests are highly expensive have limited throughput and can be difficultto administer in children. PGXL Technologies is developing a rapid sensitive and cost-effective urine-basedtest for detection of OSA in children which will support rapid cost-effective screening.


application_id: 11329371
project_number: 7R01CA276284-03
project_title: Mechanism of double-negative T cells in antitumor immunity to breast cancer
administering_ic: NCI
award_notice_date: 2025-08-28
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: CA
serial_number: 276284
program_official: LIU, YIN
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: Cellular Immunotherapy of Cancer Study Section[CIC]
contact_pi_person_id: 8264928
contact_pi: ZHANG, HUI
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Breast cancer (BC) the most common cancer globally as of 2021 and accounting for 12% of all new annualcancer cases worldwide is the most commonly diagnosed cancer among American women. Based on theexpression of estrogen receptor alpha (ER) progesterone receptor (PR) and human epidermal growth factorreceptor 2 (HER2) breast cancer can be classified into three major subtypes: luminal subtype (ER/PR+HER2-) HER2+ subtype (ERa/HR- HER2+) and triple-negative subtype (TNBC ERa/HR- HER2-). LuminalHER2+ and TN subtype makes up 70% 15-20% and 15% of BC respectively. BC is metastatic disease.Typical systemic therapies for metastatic BC are endocrine therapy for luminal BC chemotherapy plus HER2-target therapy for HER2+ BC and chemotherapy for TNBC. The median overall survival for metastatic BC is 4-5 years for luminal BC 5 years for HER2+ BC 1 year for TNBC. Once chemoresistance develops metastaticBC is incurable. Cancer immunotherapy has achieved unprecedented success in treating many advancedcancers including TNBC. However the response rate of BC patients to cancer immunotherapy is very lowbecause of the poor tumor infiltration of tumor-infiltrating lymphocytes (TIL). Developing more effective cancerimmunotherapy approaches is critical to treating and curing metastatic BC patients. Using a T cell receptor(TCR) alpha deficient Ja281 KO mouse model we found that transferring thymocytes into Ja281 KO micecould completely inhibit EO771 BC development and growth. We further found that the cell transfer-inducedantitumor immunity was mediated by tissue-resident CD4-CD8- double-negative T (DN T) cells and dependedon NK cells. Deciphering the underlying mechanism will allow us to develop a powerful immunotherapyapproach for BC treatment. The long-term goal of our research is to develop new immunotherapeutic regimensfor cancer treatment. The objective of this project is to decode the mechanism of DN T cells in antitumorimmunity to breast cancer. Our central hypothesis is that the Ja281 KO mice lack a population ofimmunoregulatory T cells which allow the transferred DN T cells to form antitumoral tissue-resident cells toinhibit EO771 tumor development and growth by eradicating tumor cells. We will test this hypothesis bypursuing the following three specific aims: Aim 1: Determine the formation and characterization of tissue-resident DN T cells from the transferred DN T cells in the Ja281 KO mice. Aim 2. Determine the antitumorfunction of tissue-resident DN T/NK cell axis. Aim 3: Determine the cells governing tissue-resident DN T cellformation and antitumor function. The finding that tissue-resident DN T cells can inhibit EO771 tumor formationand growth and eradicate breast cancer is novel. The completion of the proposed research will not only greatlyadvance our knowledge of DN T cells in antitumor immunity but also allow us to develop more effectiveapproaches for BC immunotherapy.

public_health_relevance:
Project narrativeBreast cancers are poorly immunogenic which significantly hampers breast cancerimmunotherapy. The finding that DN T cells can inhibit breast cancer development and growthis novel and has not been explored. Deciphering the cellular and molecular mechanism of howDN T cells orchestrate antitumor immune response in breast cancer will fundamentally advanceour knowledge in tumor immunology and allow us to develop more effective DN T cell-basedcancer immunotherapy for breast cancer treatment.


application_id: 11328229
project_number: 7R01AI184880-02
project_title: Determining role of 14-3-3zeta in IL-17A signaling
administering_ic: NIAID
award_notice_date: 2025-06-12
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: AI
serial_number: 184880
program_official: RICE, JEFFREY S
project_start_date: 2024-06-10
project_end_date: 2029-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 10488587
contact_pi: CHAKRAVARTI, RITU
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:
SummaryInterleukin-17 (IL-17) a pro-inflammatory cytokine is pathogenic in autoimmune diseases such asInflammatory Arthritis (IA). IA affects more than 1% of the worldwide population and remains incurable to date1.Ectopic IL17A expression in mice induces IA phenotype and provides a model to study mechanisms2. Activationof IL-17A receptor (IL-17R) recruits a signaling complex consisting of Act1 and TRAFs (Tumor Necrosis FactorReceptor Associated Factors). Activation of TRAF6 or TRAF2/5 results in transcriptional (IL6) and post-transcriptional (CXCL1) outcomes of IL-17A cytokine. TRAFs often interact with each other and influencesignaling outcomes. The crosstalk between the TRAF6 and TRAF2/5 branches in IL-17A signaling remainsunknown. Our recent PNAS publications showed that 14-3-3z is a novel component of IL-17R signaling andsuppresses IA. In IL-17A signaling 14-3-3z connects the two TRAF branches inhibits TRAF5 but promotesTRAF6. There are two motifs on 14-3-3z that interact and show specificity to TRAF5 and TRAF6 binding. Wealso showed that TRAF5 inhibits TRAF6-dependent IL-17A signaling. Our new preliminary data show that 14-3-3z modifies TRAFs and their interactions with other cellular proteins thus providing clues to its mechanism.Our long-term goal is to understand how 14-3-3z bridges TRAFs in IL-17R signaling and diseases. Wehypothesize that 14-3-3z has a dual role in IL-17 signaling by executing the opposing functions of TRAFsleading to the prevention of IA. We propose to investigate the molecular mechanisms and physiologicalrelevance of the 14-3-3z-TRAF axis in regulating IL-17R signaling and inflammatory arthritis with three specificaims. The first two aims will examine how 14-3-3z regulates TRAF5 and TRAF6 activity connects two branchesand gain an in-depth understanding of 14-3-3zs function in IL-17R signaling. In the third aim we will examinethe physiological relevance of the 14-3-3z-TRAF axis using an innovative IL-17A gene transfer model to study14-3-3z role in chronic IL-17A and IA pathogenesis using 14-3-3z knockout animals. Successful completion ofthis proposal will provide mechanistic insight into how 14-3-3z modifies TRAF proteins and their activityregulates IL-17R signaling and suppresses IA. This study is innovative because by studying 14-3-3zs role inTRAF biology we examine the molecular basis of a novel fundamental immune regulatory axis in IL-17Rsignaling and IA. Our study is significant because understanding 14-3-3z action on TRAFs advances ourfundamental knowledge of protein biochemistry immunology IL-17R signaling IA pathogenesis and otherautoimmune diseases. IA is a challenging disease with limited therapeutic options; therefore a deeperunderstanding of IA pathogenesis is desired. And as TRAFs play a critical role in many receptor signaling theimplications of 14-3-3z functions go beyond IL-17R signaling to many other autoimmune and infectiousdiseases.

project_terms:
Adaptor Signaling Protein;Affect;Animal Model;Animals;Attenuated;Autoimmune Diseases;Binding;Biology;CXCL1 gene;Chronic;Communicable Diseases;Complementary DNA;Complex;Data;Disease;Exhibits;Fibroblasts;Gene Expression;Gene Transfer;Genes;Genetic Transcription;Goals;IL17 gene;Immune;Immunology;Impairment;In Vitro;Inflammatory;Inflammatory Arthritis;Interleukin Activation;Interleukins;Investigation;Joints;Knockout Mice;Knowledge;Link;MAP Kinase Gene;Maps;Mediating;Modeling;Molecular;Molecular Chaperones;Mus;Outcome;Pathogenesis;Pathogenicity;Phenotype;Phosphorylation;Physiological;Play;Population;Predisposition;Prevention;Protein Biochemistry;Proteins;Publications;Publishing;Rattus;Receptor Signaling;Regulation;Research;Rheumatoid Arthritis;Role;Signal Transduction;Specificity;Synovitis;TBK1 gene;TNF Receptor-Associated Factors;TNF receptor-associated factor 5;TNFSF11 gene;TRAF2 gene;TRAF6 gene;Testing;Therapeutic;Tissues;Ubiquitination;Work;cytokine;design;gene induction;in vivo;innovation;insight;interleukin-17E;knockout animal;mouse model;mutant;novel;posttranscriptional;receptor;recruit

public_health_relevance:
Project NarrativeInterleukin-17A (IL-17A) plays an important role in autoimmune diseases; however the limited therapeutic utilityof blocking IL-17A in rheumatoid arthritis points to the gaps in understanding its signaling mechanisms. Werecently published 14-3-3z-TRAF interaction-mediated novel regulation of IL-17A signaling. This proposed workstudies the molecular mechanisms consequences and physiological relevance of 14-3-3z-TRAF interactionsthat will elucidate fundamental knowledge of IL-17A signaling and rheumatoid arthritis.


application_id: 11327964
project_number: 7R01CA288372-02
project_title: Targeting Disease Specific Tn Antigen in Pancreatic Cancer
administering_ic: NCI
award_notice_date: 2025-05-30
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: CA
serial_number: 288372
program_official: HARRIS, RAYMOND D
project_start_date: 2024-12-20
project_end_date: 2029-11-30
study_section: Translational Immuno-oncology Study Section[TIO]
contact_pi_person_id: 10215229
contact_pi: RADHAKRISHNAN, PRAKASH
other_pis: CUMMINGS, RICHARD D
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT / PROJECT SUMMARYPancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Over 80% of PDAC patients have locallyadvanced or highly metastatic disease at diagnosis. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are currentlyused as the standard of care for advanced PDAC patients but responses are incomplete. Thus there is anurgent and unmet need to develop novel targeted therapeutic strategies against PDAC. More than 80% ofPDACs express surface glycoproteins carrying the cancer-associated carbohydrate antigens Tn and Sialyl Tn(STn) whose expression does not normally occur in the pancreas or other tissue and is associated with poorprognosis and reduced overall survival of PDAC patients. In addition to serving as a prognostic biomarker wediscovered that Tn/STn antigens on glycoproteins alter biological activity regarding growth factors and cytokines.Our preliminary data demonstrate that overexpression of Tn/STn antigens enhances PDAC disease progressionand metastasis and reduces the overall survival of tumor-bearing animals. Also induced expression of Tn/STnantigens on glycoprotein receptors and ligands results in the activation of oncogenic signaling cascades throughthe epidermal growth factor receptor (EGFR/ErbB1) and its downstream PI3K/AKT signaling cascades thatincrease the malignant potential of PDAC cells. Treatment of Tn+ cancer cells with a newly developedafucosylated monoclonal antibody (mAb) anti-Tn (aRemab6) induces complement-dependent cytotoxicity(CDC) and antibody-dependent cellular cytotoxicity (ADCC). In addition treatment of Tn+ tumor-bearing animalswith aRemab6 inhibits in vivo tumor growth and metastasis via Natural Killer (NK) cell-mediated ADCC. Wehypothesize that the cancer-specific expression of the Tn antigen plays a major role in PDAC growth metastasisand survival. Therefore we propose (Aim 1) to determine the mechanisms by which Tn antigen enhances PDACtumor progression and identify Tn-expressing glycoproteins by glycoproteomics in the mouse model and clinicalspecimens using a unique set of samples obtained from rapid autopsies of patients that died of PDAC. (Aim 2)We will validate the roles of NK cell in aRemab6-mediated ADCC and evaluate the aRemab6 antibody-inducedantitumor immune response in genetically engineered spontaneous immunocompetent mouse models of PDACthat are further engineered to express Tn antigen on glycoproteins (KPC-CosmcKO). (Aim 3) We will determinethe off-tumor toxicity of aRemab6 and evaluate the therapeutic efficacy of aRemab6 plus gemcitabine/Nab-Paclitaxel against the Tn antigen-expressing immunocompetent spontaneous KPC and KPC-CosmcKO tumormodels. These models closely recapitulate the tumor biology of human PDAC tumors and will aid in translatingthese preclinical findings to human cancer. Together these studies will lead to a new understanding of factorscontributing to pancreatic tumor progression and metastasis. Also the studies in this proposal have the potentialto develop aRemab6-based targeted therapeutic strategy against metastatic PDAC.

project_terms:
AKT Signaling Pathway;Adenocarcinoma;Animals;Antibodies;Antibody Therapy;Appearance;Area;Autopsy;Biological;Breast;Carcinoma;Cell Proliferation;Cell surface;Cell-Mediated Cytolysis;Cells;Characteristics;Client;Clinical;Combined Modality Therapy;Complement-Dependent Cytotoxicity;Data;Development;Diagnosis;Disease;Disease Progression;Effectiveness;Endoplasmic Reticulum;Engineering;Epidermal Growth Factor Receptor;Exhibits;Family;Frequencies;Genes;Genetic Engineering;Glycoproteins;Goals;Growth;Growth Factor;Human;Human Biology;Hypermethylation;Immune response;Immunocompetent;In Vitro;Invaded;KPC model;KRASG12D;Laboratories;Lesion;Ligands;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Membrane Glycoproteins;Modeling;Molecular;Molecular Chaperones;Monoclonal Antibodies;Natural Killer Cells;Neoplasm Metastasis;Oncogenic;Outcome Study;PI3K/AKT;Paclitaxel;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Pharmacotherapy;Play;Polysaccharides;Preclinical data;Prediction of Response to Therapy;Prognosis;Prognostic Marker;Role;Sampling;Signal Transduction;Specimen;Testing;Tissues;Tn antigen;Toxic effect;Translating;Treatment Efficacy;Tumor Biology;Tumor-Associated Carbohydrate Antigens;Tumorigenicity;anti-tumor immune response;antibody-dependent cell cytotoxicity;antitumor effect;cancer cell;cytokine;effectiveness evaluation;efficacy evaluation;gemcitabine;glycoproteomics;improved;in vivo;migration;mouse model;neoplastic cell;new therapeutic target;novel;novel diagnostics;novel therapeutics;overexpression;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;premalignant;receptor;response;sialylation;standard of care;subcutaneous;targeted treatment;treatment response;tumor;tumor growth;tumor progression;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEAberrant expression of tumor-associated carbohydrate antigens Tn and STn augment pancreatic ductaladenocarcinoma (PDAC) progression and metastasis and reduce overall survival via constitutive activation ofthe epidermal growth factor (EGF) receptor family and PI3K/AKT signaling pathways. The major goals of thisapplication are to determine the mechanism by which aberrant expression of Tn/STn enhances PDACprogression and explore the effectiveness of a novel afucosylated anti-Tn antibody (aRemab6) plusgemcitabine/nab-paclitaxel combination as a therapy to treat lethal PDAC.


application_id: 11327187
project_number: 261201800013I-P00014-26100001-2
project_title: SEER CORE INFRASTRUCTURE SUPPORT
administering_ic: NCI
project_start_date: 2018-05-01
project_end_date: 2026-04-30
contact_pi_person_id: 78147083
contact_pi: DURBIN, ERIC
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data.

project_terms:
Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anti-cancer research;cancer statistics;insight;treatment pattern;trend


application_id: 11326121
project_number: 7R01NS111776-06
project_title: Reprogramming reactive glial cells into functional new neurons after SCI
administering_ic: NINDS
award_notice_date: 2025-06-11
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: NS
serial_number: 111776
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2025-03-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-E(02)M]
contact_pi_person_id: 14188836
contact_pi: WU, WEI
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 SUMMARYSevere morbidity and mortality are commonly associated with spinal cord injury (SCI). Human patients whosurvive SCI frequently live with paralysis and extremely reduced quality of life and productivity. SCI often resultsin a permanent loss of neurons and the disruption of neural circuits that are critical for normal motor sensoryand autonomic function. It is crucial to replenish the lost neurons and reconstruct the broken neural circuits forfunctional recovery. Unlike some other tissues or organs in the body such as skin and liver which can undergoself-repair through proliferation of endogenous stem or somatic cells adult spinal cord exhibits minimalregenerative capacity. Cellular transplantation of stem cell-derived neural progenitors or differentiated neuronsholds clinical potential 12-18. However cell therapy is relatively inefficient due to the failure of these cells tosurvive or fully adopt a functional phenotype especially under the chronic phase of neural injury. In contrast totransplantation-based therapy we propose to employ a novel strategy to reprogram endogenous reactive glialcells to mature neurons for functional recovery after SCI. Glial cells are abundant and ubiquitously distributed inthe adult spinal cord. They become reactive proliferate and form glial scars in response to damage and playcritical roles in modulating tissue damage and repair after injury. Of note scar formation and secretion ofchondroitin sulfate proteoglycans (CSPG) by reactive glial cells (e.g. astrocytes) are inhibitory for functionalimprovement. Attenuating reactive gliosis or reducing CSPG activity improves posttraumatic regenerationwhereas increasing reactive gliosis worsens brain injuries. Here we hypothesize that reprogramming reactiveglial cells to neurons at the injury site will reduce local glial scar formation and enhance establishment of newneural circuit resulting in functional recovery. Using a cervical C5 dorsal hemisection model (C5 DH) and forelimbfunctional recovery assessments in adult mice we will test this hypothesis with three specific aims. In Aim 1 wewill determine functional integration of glia-converted neurons after the C5 DH. In Aim 2 we will determine theanatomical integration of glia-converted neurons into local neural circuitry after the C5 DH. Lastly in Aim 3 wewill determine functional roles of descending supraspinal and/or propriospinal pathways over induced neuronsin promoting forelimb functional recovery after the C5 DH. The proposed strategy is expected to providealternative neuronal subtypes that may facilitate functional recovery after SCI.

public_health_relevance:
PROJECT NARRATIVEIn this application we propose to employ a novel strategy to convert endogenous reactive glial cells to newneurons (also called reprogramming) for functional recovery after spinal cord injury (SCI). We hypothesize thatreprogramming reactive glial cells to local new neurons may promote self-repair by the formation of new neuralcircuits for functional recovery. To test this hypothesis three specific aims are proposed to determine 1) thefunctional integration of reprogrammed neurons; 2) the anatomical integration of reprogrammed neurons intolocal neural circuitry; and 3) the functional roles of descending supraspinal and/or propriospinal pathways overreprogrammed neurons in promoting forelimb functional recovery in a model of cervical 5 dorsal hemisection (C5DH).


application_id: 11323332
project_number: 7R01NS131489-02
administering_ic: NINDS
award_notice_date: 2025-08-13
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: NS
serial_number: 131489
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2024-04-01
project_end_date: 2029-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 14188836
contact_pi: WU, WEI
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
budget_start_date: 2025-04-01
project_title:
Converting the glial scar to neurons repairs the injured neural circuits for functional recovery following spinal cord injury

project_abstract:
ABSTRACTThe cellular basis of the central nervous system (CNS) consists of neurons and glial cells. Althoughglial cells massively outnumber neurons in the CNS across species only neurons are speciallyendowed with the ability to communicate precisely and rapidly with other cells at distant sites in thebody. Unfortunately unlike glial cells the adult spinal cord is incapable of generating new neurons. Inaddition the axons also fail to regenerate after the damage even their neuron somas are survived.Thus after the adult spinal cord injury (SCI) the irreversible loss of neurons and disruption of axonslead a permanent functional deficit. The intrinsic reduced regenerative capacity of adult neurons andthe extrinsic inhibitory glial scar formation cause the regeneration failure after spinal cord injury. Anideal spinal repair strategy should 1) replenish neurons for circuit reconstruction 2) modulate theinhibitory glial scar to allow resident neural regeneration and 3) establish new functional neural circuitsfor electrical and chemical signal conduction. Our recent study has confirmed that the spinal cord failsto generate new mature neurons after injury. The critical stem cell factor SOX2 was discovered to bethe key modulator of endogenous reprogramming. We demonstrated that our SOX2-mediatedreprogramming strategy successfully converted the NG2 glia into a great number of new neurons in thelesioned spinal cord and simultaneously reduced the astrocytic glial scar. Furthermore the convertedneurons were able to make synaptic connections to the resident neurons in various areas of the CNSindicating the integration of the converted neurons into the h(1 2)post neural circuits. Importantly italso promoted forelimb functional recovery. Surprisingly our pilot study demonstrated a robustcorticospinal axonal regeneration after SCI. Together we hypothesized that our reprogrammingstrategy significantly modulates the inhibitory glial scar and activates pro-regenerative factorsallowing for axonal regeneration which will restore the signal transduction in the injured spinalcord. We aim to characterize the alteration of the glial scar and pyramidal neurons during thereprogramming process and relate it to axonal outgrowth and circuitry establishment. Thefinding from this proposal is expected to sharpen our understanding of the reprogramming-mediatedaxonal regeneration and neural circuits reorganization for the development of an optimizedreprogramming strategy to treat SCI.

project_terms:
Adult;Area;Astrocytes;Axon;Brain;CSPG4 gene;Cells;Central Nervous System;Cervical;Cervical spinal cord injury;Chemicals;Chronic;Cicatrix;Communication;Corticospinal Tracts;Development;Distal;Distant;Dorsal;Embryo;Endowment;Environment;Epigenetic Process;Failure;Forelimb;Generations;Genes;Genetic;Immunohistochemistry;Injury;Lead;Lesion;Maps;Mediating;Modeling;Molecular;Motor;Motor Cortex;Motor Pathways;Mus;Muscle;Natural regeneration;Nerve Regeneration;Nervous System;Neuroglia;Neurons;Pain;Pilot Projects;Process;Proteins;Recovery of Function;Regenerative Medicine;Regenerative capacity;Regulation;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Role;Sensory;Signal Transduction;Site;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Stem Cell Factor;Structure of rubrospinal tract;Synapses;Synaptic Transmission;System;Techniques;Testing;Therapeutic;Three-Dimensional Imaging;Tissues;Tracer;Transplantation;Viral;Virus;Western Blotting;Work;anterograde transport;axon growth;axon regeneration;combat;designer receptors exclusively activated by designer drugs;experimental study;hippocampal pyramidal neuron;in vivo;induced neural stem cells;injury and repair;mad itch virus;motor function improvement;motor recovery;nerve stem cell;neural circuit;neural repair;neurogenesis;neuron loss;neuronal cell body;neuronal circuitry;optogenetics;permissiveness;programs;reconstruction;regenerative;repair strategy;response;restoration;single-cell RNA sequencing

public_health_relevance:
Project Narrative:Our recent discovery suggests the SOX2-mediated in vivo reprogramming strategygenerated a great number of neurons for neural repair after injury with reduced astroglialscar. The preliminary experiment clearly showed that reprogramming modulates theinhibitory glia scar to a permissive environment for a robust CST axonal regenerationfollowing spinal cord injury. We will therefore investigate the alteration of the glial scarand pyramidal neurons underwent the reprogramming process in order to manipulatethis process through an optimize the reprogramming strategy to treat SCI.


application_id: 11321458
project_number: 1U18FD008567-01
administering_ic: FDA
award_notice_date: 2025-09-24
opportunity_number: PAR-23-202
application_type: 1
activity_code: U18
ic: FD
serial_number: 008567
program_official: MILLER, MEGAN
project_start_date: 2025-09-25
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZFD1 CVM-J (01)]
contact_pi_person_id: 16558681
contact_pi: ROMANO, MEGAN C
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-09-25
project_title:
Multi-laboratory validation of LC-MS/MS analyses of diagnostic samples including animal tissues and feeds for cereulide

project_abstract:
2025 Romano Vet-LIRN Project Summary/AbstractThe Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) Office ofApplied Science's Veterinary Laboratory Investigation and Response Network (Vet-LIRN)safeguards human and animal health by investigating potential animal food or drugcontamination events. During investigation of suspected microbial or chemical contamination ofanimal foods/drugs Vet-LIRN member laboratories can analyze animal diagnostic samples aswell as animal food/drug products. Animal diagnostic sample testing provides additional insightbeyond that obtained from traditional food testing laboratories. Diagnostic investigations requiredetection methods that are validated for biological samples (e.g. vomitus urine feces bloodand tissues) in addition to the typical food matrices. Vet-LIRN laboratories can also providesurge capacity testing during large-scale outbreak situations. In such instances analyticalmethods used and results reported by different laboratories must be comparable to guide sounddecision-making by regulatory officials.The overall objective of this project is to increase the number of robustly validated analyticalmethods available to Vet-LIRN member laboratories to facilitate effective coordinated analysisand reliable results. Specifically we will perform multi-laboratory validation of a method toquantify cereulide an emetic toxin produced by Bacillus cereus which has been implicated infood poisoning of humans as well as animals. The method will first be validated in pet foods atthe method-originating laboratory (UKVDL) and will then be expanded to include diagnosticsamples such as feces vomitus serum tissues and other diagnostic samples. The method willbe transferred to two other Vet-LIRN member laboratories. All participating laboratories will thencomplete a multi-laboratory blinded methods test (BMT) administered by a third party. Finallythe method will be disseminated to Vet-LIRN and its member laboratories via protocols.io.The project will improve human and animal health by increasing the number of shared multi-laboratory validated testing methods available to Vet-LIRN laboratories to use during outbreaksor events of animal feed or drug contamination or adulterations.

public_health_relevance:
2025 Romano Vet-LIRN Project NarrativeThis project will help safeguard human and animal health by enhancing the ability of networklaboratories to respond to outbreaks or events of poisoning due to contaminated animal feeds ordrugs. This will be accomplished by further expanding the number of multi-laboratory validatedanalytical methods available to FDA Vet-LIRN member laboratories and facilitating the effectivecooperation and seamless interactions which are necessary for large-scale emergency/surgecapacity testing.


application_id: 11310277
project_number: 1U19FD008591-01
project_title: KY DPH-DLS Environmental & Food Surveillance Testing
administering_ic: FDA
award_notice_date: 2025-09-18
opportunity_number: RFA-FD-25-007
application_type: 1
activity_code: U19
ic: FD
serial_number: 008591
program_official: LI, MEI-YING
project_start_date: 2025-09-20
project_end_date: 2030-06-30
study_section: Special Emphasis Panel[ZFD1 HFP-D (01)]
contact_pi_person_id: 16381471
contact_pi: JOHNSON, BETH D
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Overall Project Summary: RFA-FD-25-007 3/06/25KY DPH-DLS Environmental & Food Surveillance TestingIn order to properly and effectively conduct food surveillance and provide consumer protection in ourstate regulating entities and laboratories need not just the capability but an enhanced ability toensure that the manufacturing and production standards are being instituted and maintained to thehighest degree of safety and quality. ISO/IEC 17025 standards have become vital to many regulatingbodies when it comes to assessing the reliability and level of food safety practices. Kentucky Divisionof Lab Services (DLS) is fully accredited in both Environmental Microbiology and EnvironmentalChemistry food testing with ISO17025:2017 and maintain a quality management system compliantwith the standard. Our KY SRPs have an agreement with the FDA and maintain the MFRPS standard10 with our support and SRP maintains a Sampling Agreement mirroring the prescribed LFFMSampling Guide. Our current scopes include chemical testing for mercury in fish using the MilestoneDMA-80 and EPA method 7473 also pesticide residue detection and quantification in produceutilizing both AOAC and FERN methods. The scope of microbiological testing for pathogens iscarried out primarily using the FDA BAM but also FERN and AOAC methods. BAX Q7 and ABI 7500PCR analysis includes Salmonella Listeria E. coli O157:H7 and other STECs but also organismsassociated with food quality such as quantification of aerobic coliform and E. coli bacteria. We arealso capable of determining additional information concerning food quality by testing for foodpathogens such as Campylobacter Shigella C. perfringens S. aureus and SE Toxin B. cereus aswell as C. sakazakii. We use the Illumina MiSeq sequencing platform and have established acollaborative agreement with the University of Kentucky College of Agriculture to support the WGSthroughput track by sequencing agricultural isolates for enteric pathogens. We also have an MOU inplace to provide testing of agricultural waters and farm samples when for cause samples arecollected. We perform testing on behalf of the KY State manufactured food regulatory program(MFRPS) in the Department for Public Health / Food Safety Branch which has a current food-safetyinspection contract with the FDA and is enrolled in the MFRPS. As a member of FERN we have theability and facility to support testing for select agents using FERN methods. Both the microbiologyand chemical analysts are in the federal select agent program (SAP) and have access to BSL2 andBSL3 facilities onsite. The KY DLS is active in the Genome Trakr network meetings calls andtrainings. We currently have 2 analysts that have gone through the Galaxy Trakr training and havebeen able to use it to its capacity. We are now fully capable of submitting metadata and sequences toNCBI directly using the NCBI submission portal using this format Bio-sample and SRR. DLS has thecapability to assess sequence quality using the MicroRunQC tool in the GalaxyTrakr portal prior tosubmission. In summary none of this is sustainable without funding and we are more thanready to assist other states and the FDA if the need arises. 1

public_health_relevance:
Overall Project Narrative: RFA-FD-25-007 3/11/25KY DPH-DLS Environmental & Food Surveillance TestingKY DPH-DLS is accredited to the AIHA/ISO17025:2017 standard for food chemistry andmicrobiology. We have access to multiple molecular identification platforms and Massspec for chemistry. We are supported by the KY SRPs/MFRPS and can submitsequencing data using Genome Trakr and NCBI. We are capable of direct reporting tothe FDA via FSDX portal. We can and will share resources when requested.


application_id: 11301607
project_number: 7R01DE027958-06
project_title: Mechanisms underlying spatial interaction in the oral microbiota
administering_ic: NIDCR
award_notice_date: 2025-05-08
opportunity_number: PA-24-254
application_type: 7
activity_code: R01
ic: DE
serial_number: 027958
program_official: MCNEALY, TAMARA L
project_start_date: 2025-03-11
project_end_date: 2026-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9713548
contact_pi: RAMSEY, MATTHEW
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:
ABSTRACTHuman oral plaque is a polymicrobial community whose composition varies during health and disease.Recent advances in technology have yielded new information on the identity and abundance ofconstituent species during these conditions yet do not allow predictions of direct interactions betweenspecific organisms. The biogeography of reproducible structures within supragingival plaque has beencharacterized through advanced microscopy methods suggesting key organisms that may help arrangeplaque structure. Species-species co-proximity within these ordered structures is suggestive ofmetabolite mediated interactions between them. Our global hypothesis is that adjacent species in healthyplaque biofilms have specific metabolic and physical interactions that shape both the physical andcompositional structure of this community. To identify mechanistic interactions between adjacentspecies we must determine which species exist together in vivo. Preliminary data indicates that thehighly abundant Corynebacterium matruchotii and Haemophilus parainfluenzae bacterial species existdirectly adjacent to several Streptococcus spp. suggesting they must be able to tolerate pH and oxidativestress produced by oral streptococci. Direct imaging further suggests that some species bind directly toeach other or mutually to a host intermediate such as salivary protein. The physical means of attachmentfor C. matruchotii and H. parainfluenzae to Streptococcus spp. are unknown. This proposal willdetermine which Streptococcus species interact with C. matruchotii and H. parainfluenzae viamicroscopy (Aim 1). It will also determine if C. matruchotii and H. parainfluenzae participate in cross-feeding interactions with streptococcal produced metabolites and will identify mechanisms that eitherbacterium uses to tolerate pH and oxidative stress through transcriptome analyses mutant libraryassays and quantitative metabolite measurements (Aim 2). Lastly our proposal will determine physicalfactors produced by bacteria that are responsible for co-adhesion between different species. These willbe identified by direct and random mutagenesis of C. matruchotii and H. parainfluenzae and tested incombination with known interacting Streptococcus species. The goal of this proposal is to identifyinteracting species in healthy supragingival plaque and characterize mechanistic interactions betweenthem revealing how they may contribute to plaque structure and composition. Our rationale is that wewill identify mechanisms that promote interactions between highly abundant organisms in healthy plaqueand identify candidate species and their associated interactions for use in probiotic or prophylacticinterventions to manage oral plaque communities to prevent opportunistic infection.

public_health_relevance:
PROJECT NARRATIVEAdvances in sequencing technology have provided considerable data on relative abundance and identityof constituents of the polymicrobial human plaque biofilm and how these shift between health and oraldisease. However sequence data alone is insufficient to determine which species exist directly adjacentto each other implying interaction and the mechanism(s) of interactions between bacteria in healthycommunities. The goal of this proposal is to unite sequencing and microscopy technology to identifyinteracting species in healthy supragingival plaque and characterize mechanistic interactions betweenthem revealing ways in which they may preserve healthy plaque structure and constituency andpotentially prevent oral disease.


application_id: 11297635
project_number: 4RF1AG078338-02
project_title: Function of ceramide in extracellular vesicle-mediated neurodegenerative disease
administering_ic: NIA
award_notice_date: 2025-09-02
opportunity_number: PA-20-185
application_type: 4
activity_code: RF1
ic: AG
serial_number: 078338
program_official: DIBATTISTA, AMANDA
project_start_date: 2022-09-01
project_end_date: 2027-08-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alzheimers disease (AD) is characterized by the buildup of Amyloid  (A) peptide and hyperphosphorylatedtau both of which drive neurodegeneration and cognitive decline. There is no clarity as to how A and taudamage neurons. A critical knowledge gap and barrier to progress is the lack of a thorough understanding offactors that may enhance neurotoxicity of A and tau. Our previous studies have shown that in response to Aproduced by neurons astrocytes secrete extracellular vesicles (EVs) or astrosomes which are enriched withthe sphingolipid ceramide and bind to A. We discovered that these A-associated astrosomes (AAAs) induceneurodegeneration in AD which can be prevented by inhibition or deficiency of neutral sphingomyelinase 2(nSMase2) an enzyme that generates ceramide by hydrolysis of the membrane lipid sphingomyelin. Thereforewe hypothesize that ceramide is a key factor mediating AAA formation and neurotoxicity and preventing AAAformation and neurotoxicity by inhibiting ceramide generation is a novel strategy for AD therapy.Our studies showed that improvement of AD pathology and cognition by nSMase2 inhibition or deficiency wereonly detected in male mice indicating that additional enzymes in ceramide metabolism contribute to AAAformation and neurotoxicity independently of nSMase2. Our goal is to define enzymes in ceramide metabolismunderlying a sex-specific dimorphism in AAA formation and neurotoxicity and develop novel drug approachesthat are effective in both sexes.In our Specific Aims we will use novel and innovative approaches particularly using new mouse modelsanalytical techniques and drugs to understand the sex-specific AAA formation and target ceramide metabolismto interfere with the formation of AAAs in astrocytes (Specific Aim 1) and their neurotoxicity in neurons (SpecificAim 2) to prevent AD pathology and improve cognition independent of sex (Specific Aim 3).The impact of our study on public health is to generate knowledge that leads to the development of novel ADtherapies. While the primary focus of our study is ceramide and A in AAAs some identified factors may also beapplicable to the neurotoxicity of tau.

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

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


application_id: 11289064
project_number: 5P20GM148326-03
administering_ic: NIGMS
award_notice_date: 2025-05-07
opportunity_number: PAR-19-313
application_type: 5
activity_code: P20
ic: GM
serial_number: 148326
program_official: PEI, WUHONG
project_start_date: 2024-10-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-4(C1)
subproject_number: 6814
contact_pi_person_id: 10807626
contact_pi: PINTO, AMELIA KAHLER
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Changes in Cellular Metabolism Associated with Metabolic Syndrome Increase the Severity of Neurotropic Viral Infections

project_abstract:
Studying how viruses evolve in people with metabolic imbalances is an important and emerging area of research. People with Metabolic Syndrome (MetS)  a condition characterized by serious metabolic issues  tend to have higher death rates longer hospital stays and worse outcomes when infected by viruses. This is especially true for viruses that affect the brain like West Nile Virus (WNV). Currently over one-third of the U.S. population has MetS and nearly 40% of people in Kentucky are affected. MetS significantly disrupts cellular metabolism impacting brain function as well. Despite this the link between these metabolic issues and how viruses behave in the brain remains largely unexplored. We know that people with MetS have worse outcomes after viral infections and viruses are known to alter host metabolism. However there is no direct proof that the metabolic problems of MetS make viral infections more severe. Our goal in this study is to explore how changes in brain metabolism caused by MetS lead to more severe viral infections. We believe that the imbalance caused by MetS increases WNV activity and leads to more severe disease outcomes in the brain. To investigate this we will use advanced techniques to compare brain metabolism in healthy mice and mice with MetS. Our hope is to identify the specific metabolic changes that lead to increased viral activity and disease severity.

project_terms:
Affect;Area;Brain;Centers of Research Excellence;Death Rate;Disease Outcome;Goals;Kentucky;Lead;Length of Stay;Link;Metabolic;Metabolic syndrome;Metabolism;Mus;Outcome;Persons;Population;Research;Severities;Severity of illness;Techniques;Viral Physiology;Virus;Virus Diseases;West Nile virus;brain metabolism;neurotropic


application_id: 11272419
project_number: 1R21ES038074-01
project_title: Environmental and Health Assessment Following the Westlake Vinyl Fire: A Time-Sensitive Study
administering_ic: NIEHS
award_notice_date: 2025-09-11
opportunity_number: RFA-ES-25-003
application_type: 1
activity_code: R21
ic: ES
serial_number: 038074
program_official: O'FALLON, LIAM
project_start_date: 2025-09-12
project_end_date: 2027-09-11
study_section: Special Emphasis Panel[ZES1 LWJ-D (TS)]
contact_pi_person_id: 15852364
contact_pi: SMITH, TED R.
other_pis: HUNTINGTON-MOSKOS, LUZ G
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:
R21 Calvert City Abstract Environmental pollution from industrial activities in Calvert City Kentucky has raised signicant public health concerns following a recent industrial accident involving the release of ethylene dichloride and other hazardous air pollutants. This project addresses the urgent need for comprehensive environmental and clinical monitoring to evaluate the health risks posed by such exposures particularly given the occurrence of multiple cases of hemangiosarcoma a rare and aggressive cancer associated with exposure to these chemicals. Combining innovative environmental monitoring methods with community engagement and medical surveillance this study seeks to identify exposure pathways assess subclinical biomarkers and empower affected residents. Through the establishment of air quality monitoring sites wastewater surveillance and quarterly biological sampling the project will generate a holistic view of exposure and health risks. Advanced metabolomics analysis will be applied to measure biomarkers linked to the pathogenesis of hemangiosarcoma and related health conditions. Additionally a rapid-response framework will be developed to enable timely environmental and clinical data collection in the event of future incidents. Community engagement will play a central role with affected residents actively involved in data collection and dissemination to ensure their voices are heard and their concerns addressed. This two-year study will produce actionable data to inform community advocacy public health interventions and policy recommendations aimed at reducing cancer and cardiometabolic disease risks in Calvert City. By integrating environmental and clinical monitoring with community science this project will not only advance the scientic understanding of industrial pollution impacts but also contribute to supporting the long-term well-being of the community.

project_terms:
Acids;Address;Advocacy;Affect;Air;Air Pollutants;Area;Benzene;Biological;Biological Markers;Biological Monitoring;Blood;Breast Cancer Risk Factor;Carcinogens;Cardiometabolic Disease;Chemicals;Cities;Clinical;Clinical Data;Collection;Communities;Complex;Data;Data Collection;Disasters;Dose;Ensure;Environmental Exposure;Environmental Monitoring;Environmental Pollution;Ethylene Dichlorides;Event;Exhibits;Exposure to;Face;Fire - disasters;Funding;Future;Goals;Health;Health Care;Hearing;Hemangiosarcoma;Hepatic;Home;Human;Huntington Disease;Individual;Industrial Accidents;Industrialization;Industry;Kentucky;Laboratories;Link;Liver;Liver Fibrosis;Malignant Neoplasms;Measures;Medial;Medical Surveillance;Methods;Monitor;National Institute of Environmental Health Sciences;Nurses;Pathogenesis;Personal Satisfaction;Plants;Play;Poison;Policies;Pollution;Population;Predisposition;Process;Public Health;Recording of previous events;Registered nurse;Reporting;Research;Research Personnel;Resources;Risk;Role;Rural;Sampling;Scientific Advances and Accomplishments;Scientist;Sentinel;Series;Site;Strategic Planning;Symptoms;Time;Toxicology;Universities;Urine;Vinyl Chloride;Voice;air monitoring;cancer diagnosis;carcinogenicity;chemical accident;chemical release;community engaged approach;community engagement;community science;data dissemination;disorder risk;empowerment;experience;exposure pathway;health assessment;innovation;liver function;liver injury;manufacturing facility;member;metabolomics;monomer;policy recommendation;public health intervention;rare cancer;response;urinary;wastewater monitoring;wastewater surveillance

public_health_relevance:
NARRATIVEThis project will assess the health risks associated with industrial pollution in Calvert CityKentucky where recent chemical releases have raised concerns about exposure to hazardous airpollutants. By monitoring air and wastewater for harmful chemicals and analyzing biologicalsamples from residents the study will provide critical data on environmental exposures and theirpotential health effects. The findings will help inform public health interventions supportcommunity advocacy and guide policies to reduce future risks.


application_id: 11261387
project_number: 1RM1DA064496-01
project_title: Kentucky Women's Justice Community Overdose Innovation Network - Phase II
administering_ic: NIDA
award_notice_date: 2025-08-27
opportunity_number: RFA-DA-25-025
application_type: 1
activity_code: RM1
ic: DA
serial_number: 064496
program_official: SU, SHELLEY
project_start_date: 2025-09-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZRG1 SCIL-T (50)]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: OSER, CARRIE BETH
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:
ABSTRACT Overdose deaths among women rose nearly 500% in the past two decades a rate considerably higher than men. Yet overdose prevention approaches that target the unique risks of women particularly those involved in the criminal legal system (CLS) in underserved rural areas are limited. This application proposes to continue our work with women in the Kentucky Womens Justice Community Overdose Innovation Network Phase II (WJCOIN-II) with the overall aim of reducing overdose risk during the transition from jail to rural communities. Specific aims include: Aim 1: Compare the effectiveness of pre-release RC to RC+SPE in decreasing womens overdose risk during re-entry to rural communities. Through a multi-site 2 X 2 factorial design women will be randomly assigned to two pre-release conditions (1) Recovery Coaching (RC) only or (2) RC + support person engagement (SPE) to reduce overdose risk through the development of an overdose prevention plan and increase motivation for treatment entry within one-month post-release. Aim 2: Compare the additive effectiveness of CM initiated post-release to RC alone and RC+SPE in decreasing overdose risk and increasing treatment entry and retention among women during re-entry to rural communities. The 2 X 2 factorial randomized design also includes assignment to one of two post-release conditions: 1) continuation of pre-release intervention (RC or RC+SPE) only in the community through ongoing sessions or 2) addition of contingency management (RC+CM or RC+SPE+CM) to incentivize target behaviors (reduced days of drug use). Depending on treatment entry by the one-month post-release period (non-initiators vs. initiators of treatment) the following aims will be examined post-release from jail: Aim 2a. Among non-initiators examine the additive effectiveness of post-release CM to reduce overdose risk. Aim 2b. Among treatment initiators examine the additive effectiveness of post-release CM to increase treatment retention. Aim 3: Contextualize effectiveness of intervention components by examining the roles of perceived acceptability and appropriateness and identify barriers and facilitators to intervention implementation across the re-entry continuum. Acceptability and appropriateness of intervention components from the perspectives of women and public safety/public health stakeholders (e.g. jail staff RCs treatment providers) will be measured through individual- level survey data collection. Aim 4: Examine economic impact of the WJCOIN-II interventions pre-release and post-release in reducing womens overdose risk in rural communities. Cost effectiveness and net societal costs will be assessed by incorporating clinical (overdose risk) and service utilization (treatment entry) outcomes using tailored budget impact tools. The study will make a significant impact regarding the effectiveness implementation and sustainability of innovative overdose prevention strategies during the high-risk time of community re-entry among vulnerable CLS-involved women in rural communities. This study is part of the NIHs Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

project_terms:
American;Behavior;Cessation of life;Characteristics;Clinical;Communities;Data Collection;Death Rate;Development;Drug Screening;Drug usage;Effectiveness;Effectiveness of Interventions;Event;Funding;General Population;Health Personnel;Health Services Accessibility;Helping to End Addiction Long-term;Imprisonment;Incentives;Individual;Intervention;Interview;Jail;Joints;Justice;Kentucky;Legal system;Measures;Motivation;National Institute of Drug Abuse;Network-based;Opiate Addiction;Opioid;Outcome;Overdose;Overdose reduction;Patient Self-Report;Persons;Phase;Positioning Attribute;Prevention approach;Prevention strategy;Public Health;Randomized;Records;Recovery;Reporting;Research;Research Personnel;Resources;Risk;Risk Reduction;Role;Rural Community;Safety;Saliva;Site;Speed;Stimulant;Surveys;Time;United States National Institutes of Health;Woman;Women's mortality;Work;access to medications;budget impact;community reentry;compare effectiveness;contingency management;cost;cost effectiveness;cost-effectiveness ratio;design;economic impact;effective intervention;effectiveness/implementation trial;experience;follow-up;group intervention;health assessment;high risk;implementation facilitators;implementation intervention;improved;incremental cost-effectiveness;innovation;intervention cost;medication for opioid use disorder;member;men;motivational enhancement therapy;naloxone dispensing;opioid misuse;overdose death;overdose education;overdose prevention;overdose risk;overdose risk behaviors;preventive intervention;response;rural area;service utilization;societal costs;telehealth;tool;underserved rural area

public_health_relevance:
PROJECT NARRATIVEThis application submitted in response to RFA-DA-25-025 to continue our work with women in the KentuckyWomens Justice Community Overdose Innovation Network Phase II (WJCOIN-II) with the overall aim ofreducing overdose risk during the transition from jail to rural communities. WJCOIN-II has potential for significantimpact regarding the effectiveness implementation and sustainability of innovative overdose prevention strategiesduring the high-risk time of community re-entry among vulnerable CLS-involved women in rural communities. Thisresearch will impact the field by increasing the capacity of the criminal legal system to respond to the overdosecrisis through increased access to prevention strategies to reduce overdose risk.


application_id: 11257007
project_number: 1K01AG092253-01A1
administering_ic: NIA
award_notice_date: 2025-08-22
opportunity_number: PA-24-175
application_type: 1
activity_code: K01
ic: AG
serial_number: 092253
suffix: A1
program_official: RICE, ELISE
project_start_date: 2025-08-22
project_end_date: 2030-07-31
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 12522880
contact_pi: CONNER, LANESHIA RAE'
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Feasibility Acceptability and Preliminary Efficacy of an HIV Prevention Intervention for Older Black Women

project_abstract:
ABSTRACTBlack women continue to be disproportionately impacted by HIV making up less than 15% of the femalepopulation yet accounting for half of new HIV infections in women in the United States. While both younger andolder Black women engage in high-risk sexual behaviors older Black women are not concerned withpregnancy prevention and are less likely to use condoms which places them at risk for contracting HIV. Alsoolder Black women are often overlooked when it comes to HIV prevention services due to ageism and stigmaabout high-risk behaviors among older adults and lack of an empirical base about their sexual behavior. Dr.Laneshia Conner a junior faculty member in the College of Social Work at the University of Kentucky is inactive pursuit of developing her research skills to become an independent researcher through further training incommunity engagement mixed-methods analyses implementation science and professional development bymentors who are well funded by NIH and have a history of training early career faculty members. Through theproposed research strategy and training plan for this K01 Career Development Award through NIA Dr. Connerwill acquire skills to launch her research program in four areas: community-engaged research among olderadults mixed methods research intervention development and expansion of professional skills for asuccessful research career. The proposed project will revise and implement the Woman 2 Woman (W2W)intervention after it is adapted to address unique gaps in HIV prevention that target older Black women.Working with two low-income housing complexes for adults over the age of 50 and a community center thatserves the Black community older Black women will be recruited to participate in a multisession group-levelbehavioral intervention adapted to address both physiological risk as well as low perception of risk. Highunknown serostatus suggest that HIV prevalence may be higher than reported among older adults. The overallobjective of this innovative project is to add reproductive health histories as an intervention component ofWoman to Woman (W2W) an HIV intervention for older Black. Specific aims are: (1) Revise the W2Wintervention for older Black women to identify and incorporate key reproductive health history themes and (2)Implement the revised W2W group-level intervention for older Black women to evaluate feasibilityacceptability and preliminary efficacy through a small pilot RCT. This project provides an interventionmanualized protocol on how to adapt an HIV prevention intervention for older Black women; and preliminarydata on the feasibility acceptability and preliminary efficacy of the intervention outcomes. Secondlyimplementation and assessment procedures will inform a subsequent full-scale R01 randomized clinical trial.Lastly health disparities researcher Dr. Conner will complete career development opportunities that align withdevelopment an intervention of HIV risk reduction among older Black women.

project_terms:
AIDS prevention;Accounting;Address;Adult;Age;Ageism;Aging;Applications Grants;Area;Behavior;Behavior Therapy;Behavioral;Behavioral Model;Behavioral Research;Black American;Black race;Characteristics;Code;Communities;Complex;Contraception Behavior;Contracts;Control Groups;Data;Decision Making;Development;Dropout;Eligibility Determination;Evaluation;Evidence based intervention;Faculty;Female;Focus Groups;Funding;Goals;HIV;HIV Infections;HIV risk;Health;Housing;Human immunodeficiency virus test;Informed Consent;Intervention;Interview;K-Series Research Career Programs;Kentucky;Knowledge;Life Cycle Stages;Low income;Manuals;Measures;Mentored Research Scientist Development Award;Mentors;Mentorship;Methodology;Methods;Mission;Names;Outcome;Participant;Patient Self-Report;Physiological;Population;Prevalence;Principal Investigator;Procedures;Production;Protocols documentation;Public Health;Randomized;Randomized Controlled Trials;Recording of previous events;Reduce health disparities;Reporting;Reproductive Health;Research;Research Methodology;Research Personnel;Research Support;Risk;Risk Behaviors;Risk Reduction;Scientist;Sex Behavior;Sexual Health;Sexual Transmission;Social Characteristics;Social Work;Specialist;Structure;Testing;Training;Treatment Efficacy;United States;United States National Institutes of Health;Universities;Vulnerable Populations;Waiting Lists;White Women;Woman;Women's Group;Work;base;behavioral construct;black women;career;career development;college;community center;community engaged research;community engagement;condoms;data reduction;early-career faculty;economic disparity;evidence base;follow-up;group intervention;health disparity;high risk behavior;high risk sexual behavior;implementation science;implementation strategy;improved;infected women;informant;innovation;intervention refinement;member;multidisciplinary;older adult;older women;post intervention;pregnancy prevention;prevention practice;prevention service;preventive intervention;programs;randomized clinical trials;recruit;retention rate;risk perception;satisfaction;sexual HIV transmission;skill acquisition;skills;social stigma;social structure;success;testing uptake;therapy development;transmission process;women's reproductive health

public_health_relevance:
Project NarrativeThere are no known evidence-based interventions targeting the prevention of HIVtransmission among older Black women in the U.S. which is a major public healthconcern as there is a growing aging Black American population living with HIV. Theobjective of this innovative project is to provide the applicant Dr. Laneshia Conner withtraining and professional development to improve methodological and proceduralconsiderations for an HIV intervention name Woman to Woman (W2W). This study willrefine an HIV intervention protocol for older Black women provide a reproductive healthhistory template that is directly informed by this population develop and deliver atheoretically grounded multi-session HIV group-level intervention to reduce HIV riskand capture implementation strategies to reduce HIV transmission among thisvulnerable group.


application_id: 11253983
project_number: 1R43AG097165-01
administering_ic: NIA
award_notice_date: 2025-09-18
opportunity_number: PA-24-245
application_type: 1
activity_code: R43
ic: AG
serial_number: 097165
program_official: TSAP, LEONID V
project_start_date: 2025-09-20
project_end_date: 2026-09-19
study_section: Special Emphasis Panel[ZAG1 ZIJ-T (M3)]
contact_pi_person_id: 78337369
contact_pi: DWARAKA, VARUN BHAMIDIPATI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 118211534
primary_uei: DCV4HAV3YQB4
duns_number: 118211534
uei: DCV4HAV3YQB4
fips: US
organization_id: 10066423
organization_name: TRU DIAGNOSTICS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405032748
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-09-20
project_title:
Creation of Dynamic Non-Stochastic W Function Informed Methylation Risk Scores (MRS) for Diagnostic/Therapeutic Applications

project_abstract:
PROJECT SUMMARYCurrent disease diagnostic methods for chronic diseases rely heavily on tools that capture stochastic and causalbiological states failing to capture the dynamic nature of the diseases. The proposed project aims to develop agroundbreaking solution by creating a non-stochastic "W Function Epigenomic Roadmap" using systems-baseddynamical modeling to address these limitations. Unlike causal and stochastic measures this algorithm willsystematically quantify the dynamic interactions of epigenetic markers over time using longitudinal data.TruDiagnostic is uniquely positioned to lead this effort due to its established expertise in epigenetic testingproprietary algorithms and a robust network of healthcare providers. The projects high-level aims include (1)developing a network of epigenetic markers based on the W Function focusing on shifts in homeostatic setpoints over time; (2) validating these findings in two chronic disease models and mortality to understand howstability in epigenetic networks is altered in disease states; and (3) assess whether our novel algorithms are ableto capture more dynamic changes associated with treatments and interventions compared to traditional DNAmalgorithms. The expected outcome is a transformative diagnostic tool that will allow for personalized dynamichealth forecasts and identification of critical points for early intervention offering new pathways for treatment andimproving health outcomes across chronic diseases.

project_terms:
Address;Aging;Algorithms;Biological;Cardiovascular Diseases;Chronic Disease;Clinical;Complex;Data;Data Set;Development;Diagnostic;Diagnostic Procedure;Dimensions;Disease;Disease Progression;Drug Targeting;Early Diagnosis;Early Intervention;Early identification;Environmental Risk Factor;Epigenetic Process;Etiology;Exposure to;Face;Grouping;Health;Health Care;Health Personnel;Individual;Industry;Intervention;Lead;Life Style;Link;Maps;Marketing;Measures;Methylation;Modeling;Nature;Non-Insulin-Dependent Diabetes Mellitus;Onset of illness;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Population;Positioning Attribute;Recovery;Risk;Risk Factors;Signal Transduction;System;Testing;Therapeutic;Therapeutic Agents;Time;Variant;Weight;Work;age related;aging mechanism;biobank;biological age;cohort;comparison intervention;cost effective;denoising;diagnostic tool;disease diagnosis;disease diagnostic;disease model;disorder prevention;disorder risk;drug development;effective therapy;epigenetic clock;epigenetic marker;epigenetic regulation;epigenomics;frailty;glucagon-like peptide 1;hazard;improved;large datasets;longevity intervention;longitudinal analysis;longitudinal dataset;mortality;novel;polygenic risk score;predictive tools;time use;tool;trait

public_health_relevance:
PROJECT NARRATIVEChronic disease progression is often influenced by environmental factors as well as aging and current diagnostictools rely on stochastic and causal tools which fail to capture its dynamic nature. This project will develop adynamic non-stochastic "W Function Epigenomic Roadmap" to quantify the time-dependent interactions ofepigenetic markers enabling more accurate predictions of health trajectories. With TruDiagnostics expertise inepigenetic testing and proprietary algorithms this roadmap will offer personalized health forecasts and identifyearly intervention points for disease prevention.


application_id: 11248163
project_number: 7R35GM150599-03
project_title: Bacterial ribosome heterogeneity and gene expression
administering_ic: NIGMS
award_notice_date: 2025-05-15
opportunity_number: PAR-20-117
application_type: 7
activity_code: R35
ic: GM
serial_number: 150599
program_official: REDDY, MICHAEL K
project_start_date: 2023-08-15
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZRG1-MGG-J(55)R]
contact_pi_person_id: 10506803
contact_pi: RAMSEY, KATHRYN MARY
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:
PROJECT SUMMARY As antibiotic resistance increases globally there is an urgent need for new drugs tocombat bacterial infections. Approaches to developing new antimicrobials include inhibitingessential steps in gene expression and inhibiting virulence factor production. The overarchingfocus of the research program in my laboratory is to understand how bacterial cellsregulate gene expression to ultimately identify novel targets for antimicrobialdevelopment. The research funded by this award will leverage the Ramsey laboratorysexpertise in bacterial genetics and state of the art technologies to examine the impacts ofribosome heterogeneity in multiple bacterial species. The Ramsey laboratory identified aspecific homolog of the ribosomal protein bS21 that governs virulence gene expression in abacterial pathogen. These findings suggest that heterogeneity in ribosomes which are significantdrug targets can lead to changes in gene expression. The impacts of ribosome heterogeneity ontranslation gene expression and drug efficacy are generally not well understood and representkey gaps in our knowledge. Over the next five years we propose to continue our studies tounderstand the effects of ribosome heterogeneity on multiple bacterial species. The proposedwork is innovative because it takes a rigorous reductionist approach to examine one poorly-understood source of ribosome heterogeneity with species-specific impacts on translation toelucidate fundamental features of translation and inform the design of novel antimicrobials. Ourgoals include determining how multiple bS21 homologs function to govern gene expression whybS21 is essential in some cells and how bS21 contributes to antibiotic sensitivity. We expect ourwork will allow us to make clear connections between ribosome composition and functionaloutcomes as we will limit the complexity of ribosomal heterogeneity to changes in a singleribosomal protein bS21. Expected future work will include developing screens for novel specificribosome inhibitors and studying the function of bS21 or other independent sources of ribosomeheterogeneity in these and/or other organisms. Ultimately our studies will provide key insights intoribosome function gene expression and may identify novel targets for antimicrobial drugs.

public_health_relevance:
NARRATIVEAntimicrobial resistance is an increasing public health threat in the United States and there is anurgent need to develop novel antimicrobials. The work proposed here will improve ourfundamental knowledge of a key antibiotic target the ribosome and potentially reveal newavenues for antimicrobial development.


application_id: 11246639
project_number: 1R13HL182218-01
project_title: Don S. Fredrickson Lipid Research Conference
administering_ic: NHLBI
award_notice_date: 2025-08-15
opportunity_number: PA-25-080
application_type: 1
activity_code: R13
ic: HL
serial_number: 182218
program_official: LIU, LIJUAN
project_start_date: 2025-09-01
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZHL1 CSR-O (M1)]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
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:
The Don S. Fredrickson Lipid Research Conference (FLRC) brings together scientists and trainees investigating the impact of lipid and lipoprotein metabolism on the development and treatment of Cardiometabolic Disease. The FLRC is named after the late Don S. Fredricks who as the director of the National Heart Institute (now the NHLBI) from 1966  1974 and later the NIH developed the clinical classification for dyslipidemias (Type I-V) described Tangiers Disease and made seminal discoveries in lipoprotein metabolism. Most importantly he trained both basic and clinical scientists and practitioners who have had a tremendous impact on the field of lipoprotein metabolism.Since 2016 the FLRC has employed a rotating institutional host model and has been hosted by the University of Kentucky (16 17 21) Vanderbilt University (18 23) the University of Cincinnati (19) Duke University and the University of North Carolina (22). The FLRC will be hosted by the Medical College of Wisconsin in 2025 and return to UK in 2027.Keynote Lectures at the 2025 Fredrickson conference include Ira Tabas Columbia University and David Ginsburg University of Michigan. The thematic scientific sessions include Genetic determinants of lipids and CVD; Lipoprotein structure and omics; Immune cell lineage/immunity and lipids in CVD; Microvascular adipose and lipids; Novel perspectives in lipid research; and Lipids in atherothrombosis and hemostasis. The FLRC places a strong emphasis students fellows and early career faculty. In accordance with that mission the agenda also includes additional scientific talks dedicated for trainees a Research Blitz session (90-second presentations) and a judged poster session. By design the agenda affords every trainee in attendance the opportunity to present their research on stage network with leaders in the field and broaden their scope and understanding of research in lipid metabolism and Cardiometabolic Diseases.Our format encourages informal interactions between scientists at all levels providing an innovative approach to the exchange of ideas and synthesis that will move the field of lipid research forward. The conference will have high impact as the program spans basic science discovery to clinical significance. It is therefore expected that the meeting will provide new insights not only into basic aspects of lipid metabolism but also how to treat and ultimately cure a wide variety of Cardiometabolic Disease states.

project_terms:
Address;Adipose tissue;Award;Basic Science;Blood Coagulation Factor;Blood Vessels;Cardiometabolic Disease;Cardiovascular Diseases;Cell Lineage;Cholesterol;Classification;Clinical;Clinical Investigator;Collaborations;Dedications;Development;Dyslipidemias;Ensure;Faculty;Fostering;Genetic Determinism;Goals;Heart;Hemostatic function;Hypertension;Hypertriglyceridemia;Immune;Immunity;Inflammation;Institution;Insulin Resistance;Kentucky;Lipids;Lipoproteins;Metabolic syndrome;Metabolism;Michigan;Midwestern United States;Mission;Modeling;Names;National Heart Lung and Blood Institute;North Carolina;Obesity;Oral;Participant;Regulation;Research;Research Personnel;Research Project Grants;Resolution;Role;Rotation;Science;Scientist;Seminal;Senior Scientist;Structure;Students;Tangier Disease;Technology;Training;United States National Institutes of Health;Universities;Wisconsin;atherothrombosis;cardiovascular risk factor;career;career development;clinically significant;design;early-career faculty;experience;innovation;insight;lectures;lipid metabolism;medical schools;meetings;new technology;novel;posters;programs;receptor;relative cost;social;social engagement;symposium;translational scientist

public_health_relevance:
Project NarrativeThe Don S. Fredrickson Lipid Research Conference brings together scientists in the field of lipid andlipoprotein metabolism investigating cardiometabolic disease. Its goal is to provide a venue forscientific exchange opportunities for collaborations and career development for young scientists.


application_id: 11245119
project_number: 1F31HL178293-01A1
project_title: Biochemical Silencing of Maladaptive Inflammation in Heart Failure
administering_ic: NHLBI
award_notice_date: 2025-07-30
opportunity_number: PA-23-272
application_type: 1
activity_code: F31
ic: HL
serial_number: 178293
suffix: A1
program_official: HUANG, LI-SHIN
project_start_date: 2025-09-01
project_end_date: 2027-08-31
study_section: Special Emphasis Panel[ZRG1 F10A-R (20)]
contact_pi_person_id: 78816499
contact_pi: DOELLING, BENJAMIN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project AbstractPathologic remodeling is a central feature of heart failure. Remodeling is characterized byoxidative stress and inflammation. Current pharmacological interventions only slow theprogression of heart failure and do not target the underlying pathology. Thus an innovativeapproach is needed to correct the underlying pathology and improve the function of failing hearts.Extensive work has shown the association between inflammation and cardiac remodeling;however previous attempts to target inflammation in heart failure patients were ineffective. Theharmful effects of oxidative stress are mediated by reactive aldehydes formed by the oxidationof lipid membranes. These reactive aldehydes possess two electrophilic moieties which bindwith proteins forming aldehyde-modified protein adducts. The free aldehydic groups within thesemodified proteins behave as aldehyde-modified damage associated molecular patterns(ADAMPs) and elicit adaptive immune responses. Extensive studies show ADAMPs areincreasingly generated in failing hearts; however no attempt has been made to diminish theantigenicity of ADAMPs and examine their impact in heart failure. In the heart there are smallhistidyl dipeptides such as carnosine which can act as nucleophiles. Carnosine is synthesizedby the enzyme carnosine synthase which could bind with reactive aldehydes. Our preliminarystudies show carnosine can bind with aldehyde modified protein adducts (like ADAMPs); itslevels are depleted in failing hearts; and supplementing the precursor amino acid (-alanine)improves cardiac function. Based on these preliminary results we hypothesize that capping ofADAMPs with carnosine could limit inflammation and improve cardiac function in failing hearts.For this we will examine the extent to which overexpression and deletion of CARNS affectscardiac function in failing hearts. Furthermore we will examine how altering the levels ofcarnosine per se in the heart influences the capping of aldehyde modified protein adducts andsubsequent immune responses. These studies create extensive opportunities for professionaldevelopment and for the creation of new fundamental insights into the pathophysiology of heartfailure.

project_terms:
4 hydroxynonenal;Acrolein;Affect;Aldehydes;Amino Acids;Anserine;Anti-Inflammatory Agents;Antibodies;Antigen Presentation;Area;Attenuated;Binding;Biochemical;CD4 Positive T Lymphocytes;Cardiac;Cardiac Myocytes;Carnosine;Cause of Death;Cells;Clinical;Complex;Dendritic Cells;Development;Dipeptides;Disease;Echocardiography;Enzymes;Excision;Exercise;Exhibits;Fibrosis;Functional disorder;Glutathione;Goals;Health;Heart;Heart failure;Histidine;Hypertrophy;Immune response;Immunology;Inflammation;Inflammatory;Inflammatory Response;Knockout Mice;Liver;MHC Class II Genes;Malondialdehyde;Mature T-Lymphocyte;Mediastinal;Mediating;Membrane Lipids;Modeling;Modification;Molecular;Mus;Muscle Cells;Myocardial;Myocardial dysfunction;Operative Surgical Procedures;Oxidative Stress;Pathologic;Pathology;Pathway interactions;Patients;Pattern;Peptides;Pharmacotherapy;Pilot Projects;Process;Prognosis;Proteins;Research;Role;Running;Scientist;Structure;Supervision;Supplementation;Symptoms;T cell infiltration;T cell response;T-Cell Depletion;T-Lymphocyte;Testing;Therapeutic;Training;Transgenic Organisms;Ventricular Remodeling;Work;adaptive immune response;adduct;analog;functional improvement;heart function;heart preservation;immunogenicity;improved;inflammatory marker;innovation;insight;novel;overexpression;oxidation;pressure;therapeutic target;-Alanine

public_health_relevance:
Project NarrativeHeart failure is a complex disease with many different causes symptom and prognoses yet commonfeatures to many presentations are inflammation and oxidative stress. This proposal seeks to determinethe ability of the endogenous histidyl dipeptide carnosine to quench pro-inflammatory products ofoxidative stress. Cardiac-specific overexpression and deletion of carnosine synthase will be used todetermine carnosine-mediated changes to these products as well as cardiac function and remodeling infailing hearts.


application_id: 11244449
project_number: 1R01CA305985-01
project_title: Protecting the kidney from cisplatin induced injury and progression to chronic kidney disease
administering_ic: NCI
award_notice_date: 2025-06-12
opportunity_number: PAR-21-329
application_type: 1
activity_code: R01
ic: CA
serial_number: 305985
program_official: PERLOFF, MARJORIE
project_start_date: 2025-06-12
project_end_date: 2030-05-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
other_pis: BEVERLY, LEVI J
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:
This proposal is in response to PAR-21-329 Clinical Characterization of Cancer Therapy-Induced AdverseSequelae and Mechanism Based Interventional Strategies. Cisplatin is prescribed as a first-line treatment innearly 20% of tumor chemotherapies but efficacy is hindered by dose-dependent nephrotoxicity. Thirty percentof cancer patients receiving cisplatin develop acute kidney injury (AKI) a rapid decline in kidney function. AKInot only contributes to substantial morbidity but also dramatically increases risk of chronic kidney disease(CKD) a leading cause of mortality worldwide. There are no FDA-approved drugs for the treatment of cisplatin-induced AKI-CKD. The ultimate goal of this work is to protect the kidney from cisplatin-induced AKI andprevent its progression to CKD to improve cancer cure rates and enhance quality of life for cancer survivors. This proposal employs a new more clinically relevant model of cisplatin-induced AKI-CKD that wasdeveloped in our laboratories termedRepeated Low Dose Cisplatin (RLDC) that involves weekly low doses ofcisplatin over four weeks; cancer is included in the model as an important co-morbidity. This RLDC modelinduces kidney injury fibrosis and CKD (RLDC-AKI-CKD) reminiscent of the clinical condition. Data indicatethat the presence of a distant tumor adversely alters kidney function and physiology independently exacerbatesRLDC-AKI-CKD and perhaps most importantly compromises the effect of agents previously shown to benephroprotective in non-cancer bearing animals treated with RLDC. These data indicate the existence of apreviously unappreciated cancer-kidney crosstalk and provide rationale for further investigation intounderlying mechanisms of RLDC-AKI-CKD.theOur preliminary data indicate a mechanistic role for kidney infiltrating and resident macrophages(KIRMs) in the cancer-kidney crosstalk and RLDC-AKI-CKD. Cancer-induced KIRM accumulation leads to anepithelial to mesenchymal transition that involves loss of key epithelial proximal tubule components includingthe sodium glucose co-transporter 2 (SGLT2) and the 5-HT1F receptor; FDA approved drugs that inhibit SGLT2or act as agonists of the 5-HT1F receptor are protective in RLDC models without cancer but are entirelyineffective in RLDC models that include cancer due to the KIRM-induced PT EMT and resulting loss of drugtargets. This proposal tests the hypothesis that distant tumors increase KIRMs to induce PT EMT and fibrosisthereby sensitizing the kidney to RLDC-AKI-CKD; depletion of KIRMs will restore the efficacy of drugs thatprotect the kidney from RLDC-AKI-CKD. We will (1) determine the role and mechanism of specific KIRMsubpopulations in the cancer-kidney crosstalk and RLDC and (2) determine if therapeutic targeting of KIRMsrestores the efficacy of nephroprotectants in RLDC-AKI-CKD. These studies will provide essential translationaldata for development of therapies to prevent long term cancer and chemotherapy-induced kidney sequalae.

project_terms:
Acute Kidney Failure;Agonist;Animal Model;Animals;Automobile Driving;Biological Markers;Cancer Model;Cancer Patient;Cell membrane;Cells;Chemotherapy-Oncologic Procedure;Chronic Kidney Failure;Cisplatin;Clinical;Complex;Cytometry;Data;Distal;Distant;Dose;Drug Targeting;Epithelium;Euthanasia;FDA approved;Fibrosis;Flow Cytometry;Genetic;Glomerular Filtration Rate;Glucose;Goals;Health;Image;Immune;Infiltration;Injury;Injury to Kidney;Intervention Strategies;Investigation;Kidney;Laboratories;Literature;Lung Adenocarcinoma;Lung Neoplasms;Macrophage;Malignant Neoplasms;Measures;Mediator;Membrane Transport Proteins;Modeling;Morbidity - disease rate;Mus;Non-Small-Cell Lung Carcinoma;Organ;Outcome;Pathology;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Physiology;Prevention;Renal Carcinoma;Renal function;Risk;Rodent;Role;Serum;Sodium;Standard Model;Testing;Time;Urine;Work;cancer initiation;cancer therapy;carcinogenesis;chemotherapy;clinically relevant;comorbidity;drug efficacy;epithelial to mesenchymal transition;improved;inhibitor;kidney fibrosis;mortality;neglect;nephrotoxicity;novel therapeutics;pharmacologic;pre-clinical;preclinical study;prevent;quality of life for cancer survivors;receptor;response;single-cell RNA sequencing;spatial relationship;symporter;therapeutic target;therapy development;tumor

public_health_relevance:
Protecting the kidney from cisplatin induced injury and progression to chronic kidney disease Many cancer patients have decreased kidney function prior to initiation of cancer treatment and followingtreatment with cisplatin up to 30% of patients will suffer acute kidney injury. We have found that the presenceof a distal lung tumor is sufficient to alter kidney physiology and establish a pre-fibrotic niche within the kidney.Herein we will examine the mechanisms of cancer and cisplatin induced kidney injury and test noveltherapeutics to block kidney injury and progression to chronic kidney disease.


application_id: 11243845
project_number: 1F30NS141486-01A1
administering_ic: NINDS
award_notice_date: 2025-07-31
opportunity_number: PA-23-261
application_type: 1
activity_code: F30
ic: NS
serial_number: 141486
suffix: A1
program_official: MATTHEWS, MARGUERITE
project_start_date: 2025-08-24
project_end_date: 2028-08-23
study_section: Special Emphasis Panel[ZRG1 F01A-S (20)]
contact_pi_person_id: 79477576
contact_pi: MCATEE, ANNABEL
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Fellowship for Annabel McAtee: Elucidating the role of the dura mater in the post-stroke B cell response

project_abstract:
After ischemic stroke B cells play both detrimental and beneficial roles in injury and/or functional recoverydepending on responding subset and timing of activation. There is interest in developing novel immune-modulating therapies for stroke patients but clinical trials have had limited success partly because key factorsthat determine which subsets are helpful or harmful remain to be elucidated. Recent discoveries show that thedura mater plays an active role in the immune environment of the brain in health and disease. Further the durawas recently shown to be a hub of B cell development from immature to mature antibody-secretingpopulations. However the roles of dura-localized B cells after stroke are unknown. The overall objective of thisproposal is to determine if after stroke B cells in the dura form antibody-secreting subsets that travel to thebrain and worsen functional recovery. This project will address a key gap in knowledge on the uniqueproperties of immune cells in this novel niche and may allow for the development of therapies that differentiallytarget these cells without affecting other populations. The central hypothesis is that after stroke dura-localizedB cells mature into plasma cells travel to the brain through the arachnoid and pia mater and release CNSantigen-specific antibodies that impede functional recovery. To test this hypothesis a mouse model of transientmiddle cerebral artery occlusion (tMCAo) in aged male and female mice (>16 mos. n=12-18/sex) combinedwith B cell depletion methods will be used. Aim 1 hypothesis is that dura B cells are exposed to moreinflammatory cytokines compared to cervical lymph node B cells leading to a robust development of B cellactivation and maturation that is stronger than lymph node activation. This aim will achieve a fullcharacterization of dura B cells at 3 days 10 days and 7 weeks following stroke using 1) flow cytometry 2)histology and 3) single cell B cell receptor sequencing. Aim 2 hypothesis is that ischemic stroke inducesmaturation of dura-localized B cells that travel through the pia/arachnoid to the brain to worsen functionaloutcome. This aim includes a series of selective B cell depletion assays in human (h)CD20-expressing micewith dura versus systemic population depletion via Rituximab for 7 weeks. Motor and cognitive testing (rotarodY maze) will be assessed every week and B cell depletion by niche will be confirmed. The expected outcome isan increased understanding of the role of dura-localized B cells in post-stroke recovery leading to eventualdevelopment of effective immunotherapies. The trainee will gain experience with a number of experimentaltechniques and statistical analyses and will be well positioned for a career as a neurosurgeon-scientist.

project_terms:
Active Sites;Acute;Adaptive Immune System;Affect;Alteplase;Antibodies;Antigens;Arachnoid mater;B-Cell Activation;B-Cell Development;B-Lymphocyte Subsets;B-Lymphocytes;B-cell receptor repertoire sequencing;Behavior assessment;Biological Assay;Brain;Brain Diseases;Brain Injuries;Cause of Death;Cell Maturation;Cells;Central Nervous System;Cerebrospinal Fluid;Cervical lymph node group;Chronic;Clinical Trials;Development;Disease;Dura Mater;Environment;Exposure to;Fellowship;Female;Flow Cytometry;Foundations;Health;Histology;Human;Immune;Immune response;Immunotherapy;Impaired cognition;Infarction;Inflammation;Inflammatory;Injury;Ischemic Stroke;Knowledge;Leukocytes;Location;MS4A1 gene;Magnetic Resonance Imaging;Mature B-Lymphocyte;Meninges;Methods;Middle Cerebral Artery Occlusion;Modeling;Motor;Mus;Neurosurgeon;Outcome;Patient-Focused Outcomes;Peripheral;Phenotype;Pia Mater;Plasma Cells;Play;Population;Positioning Attribute;Proliferating;Property;Recovery;Recovery of Function;Rehabilitation therapy;Role;Scientist;Series;Signal Transduction;Site;Spleen;Statistical Data Interpretation;Stroke;Techniques;Testing;Thrombectomy;Travel;United States;Work;adaptive immune response;aged;behavioral outcome;career;cognitive recovery;cognitive testing;cytokine;disability;experience;functional outcomes;immunomodulatory therapies;improved;injury recovery;interest;lymph nodes;lymphatic vessel;male;motor recovery;mouse model;multidisciplinary;neurosurgery;novel;old mice;post stroke;response;rituximab;sex;stroke patient;stroke recovery;success;therapy development;translational neuroscience

public_health_relevance:
Recent studies show that the dura mater a protective layer surrounding the brain may be a location of harmfulimmune cell development after brain injury or disease. This project will determine if after stroke B cells a typeof white blood cell develop harmful features travel to the brain directly through the meninges and contributeto cognitive decline. These findings will allow us to better understand how dura-derived B cells differ from othercell populations after stroke knowledge that is critical for development of immunotherapies.


application_id: 11243082
project_number: 1F31AA032200-01A1
project_title: Next-Day Effects of Binge Drinking on Inhibitory Control in Laboratory and Naturalistic Settings
administering_ic: NIAAA
award_notice_date: 2025-09-09
opportunity_number: PA-23-272
application_type: 1
activity_code: F31
ic: AA
serial_number: 032200
suffix: A1
program_official: GRAKALIC, IVANA
project_start_date: 2025-09-21
project_end_date: 2027-09-20
study_section: Special Emphasis Panel[ZAA1 GG (32)]
contact_pi_person_id: 78724269
contact_pi: VERLINDEN, JUSTIN JAMES
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:
Project Summary/AbstractBinge drinking occurs at an alarmingly high rate despite its negative consequences on behavior health andcognition. One acute cognitive consequence of binge drinking is the impairment of inhibitory control or theability to stop oneself from engaging in maladaptive or inappropriate behaviors. Specifically during a bingeepisode individuals display impaired inhibitory control while completing Go/NoGo or Stop Signal Tasks (SST).This impairment has been shown to be maintained for up to five hours post-drinking even as breath alcoholconcentration (BrAC) approaches zero. Evidence also suggests that binge drinking results in next-day deficitsin attention memory and psychomotor speed. However no study to date has assessed the next-day effects ofbinge drinking on inhibitory control. The objective of this proposal is to determine the influence of bingedrinking on next-day inhibitory control. This objective will be addressed through two specific aims: 1) todetermine the next-day effects of binge drinking on inhibitory control in a laboratory setting and 2) to determinethe next-day effects of binge drinking on inhibitory control in a real-world setting. For Aim 1 frequent bingedrinkers will come to the laboratory for two sessions in which they will complete the SST to assess inhibitorycontrol during a 90-minute intravenous infusion of either saline or a binge-equivalent dose of alcohol (peakBrAC of 100mg%) in a counterbalanced manner. Then participants will spend the night in the laboratory understrict observation and complete the SST again the following morning (9 hours post-infusion) when BrAC is at ornear zero. For Aim 2 the same participants from Aim 1 will complete the SST from home and answerquestions about their previous day alcohol consumption every morning for 30 days. It is hypothesized that forboth aims a prior evening binge episode will result in next-day impairments in inhibitory control relative tomornings in which no alcohol was consumed the evening prior. Completion of this research plan in conjunctionwith mentored-directed training coursework and workshops will provide training in three critical areas: 1)laboratory alcohol and cognitive research; 2) naturalistic alcohol and cognitive research; and 3) multilevelstatistical modeling and multiple imputation. Results from these studies will lay the foundation for futureresearch evaluating how next-day cognitive impairments from binge drinking influence subsequent drinkingand risk-taking behaviors. The proposed training plan will provide crucial skills needed to continue this line ofresearch focused on the cognitive and behavioral consequences of binge drinking.

project_terms:
Acute;Address;Alcohol consumption;Alcohols;Area;Attention;Behavior;Behavioral;Cognition;Cognitive;Complex;Consumption;Dangerousness;Data Collection;Dose;Driving While Intoxicated;Educational workshop;Exanthema;Foundations;Goals;Habits;Harm Reduction;Health;Home;Hour;Human;Impaired cognition;Impairment;Individual;Infusion procedures;Intoxication;Intravenous infusion procedures;Laboratories;Laboratory Study;Measures;Memory;Mentors;Participant;Patient Self-Report;Performance;Phase;Psychopharmacology;Public Health;Reporting;Research;Research Personnel;Risk Behaviors;Risk Taking;Saline;Sampling;Sex Behavior;Signal Transduction;Speed;Statistical Data Interpretation;Statistical Models;Task Performances;Training;United States;aged;alcohol use disorder;binge drinker;binge drinking;breath alcohol measurement;career development;cognitive function;comparison control;design;diaries;disorder prevention;drinking;drinking behavior;interdisciplinary collaboration;intravenous administration;multilevel analysis;programs;skills;sleep health;smartphone based assessment

public_health_relevance:
This project is part of a research program designed to address gaps in our understanding of how bingedrinking influences subsequent cognition and behavior. Impaired inhibitory control the day after a bingeepisode could influence both subsequent drinking behaviors and risky behaviors in general. Evaluating thisunderstudied post-drinking period could reveal crucial information about cognition and behavior which can beincorporated into existing AUD prevention and treatment efforts.


application_id: 11242313
project_number: 1R21HD119902-01
administering_ic: NICHD
award_notice_date: 2025-07-23
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: HD
serial_number: 119902
program_official: SURPRIS, MARIPIERRE PAYEN
project_start_date: 2025-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1 MGG-D (90)]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: VARSHNEY, GAURAV K
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-01
project_title:
Elucidating mechanisms underlying the pathogenesis of Hao Fountain Syndrome a rare disease caused by USP7 variants

project_abstract:
SUMMARYRare genetic diseases affect about 8% of the world's newborn population. Although current technologicaladvances in the exome and genome sequencing of patients with suspected genetic syndromes allow forgenetic diagnosis most rare diseases have no treatment. Many rare disorders remain untreated because thefunctional follow-up into the pathogenesis lags. This proposal addresses a rare condition Hao-Fountainsyndrome HAFOUS caused by mutations in the gene coding for the deubiquitinating enzyme USP7. Wedetermined that USP7 is a critical regulator of signals transmitted through the fundamental molecular axis ofthe extracellular signal-regulated kinases 1 and 2 (ERK1/2) signal pathway. Based on this preliminary data thecentral hypothesis of this proposal is that hereditary USP7 variants lead to increased ERK1/2 activity whichduring early morphogenesis hampers the development of NC-derived tissues leading to congenitalmalformation in HAFOUS patients. We will test our hypothesis by pursuing two Specific Aims: 1) Elucidate theeffect of HAFOUS variants on ERK1/2 signal transmission in vivo and 2) Assess the effect of USP7 HAFOUSpathogenic variants on embryonic tissue development. To investigate the in vivo effect of HAFOUS variants onthe early stages of embryonic development we will use zebrafish as a vertebrate model. Zebrafish offerdistinct advantages for studies of embryonic development including their transparency and their external andrapid development. The proposed research applies our unique expertise and capacity to integrate zebrafishwith biochemical methodologies. In this project we are poised to uncover a novel mechanistic effect of USP7mutations on signaling outcomes associated with morphogenesis. The proposed work will establish preliminarydata critical for successful future studies focused on the strategies for therapeutic approaches addressingUSP7-linked abnormalities.

project_terms:
Address;Affect;Apoptosis;Automobile Driving;Behavioral;Binding;Biochemical;Biochemical Pathway;CRISPR/Cas technology;Cardiac;Cartilage;Cell Physiology;Cells;Cephalic;Characteristics;Child;Code;Congenital Abnormality;DNA Repair;Data;Dental;Deubiquitinating Enzyme;Development;Developmental Delay Disorders;Diagnosis;Disease;Embryonic Development;Enzymes;Exhibits;Eye;Face;Fibroblasts;Fluorescence Microscopy;Fountain syndrome;Functional disorder;Future;Gene Expression;Genes;Genetic;Goals;Guidelines;Health;Impairment;Individual;Inflammation;Inherited;Investigation;Knock-out;Lead;Link;MAPK3 gene;MDM2 gene;MEKs;Mediating;Methodology;Methods;Missense Mutation;Modeling;Molecular;Morphogenesis;Motor;Mutation;Neural Crest;Neural Crest Cell;Neurodevelopmental Disorder;Neurons;Newborn Infant;Outcome;Pathogenesis;Pathogenicity;Pathology;Pathway interactions;Patients;Peripheral;Persons;Pigments;Play;Point Mutation;Population;Pre-Clinical Model;Proliferating;Proteins;Proteomics;Rare Diseases;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Spatial Distribution;Specific qualifier value;Symptoms;Syndrome;System;TP53 gene;Targeted Research;Technology;Testing;Therapeutic;Tissues;Ubiquitination;United States;Variant;Virus Diseases;Work;Zebrafish;autism spectrum disorder;autosome;biological adaptation to stress;bone;developmental disease;disability;disease model;early embryonic stage;embryo tissue;exome sequencing;feeding;follow-up;genetic disorder diagnosis;genetic variant;genome editing;genome sequencing;improved;in vivo;inhibitor;innovation;insight;malformation;neurodevelopment;non-verbal;novel;novel strategies;precision medicine;programs;proteostasis;public health relevance;rare condition;rare genetic disorder;therapeutic candidate;trafficking;transcription factor;transcriptome;transmission process;tumor progression;ubiquitin isopeptidase;ubiquitin-specific protease;zebrafish genome

public_health_relevance:
Public Health Relevance StatementRare diseases collectively affect approximately 25-30 million people in the United States anddisproportionally affect children. The proposed work will result in a novel vertebrate model and novelinsights into the pathogenesis of the rare developmental disorder associated with USP7 variants.Ultimately this work will provide a model for the future development of guidelines for the diagnosis andtreatment of Hao-Fountain Syndrome.


application_id: 11239505
project_number: 1R03LM014928-01
project_title: Enabling Large Scale Metabolomics Meta-Analyses and Data Integration of Metabolomics Workbench
administering_ic: NLM
award_notice_date: 2025-09-27
opportunity_number: RFA-OD-24-010
application_type: 1
activity_code: R03
ic: LM
serial_number: 014928
program_official: FARRELL, CATHERINE MARY
project_start_date: 2025-09-27
project_end_date: 2027-08-31
study_section: Special Emphasis Panel[ZRG1 MCST-E (51)]
contact_pi_person_id: 9542008
contact_pi: MOSELEY, HUNTER NATHANIEL
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (30 lines) The practical reuse of genomics and transcriptomics datasets is well-demonstrated due to the use ofuniversal gene identifiers that facilitate the matching of features across these datasets high feature coveragestandardized metadata and data deposition formats and a maturity in deposition quality and consistency.However metabolomics datasets are much harder to reuse due to the lack of standardized metabolitefeature identification heterogeneity in feature coverage and high variability in deposition quality andconsistency. Therefore it is much harder to both find relevant metabolomics datasets from repositorieslike Metabolomics Workbench (MWbench) and effectively reuse these datasets to generate and/or testhypotheses. To address these difficulties in reusing metabolomics datasets the quality of deposited datasetsmust be improved. Furthermore methods that enable the effective harmonization and utilization of MWbenchdatasets are needed especially for large meta-analyses and integrative multi-omics analyses. We are thedevelopers of the only set of available open-source tools for parsing generating validating and depositingmwTab formatted repository files. Our experience developing the open-source mwtab and MESSES Pythonpackages makes us uniquely qualified to develop methods to improve the FAIRness especially Reusability ofMWbench datasets. Also we have provided periodic feedback to MWbench based on systematic evaluations ofthe repository to enable the improvement of this growing public resource (2). Therefore we propose to implementnew methods and open-source tools that will improve the FAIRness of MWbench datasets through the followingspecific aims: Aim 1: Implement comprehensive repair cleaning and data harmonization tools for MetabolomicsWorkbench; Aim 2: Disseminate repaired cleaned and harmonized Metabolomics Workbench datasets to thebroader biomedical community. The major innovations from this proposal are: i) advanced data repair andcleaning methods to recover unusable MWbench datasets ii) effective data harmonization that enable multi-dataset analyses iii) advanced search methods for finding relevant MWbench datasets iv) effectivedissemination of open-source tools with application programming interfaces (APIs) and command line interfaces(CLIs) implemented at high industrial coding and package management and delivery standards and v) a light-weight easy to maintain website (meta-repository) for cleaned dataset dissemination through a web userinterface (WebUI). The significance and overall impact of this proposal comes from implementingeffective open-source tools that: a) comprehensively repair clean and harmonize MWbench datasets greatlyimproving the quality of MWbench datasets especially for large-scale reuse and b) broadly disseminate thesegreatly improved datasets through a combination of API CLI and WebUI methods. This combination of open-source tools and open web infrastructure will enhance the overall utility and FAIRness of MetabolomicsWorkbench especially reuse enabling large-scale meta-analyses and multi-omics data integrations.

project_terms:
Address;Biomedical Research;Chemicals;Code;Communities;Computer software;Data;Data Analyses;Data Set;Deposition;Documentation;Evaluation;Feedback;Funding;Genes;Genomics;Heterogeneity;Human Biology;Industrialization;Infrastructure;International;Internet;Life;Meta-Analysis;Metabolism;Metadata;Methods;Multiomic Data;Periodicals;Process;Pythons;Qualifying;Resources;Role;Standardization;Testing;Validation;application programming interface;data cleaning;data format;data harmonization;data integration;data repository;data reuse;data submission;experience;human disease;improved;innovation;light weight;metabolomics;metadata standards;multiple omics;open source;open source tool;repaired;repository;tool;transcriptomics;web site

public_health_relevance:
PROJECT NARRATIVE (3 sentences)We will develop methods and tools needed to effectively repair and clean public biomedical datasets describingthe thousands of small biomolecules (metabolomics) involved in human biology and disease. We willsystematically apply these tools to thousands of datasets in the Metabolomics Workbench to greatly improvetheir reuse in biomedical research especially to study the role that metabolism i.e. the chemical processes oflife has in human disease.


application_id: 11230393
project_number: 1R21AI187755-01A1
administering_ic: NIAID
award_notice_date: 2025-06-25
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 187755
suffix: A1
program_official: VINCENT, LEAH REBECCA
project_start_date: 2025-07-01
project_end_date: 2027-06-30
study_section: Bacterial-Host Interactions Study Section [BHI]
contact_pi_person_id: 9776107
contact_pi: WOLF, KATERINA
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Investigation of the role(s) chlamydial polymorphic membrane proteins (Pmps) play during infection with C. trachomatis

project_abstract:
AbstractChlamydia trachomatis is an obligate intracellular Gram-negative human pathogen causing avariety of acute as well as chronic diseases. This bacterium infects primarily epithelial cells ofmucosal surfaces of the urogenital tract and the human eye. Chlamydia-mediated genitalinfections represent the leading cause of bacterial STDs in the United States with 1649716infections reported to the CDC in 2022. Conversely Chlamydia-mediated ocular infectionscause follicular conjunctivitis which can result in scaring of the eyelid and blindness. C.trachomatis is subdivided into 15 major serovariants based on antibody response of infectedpatients to the chlamydial porin major outer membrane protein (MOMP). In addition to MOMPsera obtained from chlamydia-infected individuals showed a significant reactivity to the surfaceexposed autotransporters polymorphic membrane proteins (Pmps). Although all nine pmpA topmpI of C. trachomatis are immunogenic PmpB C D and I are the most prevalent. This familyof proteins are chlamydial adhesins secreted by type V secretion system and represent potentialvirulence factors yet their role during chlamydial pathogenesis is mostly still unknown. Ourpreliminary data indicate that pmpI may play a distinct role(s) in infectious elementary bodiesthan in replicating reticulate bodies. We show that the deletion of pmpI in C. trachomatisresulted in an impaired initial infection with chlamydial elementary bodies but a formation ofsmaller chlamydial inclusions and a reduced number of new infectious progeny was alsoobserved. We propose to delineate the specific function(s) of pmpI during different stages of thechlamydial developmental cycle. Since Pmps are predicted chlamydial adhesins we also intendto identify and characterize either eukaryotic and/or chlamydial pmpI interacting partner(s)during infection with the microorganism. Furthermore we propose to utilize the conditionallyreplicating pKW shuttle vector in targeting the entire Pmp loci in order to determine whetherindividual Pmps of each locus may assume similar or distinct function during attachmentinvasion and/or throughout the developmental cycle. Phenotypical analyses of pmpABCpmpFE and pmpGH chlamydiae will be compared with WT and corresponding cis-complemented strains. Phenotypical outcomes will also be tested with other chlamydial speciesand various human and murine cell cultures to identify possible species-specific and host-specific interactions.

project_terms:
Acute;Alleles;Antibody Response;Antigens;Bacteria;Bacterial Adhesins;Blindness;Cell Culture Techniques;Cell Wall;Cells;Centrifugation;Chlamydia;Chlamydia Infections;Chlamydia muridarum;Chlamydia trachomatis;Chronic;Chronic Disease;Cicatrix;Conjunctivitis;Data;Development;Disease;Disease Outcome;Disease Progression;Epithelial Cells;Eye;Eye Infections;Eyelid structure;Family;Future;Gene Mutation;Generations;Genome;Gram-Negative Bacteria;Human;Immune Evasion;Impairment;In Vitro;Individual;Infection;Infectious Agent;Invaded;Investigation;Laboratories;Mediating;Mediator;Membrane;Membrane Proteins;Molecular Weight;Mouse Cell Line;Mucous Membrane;Mus;Mutagenesis;Outcome;Pathogenesis;Pathogenicity;Patients;Phase;Play;Protein Family;Proteins;Reporting;Role;Shuttle Vectors;Surface;System;Testing;Time;Tropism;United States;VDAC1 gene;Virulence Factors;cell type;experience;genital infection;homologous recombination;human pathogen;immunogenic;in vivo;major outer membrane protein;member;microorganism;mutant;novel;paralogous gene;pathogen;skills;urogenital tract

public_health_relevance:
PROJECT NARRATIVE (RELEVANCE)Surface-exposed proteins of infectious organisms represent major mediators in interactionsbetween pathogens and their host. We propose to identify and characterize interactingpartner(s) of Chlamydia polymorphic membrane protein pmpI and determine the role this Pmpis playing in pathogenesis of chlamydial infection. To further understand the significance ofPmps in diseases with these bacteria we intend to investigate the pmpABC pmpFE andpmpGH loci.


application_id: 11229563
project_number: 5P20GM121327-09
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: GARTRELL, KYUNGSOOK
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 5644
contact_pi_person_id: 11465648
contact_pi: MOHRIN, MARY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Targeting SIRT7 Regulation of Mitochondrial Quality Control to Short Circuit Age-Related Diseases of the Hematopoietic System

project_abstract:
SIRT7 is a longevity regulator and integrator of many cell stress response pathways. SIRT7 expression is decreased with chronological age as such SIRT7 KO mice are short lived and mimic many facets of human aging such as hepatic steatosis cardiac dysfunction and a myeloid-skewed hematopoietic system. Here I aim to demonstrate that mitochondrial quality control (mitoQC) responses are dysregulated with age due to loss of SIRT7 and that this contributes to defects in the aged hematopoietic system such as clonal hematopoiesis. Clonal hematopoiesis is a pre-leukemic state driven by the outgrowth of hematopoietic stem and progenitor cell (HSPC) clones and is associated with an increased risk for acute myeloid leukemia as well as diseases of the periphery like cardiovascular disease due to the actions of HSPC progeny - tissue infiltrating innate immune cells. Targeting the SIRT7-mitoQC axis in the aged hematopoietic system will have far reaching effects as the hematopoietic system touches all tissues through immune surveillance and immune cells ability to take up residence in peripheral tissues.

project_terms:
Acute Myelocytic Leukemia;Age;Aging;Cancer Center;Cardiovascular Diseases;Cells;Cellular Stress;Chronology;Clone Cells;Defect;Disease;Fatty Liver;Hematopoietic System;Hematopoietic stem cells;Human;Immune;Immunologic Surveillance;Infiltration;Kentucky;Knockout Mice;Longevity;Mitochondria;Myelogenous;Myocardial dysfunction;Pathway interactions;Peripheral;Preleukemia;Quality Control;Regulation;Risk;Tissues;Touch sensation;Universities;age-related disease;aged;biological adaptation to stress;clonal hematopoiesis;residence;response;tumor metabolism


application_id: 11229378
project_number: 1R21DE034521-01A1
project_title: Mechanisms of cannabinoid-resistance among oral spirochetes
administering_ic: NIDCR
award_notice_date: 2025-07-08
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: DE
serial_number: 034521
suffix: A1
program_official: MCNEALY, TAMARA L
project_start_date: 2025-07-15
project_end_date: 2027-07-14
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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
project_abstract:
PROJECT SUMMARYPeriodontitis a microbial-driven destructive disease of the tissues surrounding the teeth occurs inapproximately 50% of the population and is associated with several debilitating systemic conditionsincluding vascular and lung diseases diabetes mellitus pre-term birth specific cancers andAlzheimers disease. Patients who smoke marijuana have increased susceptibility to periodontitis.Indeed the most recent epidemiological evidence suggests that marijuana both exacerbates theseverity of disease and induces periodontal disease at a significantly younger age than is normal. Onekey predisposing mechanism is likely to be the induction of a disease-related dysbiotic plaque bycannabis. Based on a preliminary study of the oral microbiome of cannabis users and non-users wehave shown that  unlike many oral bacteria  Treponema putidum and multiple strains of Treponemadenticola are resistant to physiological and supraphysiological doses of the primary anti-microbialphytocannabinoids (CBN CBD THC). We have also identified CBD-regulated genes involved intranscriptional regulation and toxin control that help explain such resistance in the T. denticola typestrain ATCC 35405. We now plan to extend these studies by (Aim 1) identifying furtherphytocannabinoid resistant oral spirochetes; delineating their individual responses tophytocannabinoid-induced stress; and generating the first oral spirochete pantranscriptome in thecontext of the spirochetal pangenome. Thus we will identify species-specific and global pan-spirochetal CBD-related resistance and virulence traits. In Aim 2 we will generate mutants (andcomplemented strains) in ubiquitously CBD-regulated genes and assess their cannabinoid-relatedfitness thus facilitating future in depth comparative fitness and other mechanistic studies at the R01level.

project_terms:
Address;Alzheimer's Disease;Anti-Bacterial Agents;Bacteria;Bioinformatics;Cannabidiol;Cannabinoids;Cannabinol;Cannabis;Communities;Complement;Data;Data Set;Development;Diabetes Mellitus;Disease;Dose;Environment;Epidemiology;Exhibits;Exposure to;Fusobacterium nucleatum;Future;Gene Deletion;Generations;Genes;Genetic;Genetic Transcription;Growth;Individual;Infection;Investigation;Laboratories;Life;Literature;Lung Diseases;Malignant Neoplasms;Maps;Marijuana;Operon;Oral;Oral cavity;Order Spirochaetales;Organism;Oxygen;Patients;Periodontal Diseases;Periodontitis;Periodontium;Physiological;Plasmids;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Proteins;Resistance;Risk Factors;Severity of illness;Site-Directed Mutagenesis;Smoke;Stress;Syphilis;Technology;Tetrahydrocannabinol;Time;Tissues;Tobacco smoking behavior;Tooth structure;Toxin;Transcriptional Regulation;Trees;Treponema;Treponema denticola;Treponema pallidum;Treponema socranskii;Vascular Diseases;Virulence;Work;antimicrobial;bacterial resistance;chelation;comparative;demographics;dysbiosis;early onset;environmental stressor;fascinate;fitness;genetic manipulation;human disease;in vivo;individual response;infancy;innovation;insight;marijuana smoke;marijuana use;marijuana user;microbial;mutant;novel;oral bacteria;oral microbiome;oral pathogen;oral spirochetes;pan-genome;pathobiont;periodontopathogen;phytocannabinoid;response;sensor;tool;trait;transcriptome sequencing;uptake;virulence gene;younger age

public_health_relevance:
PROJECT NARRATIVECannabis use has recently emerged as a major risk factor for destructive periodontitis (gum disease)although the underlying mechanisms are unknown. We plan to characterize for the first time how akey group of pathogens - the oral spirochetes - survive exposure to the major anti-bacterialcomponents found in marijuana smoke (the phytocannabinoids) while other periodontal bacteria donot. This will provide some of the first information to facilitate a better understanding of marijuana-bacterial interactions and their relevance to a highly prevalent human disease.


application_id: 11228856
project_number: 1R01DA064144-01
project_title: Advancing Non-Abstinence Outcomes in the Treatment of Methamphetamine Use Disorder
administering_ic: NIDA
award_notice_date: 2025-09-19
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: DA
serial_number: 064144
program_official: FOSTER, KATRINA L
project_start_date: 2025-09-30
project_end_date: 2030-05-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
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:
ABSTRACT This project will provide critical evidence to advance multiple non-abstinence endpoints through the conductof a clinical trial that will evaluate how reduced methamphetamine use impacts a diverse range of outcomes inindividuals seeking treatment for Methamphetamine Use Disorder (MUD). The rise in MUD is a growing publichealth concern with rates of methamphetamine-associated overdose greatly increasing especially inunderserved populations made worse by a lack of approved or implemented MUD interventions.Methamphetamine use is associated with a range of health concerns that can be non-abstinence treatmenttargets but that have yet to be prospectively evaluated in clinical trials. This trial seeks to determine whetherreduced methamphetamine use improves outcomes like cardiovascular health immune function sleep qualityand other measures related to psychosocial function. We propose a randomized controlled 12-week trial usingincentives to reduce methamphetamine use with an additional 12 weeks of follow up. We will randomly assigntreatment seeking subjects with MUD to one of two groups (1:1; n=100/group): 1) incentives for providing oneor fewer methamphetamine positive urine samples per week in the trial in which frequency of use is expectedto be substantially reduced or 2) a non-contingent control group in which frequency of use is expected toremain stable. We will assess improvements in selected outcomes using validated self-report items andobjective measures including blood biomarkers. This research will fill a critical knowledge gap with impactfuldata about the biomedical and psychosocial benefits of reduced methamphetamine use which can then beused to advance non-abstinence outcomes as treatment indicators for MUD trials.

project_terms:
Abstinence;Acceleration;Adoption;Aftercare;Behavioral;Biological Markers;Blood;Blood Pressure;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Circadian Rhythms;Clinical Trials;Cognitive;Control Groups;Counseling;Data;Drug usage;Eating;Emotional;Endothelin-1;Ensure;Ethnic Origin;Evidence based intervention;FDA approved;Fatty acid glycerol esters;Frequencies;Goals;Health;Heart Rate;Heavy Drinking;Immunologic Markers;Immunosuppression;Impairment;Incentives;Individual;Infection;Intervention;Kentucky;Knowledge;Laboratories;Life Style;Literature;Measures;Medical;Mental Health;Methamphetamine;Methamphetamine use disorder;Minority Groups;Myocardial Infarction;Outcome;Overdose;Patient Self-Report;Performance;Persons;Pharmaceutical Preparations;Pittsburgh Sleep Quality Index;Predisposition;Problem behavior;Provider;Psyche structure;Psychosocial Assessment and Care;Public Health;Quality of life;Questionnaires;Race;Randomized;Randomized Controlled Clinical Trials;Research;Risk;Sampling;Sleep;Social Functioning;Social Interaction;Standardization;Substance Use Disorder;TNF gene;Testing;Treatment Efficacy;Underserved Population;Urine;Woman;actigraphy;active method;adverse outcome;alcohol use disorder;biopsychosocial;blood pressure reduction;cardiovascular health;clinical effect;clinically relevant;cocaine use;craving;discounting;drinking;expectation;follow-up;immune function;immune health;immunological status;improved;improved outcome;improvement on sleep;loved ones;men;methamphetamine use;patient oriented;prevent;prospective;psychosocial;recruit;sleep quality;success;therapy development;trial enrollment;week trial

public_health_relevance:
PROJECT NARRATIVEReduced drug use and its attendant positive health effects are clinically meaningful targets for treatmentdevelopment but few studies have evaluated the positive impacts produced by this behavioral changepreventing adoption of these endpoints in clinical trials. The proposed trial will fill that critical knowledge gap byprospectively demonstrating the biopsychosocial benefits of reduced methamphetamine use. These data willbe used to change current accepted treatment endpoints and accelerate identification of therapies forMethamphetamine Use Disorder.


application_id: 11226244
project_number: 1R01HL177556-01A1
project_title: Targeting NINJ1-mediated Plasma Membrane Rupture to Prevent Thrombosis
administering_ic: NHLBI
award_notice_date: 2025-09-10
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 177556
suffix: A1
program_official: WARREN, RONALD Q
project_start_date: 2025-09-15
project_end_date: 2030-06-30
study_section: Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT]
contact_pi_person_id: 14992976
contact_pi: WU, CONGQING
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractThis proposal focuses on investigating the role of plasma membrane rupture (PMR) of pyroptotic macrophagesin thrombosis and examine the potential therapeutic approaches targeting pyroptosis and PMR. Thromboticcomplications remain a leading cause of morbidity and mortality worldwide. Current antithrombotic therapiestarget platelets and the coagulation cascade common pathways for normal blood clotting upon injury(hemostasis) and the pathological formation of blood clot (thrombosis). These treatments often carry bleedingrisks by disrupting hemostasis and do not address the inammatory roots of thrombosis. Inammation-dependent blood clotting is part of the body's response to pathogens but excessive inammation can result inthrombosis. Emerging research underscores inammation's pivotal role in thrombosis across various conditionsincluding heart disease deep vein thrombosis sepsis and COVID-19. Targeting PMR offers a strategy tosimultaneously manage inammation and thrombosis while preserving normal clotting mechanisms. Pyroptosisa lytic form of cell death in monocytes/macrophages triggered by inammasomes is crucial in responding tobacterial infection and sterile inammation with PMR being a terminal event in this process. Our previousresearch has identied macrophage pyroptosis as a key contributor to thrombosis through the release ofmicrovesicles containing tissue factor (a key initiator of the coagulation cascade together with factor VII/VIIa).This mechanism is linked to PMR highlighting PMR as a potential trigger of thrombosis and as a desirableinammatory target. Because it is the nal step in a chain of inammatory processes targeting PMR may carrylow risk of immunosuppression. NINJ1 initially identied in nerve injury emerges as the executioner of PMRthat was previously thought to be passive and uncontrollable. This discovery unveils a potential new target forthrombosis intervention. Our preliminary studies showed reduced NINJ1 expression decreased thrombosis andthe release of pyroptotic microvesicles. This research aims to investigate the role of myeloid NINJ1 inthrombosis the mechanisms behind the release of pyroptotic microvesicles and the feasibility of targetingpyroptosis and NINJ1-mediated PMR for thrombosis prevention. The expected results will enhance ourunderstanding of NINJ1-mediated PMR in immune cell-induced thrombosis potentially leading to targetedtreatments for thrombosis-related conditions like heart disease venous thromboembolism cancer andinfectious disease.

project_terms:
Address;Antibodies;Bacteria;Bacterial Infections;Bacterial Proteins;Belief;Binding;Blood;Blood Coagulation Disorders;Blood Coagulation Factor VII;Blood Platelets;Blood coagulation;Body part;COVID-19;Cardiovascular Diseases;Cell Adhesion Molecules;Cell Death;Cell membrane;Cells;Coagulation Process;Communicable Diseases;Dangerousness;Data;Deep Vein Thrombosis;Disseminated Intravascular Coagulation;Disulfiram;Elements;Escherichia coli;Event;Fibrin fragment D;Heart Diseases;Hemorrhage;Hemostatic function;Host Defense;Immune;Immune response;Immunosuppression;In Vitro;Inflammasome;Inflammation;Inflammatory;Injury;Intervention;Knockout Mice;Link;Lytic;Macrophage;Malignant Neoplasms;Mediating;Modeling;Molecular;Morbidity - disease rate;Mus;Myelogenous;Myocardial Infarction;Pathologic;Pathway interactions;Phosphatidylserines;Plasma;Prevention;Process;Research;Risk;Role;Rupture;Sepsis;Stenosis;Sterility;Stroke;Testing;Therapeutic;Thromboplastin;Thrombosis;biobank;clinically relevant;exposure pathway;glycosylation;improved;inhibitor;insight;microvesicles;monocyte;mortality;nerve injury;nerve repair;novel;particle;pathogen;preservation;prevent;programs;response;sepsis mortality;septic patients;targeted treatment;thrombotic;thrombotic complications;trafficking;venous thromboembolism;vesicular release

public_health_relevance:
Project NarrativeThis study aims to understand how a cell death program called pyroptosis in immune cells can lead to dangerousblood clotting which is a common problem in cardiovascular diseases and bacterial infections. We'vediscovered that when the cell membrane ruptures in immune cells through pyroptosis they release tiny particlesthat promote blood clot formation. We're investigating a way to stop this process to prevent abnormal bloodclots and thus improve the treatments for cardiovascular diseases and bacterial infections.


application_id: 11225187
project_number: 1R01ES036210-01A1
project_title: RNA modifications in apolipoprotein regulation by environmental exposures
administering_ic: NIEHS
award_notice_date: 2025-09-10
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: ES
serial_number: 036210
suffix: A1
program_official: HOLLANDER, JONATHAN
project_start_date: 2025-09-11
project_end_date: 2029-08-31
study_section: Environmental Determinants of Disease Study Section [EDD]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: CAVE, MATTHEW C
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Exposure to persistent environmental contaminants including polychlorinated biphenyls (PCBs) contributes tometabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD). Although PCBexposures are positively associated with altered liver enzymes miRNAs MASLD and mortality in humancohorts how PCBs act in collaboration with a high fat diet (HFD) to promote increased hepatic triglycerideaccumulation fibrosis and inflammation in progression to metabolic-dysfunction associated steatohepatitis(MASH) remains unknown. Further although liver sexual dimorphism and sex-specific differences in humanhealth outcomes after PCB exposure have been reported few mechanistic studies have addressed thesedifferences. We reported that livers from HFD-fed male mice with MASH after a single oral exposure to anenvironmentally-relevant mixture of non-dioxin-like PCBs Aroclor1260 (Ar1260) and the dioxin-like PCB126showed increased N(6)-methyladenosine (m6A) the most common RNA modification that regulates transcriptstability and alternative splicing (AS). We identified m6A in Apob (apolipoprotein b) and other MASLD-relatedtranscripts using m6A mRNA immunoprecipitation (RIP)-sequencing and confirmed select m6A-differentiallyexpressed genes using Nanopore direct RNA-seq. in AML12 mouse hepatocytes. Reduced APOB protein iscritical for hepatic lipid accumulation in human MASLD. Apob is constitutively transcribed suggesting that post-transcriptional regulation and protein stability determine APOB levels. These data support our overarchinghypothesis that PCB exposures and diet alter m6A to regulate lipid metabolism pathways in MASLD. We addressa critical knowledge gap in how diet environmental pollutant exposures and sex modify the m6Aepitranscriptome to regulate apolipoprotein homeostasis. We will 1) Determine if the altered m6A marks in theApob transcript with PCB exposures regulate transcript stability and translation. 2) Determine how sex and dietimpact m6A marks in lipoprotein transcripts in a high fat high fructose diet (HFHFD) + PCB exposure model ofMASH. 3) Identify the extent of m6A-induced alternative splicing (AS) in livers in HFHFD-fed mice with PCBexposures. The resulting data will be the first to directly examine how mA6-containing Apob regulates proteinabundance affecting hepatic lipid pathology. Determining the mechanistic interplay of m6A diet and PCBexposures in promoting NAFLD progression will reveal possible targets for therapeutic intervention.

project_terms:
Address;Affect;Alternative Splicing;Apolipoproteins;Apolipoproteins B;Area;Binding;Biological Assay;Biology;Cells;Chemicals;Collaborations;Computational Biology;Data;Data Science;Deposition;Diet;Dioxins;Disease Progression;Environment;Environmental Exposure;Environmental Pollutants;Enzymes;Event;Exons;Exposure to;Fatty acid glycerol esters;Female;Fibrosis;Fructose;Gene Expression;Genes;Genetic Transcription;Goals;Health;Hepatic;Hepatocyte;High Fat Diet;Homeostasis;Human;Immunoprecipitation;In Situ;Inflammation;Intervention;Knowledge;Lipids;Lipoproteins;Liver;Liver diseases;Messenger RNA;Metabolic Diseases;Metabolic dysfunction;Metabolism;MicroRNAs;Modeling;Modification;Mus;National Institute of Environmental Health Sciences;Obesity;Oral;Outcome;Palmitic Acids;Pathology;Pathway interactions;Pattern;Polychlorinated Biphenyls;Positioning Attribute;Post-Transcriptional Regulation;Prevalence;Protein Isoforms;Proteins;RIPK2 gene;RNA;RNA Splicing;Reader;Regulation;Reporting;Research;Role;Sampling;Serum;Sex Differences;Site;Small Interfering RNA;Steatohepatitis;Strategic Planning;Structure;Tacrolimus Binding Proteins;Testing;Therapeutic Intervention;Toxicology;Transcript;Translations;Triglycerides;Western Blotting;biological sex;cohort;differential expression;epitranscriptome;epitranscriptomics;experimental study;exposomics;knock-down;lipid metabolism;male;mortality;mouse genome;nanopore;non-alcoholic fatty liver disease;novel;response;sex;sexual dimorphism;spatial transcriptomics;targeted treatment;transcriptome sequencing

public_health_relevance:
Environmental exposures to polychlorinated biphenyls (PCBs) increase progression of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by a high fat diet. The mechanisms by which PCB-inducedm6A modifications of apolipoproteins and alternative splicing impact MASLD is unknown. The goal of this studyis to determine how m6A regulates transcripts resulting in sex-specific gene changes in MASLD.


application_id: 11225177
project_number: 1R01DE034438-01A1
project_title: Engineering Mechanisms Causing Adverse Biofilm Responses to 3D Printed Titanium Surfaces
administering_ic: NIDCR
award_notice_date: 2025-07-25
opportunity_number: PAR-22-242
application_type: 1
activity_code: R01
ic: DE
serial_number: 034438
suffix: A1
program_official: LOPEZ, ORLANDO
project_start_date: 2025-08-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZRG1 BBBT-G (83)]
contact_pi_person_id: 14741591
contact_pi: GRADY, MARTHA
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT This project enables the future of personalized dental implants by monitoring biofilm responses to the differentsurface textures and chemistries produced by 3D metal additive implant manufacture. Metal additivemanufacturing offers implantology the freedom to incorporate advanced configurations half sizes for patient-specific needs and control over near-surface properties important for osseointegration such as multi-scaletexture and topography. However implant surfaces that are exposed to the oral cavity are difficult to keep freeof plaque and disease. Because bacterial biofilms are competing in this environment specific attention is neededto understand how biofilm properties are affected by the surfaces produced from the AM process. The focus of this proposal is on improving implant design through development of a suite of experimentalmechanics tools to understand biofilm response and to improve biocompatibility screening. We will provideinsight into the propensity for adverse biofilm structure and adhesion on 3D printed metal implant formulations.Adverse biofilm structures are those biofilm configurations that resist deformation and have large adhesionstrength (difficult removal) and resist small particle diffusion (difficult to kill by diffusing antimicrobials). We willmeasure the structural deformation and diffusive properties of single and multispecies oral biofilms on relevantand futuristic titanium implant materials. In addition to biofilm response a numerical factor that makes theinterpretation of the measurements easy to implement is needed. We will measure the Adhesion Index ofadditively manufactured titanium using the laser-induced spallation technique. Successful completion of thisresearch results in new tools for quantitative deformation diffusion and adhesion measurement of oral biofilmson additively manufactured titanium interfaces.

project_terms:
3-Dimensional;3D Print;Adhesions;Adhesives;Affect;Alloys;Antibiotic Therapy;Antibiotics;Attention;Bacterial Adhesion;Beds;Biocompatible Materials;Cell Adhesion;Cell surface;Characteristics;Chemistry;Data;Debridement;Dental;Dental Implants;Dental Materials;Dentistry;Development;Diffusion;Disease;Drug Industry;Engineering;Environment;Excision;Exhibits;Exposure to;Failure;Formulation;Freedom;Funding;Fusobacterium nucleatum;Future;Goals;Implant;Infection;Laser Scanning Confocal Microscopy;Lasers;Measurement;Measures;Mechanics;Metals;Methods;Microbe;Microbial Biofilms;Microbiology;Minerals;Modeling;Monitor;Morphology;Mucous Membrane;National Institute of Dental and Craniofacial Research;Nature;Oral;Oral cavity;Osseointegration;Patients;Pharmaceutic Aids;Pharmacologic Substance;Polymers;Porosity;Porphyromonas gingivalis;Powder dose form;Printing;Process;Property;Protocols documentation;Research;Stratification;Streptococcus gordonii;Streptococcus oralis;Streptococcus sanguis;Structure;Surface;Surface Properties;Techniques;Testing;Texture;Titanium;War;Water;Work;anti-microbial tolerance;antimicrobial;biofilm species;biomaterial compatibility;bone;bone loss;conditioning;density;design;disease model;extracellular;fabrication;implant design;implant material;improved;indexing;insight;manufacture;manufacturing process;materials science;mechanical properties;nanoparticle;oral biofilm;particle;peri-implantitis;polymicrobial biofilm;response;screening;tool;viscoelasticity

public_health_relevance:
PROJECT NARRATIVEThis project harnesses interdisciplinary expertise in materials science dentistry microbiology manufacturingand engineering to move toward metal 3D printed personalized dental implants. Deformation adhesion anddiffusion measurements will reveal the difficulty to remove and kill biofilms formed on implant surfaces.Successful completion of this work will result in important biofilm response metrics for fabricating patient-specificadditively manufactured dental implants that reduce the propensity for implant infections.


application_id: 11224758
project_number: 1R01HL175510-01A1
project_title: Emergency Granulopoiesis in Ventricular Remodeling
administering_ic: NHLBI
award_notice_date: 2025-09-12
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 175510
suffix: A1
program_official: POIZAT, CORALIE ISABELLE
project_start_date: 2025-09-15
project_end_date: 2030-06-30
study_section: Integrative Myocardial Physiology/Pathophysiology B Study Section[MPPB]
contact_pi_person_id: 11176762
contact_pi: WYSOCZYNSKI, MARCIN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Myocardial infarction (MI) activates an acute immune response to instigate a wound-healing response. Thecoincidence of these two processes suggests a relationship between the two. Activation of an acute responseinvolves the recruitment and activation of massive numbers of neutrophils. Studies in patients show thatincreases in circulating neutrophils even within the normal range predict cardiovascular disease. Likewise thenumber of neutrophils in circulation at the time of MI correlates with the severity of ventricular dysfunction. Yetsystemic depletion of neutrophils in mice prior to MI impairs wound healing response and results in ventricledilatation. Hence there may be a balance between too many and too few neutrophils. Collectively theseobservations demonstrate a balance between the processes of inflammation and scar formation and the extentto which this balance is perturbed could drive pathology. We contend however that neutrophil abundance aloneis not the complete picture. Neutrophils are among the shortest-lived immune cells and are continuouslyproduced via granulopoiesis. Despite the inexorable nature of this process acute increases in neutrophilproduction in response to stress occur and such demand-driven (or emergency) granulopoiesis may impactneutrophil phenotype and function. Yet the extent to which and how emergency granulopoiesis contributes tofunctional diversity and scar formation is not known. Given this gap in knowledge related to how neutrophilfunction is regulated after MI we posit that the functional diversitynot simply total numbersof neutrophilsdictates the extent to which the immune response promotes or antagonizes ventricular remodeling after MI.furthermore there is lack of clarity on how heart communicates to bone marrow to instigate emergencygranulopoiesis. This project will identify neutrophil-specific events involved in tissue inflammation and ventricularremodeling delinate the role of activated T cells in regulation of emergency granulopoiesis in bone marrow. Themain objectives of this proposal are to: i) delineate the role of T cells in activation of emergency granulopoiesisafter MI; ii) elucidate the impact of emergency granulopoiesis on neutrophil dynamics and phenotype; iii)determine the role of neutrophil produced via emergency granulopoiesis on monocyte/macrophage dynamicsafter MI; vi) test the extent to which neutrophil produced via emergency granulopoiesis contribute to ventricularremodeling after MI. This project will create substantial knowledge about the mechanisms regulating emergencygranulopoiesis after MI. Moreover we will establish how neutrophils emergency granulopoiesis neutrophilsregulate tissue inflammation and contribute to ventricular remodeling thereby establishing fundamentalinnovative concepts at the nexus between inflammation and ventricular structure and function.

project_terms:
Acute;Address;Adoptive Transfer;Bone Marrow;Cardiac;Cardiovascular Diseases;Cells;Cessation of life;Chronic;Cicatrix;Circulation;Collagen;Communication;Data;Dilatation - action;Emergency Situation;Equilibrium;Event;Fibroblasts;Flow Cytometry;Generations;Glucocorticoids;Granulopoiesis;Heart;Hematopoietic;Home;Homing;Immune;Immune response;Immune system;Immunophenotyping;Impaired wound healing;Infarction;Inflammation;Inflammation Process;Inflammatory;Injury;Kinetics;Knowledge;Leukocytes;Lymphocyte;Lymphopenia;Macrophage;Maps;Mus;Muscle Cells;Myocardial Infarction;Nature;Neutrophil Infiltration;Neutrophilia;Normal Range;Outcome Study;Pathology;Pathway interactions;Patients;Pattern;Phenotype;Plasma;Population;Process;Production;Regulation;Resistance;Role;Rupture;STAT3 gene;Severities;Signal Transduction;Site;Stress;Structure;T-Cell Activation;T-Cell Depletion;T-Lymphocyte;Testing;Time;Tissues;Ventricular;Ventricular Dysfunction;Ventricular Remodeling;Work;chemokine;cytokine;functional plasticity;healing;innovation;insight;monocyte;necrotic tissue;neutrophil;novel;preservation;recruit;repaired;response;second harmonic;sex;single-cell RNA sequencing;tissue injury;transcriptomics;wound healing

public_health_relevance:
The immune system is an important component of the bodys response to a heart attack. In this project we willexamine how the function of specific immune cells is regulated following a heart attack and how such cellscontribute to the bodys response following a heart attack.


application_id: 11223778
project_number: 1R01NS141156-01A1
project_title: Propriospinal Plasticity and Recovery After Incomplete Spinal Cord Injury.
administering_ic: NINDS
award_notice_date: 2025-06-02
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 141156
suffix: A1
program_official: DOPERALSKI, ADELE ELIZABETH
project_start_date: 2025-06-03
project_end_date: 2030-05-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
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
project_abstract:
Project Summary/Abstract: After a spinal cord injury (SCI) some neurons undergo anatomical expansion oftheir terminal fields via collateral sprouting that may be adaptive leading to improved recovery and/ormaladaptive leading to reduced recovery. However as a field we have had few opportunities to directly linkobserved anatomical plasticity of spinal cord interneurons with functional changes. We have used virus-basedtools to synaptically silence or anatomically trace specific spinal cord interneurons the long-ascendingpropriospinal neurons (the LAPNs) that reside at L2 and project to C6 segments critical for hindlimb andforelimb activity during locomotion. Our recent work suggests that LAPN plasticity after a SCI may bemaladaptive and impede or limit functional recovery. In combination with iDISCO tissue clearing and confocalimaging we are studying their dendritic and axonal anatomy before and after a variety of SCIs in the adult rat.In addition our main collaborator on this project will enable us to use tried and true anterograde tract tracing tocharacterize interactions between reticulospinal axons and the LAPNs before and after a contusive spinal cordinjury and following a standard lateral hemisection injury. For both video and machine-learning aided locomotoranalysis and as a novel activity/training strategy we use a 10 foot long plexiglass tank that allows the animalsto run back and forth expressing the full range of speed-dependent gaits and gait transitions. With these toolswe will investigate the anatomical plasticity exhibited by LAPNs after a T9 contusion injury in male and femaleSD rats and in females only with and without acute or chronic activity/training (Aim 1) the impact of silencingthe LAPNs on both acute functional recovery and chronic recovered function after a T9 injury (Aim 2) and theroles the LAPNs play in recovered function following a lateral hemisection where the silenced LAPNs are eitherspared or axotomized (Aim 3). These studies will have translational importance for cell and drug therapies inaddition to neuromodulation approaches including epidural and transcutaneous spinal cord stimulation and willallow us to address the confusing adaptive/maladaptive concepts driving the neuroanatomical-functionalparadox that plagues the field of spinal cord injury.

project_terms:
Acute;Address;Adult;Adult women;Anatomy;Animals;Automobile Driving;Axon;Axotomy;Back;Body Size;Cell Therapy;Cells;Chest;Chronic;Compensation;Confusion;Contralateral;Contusions;Dendrites;Dorsal;Exhibits;Extensor;Female;Fiber;Flexor;Forelimb;Gait;Goals;Hindlimb;Injury;Interneurons;Ipsilateral;Label;Lateral;Left;Lifting;Link;Locomotion;Locomotor Recovery;Lumbar spinal cord structure;Machine Learning;Measurable;Modeling;Morphology;Neuroanatomy;Neuronal Plasticity;Neurons;Neurostimulation procedures of spinal cord tissue;Output;Pattern;Pharmacotherapy;Play;Plexiglass;Population;Positioning Attribute;Posture;Process;Rattus;Recovery;Recovery of Function;Role;Running;Serotonin;Shapes;Site;Speed;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal Cord Plasticity;Spinal cord injury;Synapses;System;Tail;Therapeutic;Tissues;Training;Travel;Viral;Virus;Work;anatomical tracing;confocal imaging;foot;imaging study;improved;injury recovery;kinematics;male;neuroregulation;novel;prevent;rehabilitation strategy;tool;white matter

public_health_relevance:
Project Narrative. This project focuses on the role that plasticity of the long ascending propriospinal neurons(LAPNs) plays in the recovery of locomotion after a spinal cord injury. We will use a combination of contusionand hemisection injuries viral-based synaptic silencing and tracing tissue clearing IHC with confocal imagingand comprehensive gait and kinematic analysis to gain a deeper understanding of how adaptive (good) andmaladaptive (bad) plasticity of interneurons promotes or prevents recovery and if acute or chronicactivity/training can influence the process.


application_id: 11223459
project_number: 1R01HD116735-01A1
project_title: Harnessing the inflammatory response to promote regeneration in mammals
administering_ic: NICHD
award_notice_date: 2025-07-23
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HD
serial_number: 116735
suffix: A1
program_official: MUKHOPADHYAY, MAHUA
project_start_date: 2025-08-01
project_end_date: 2030-04-30
study_section: Skeletal Biology Structure and Regeneration Study Section[SBSR]
contact_pi_person_id: 15343300
contact_pi: SIMKIN, JENNIFER
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:
PROJECT SUMMARYBone and soft tissue regeneration after amputation remains an enigmatic phenomenon in human biologycontrasting starkly with the regenerative abilities displayed by other bone injuries (e.g. fracture). Macrophageshave emerged as key players in creating regeneration-permissive environments promoting bone regrowth whenproperly guided. However the mechanisms underlying macrophage-mediated regeneration remain poorlyunderstood leaving unanswered questions regarding their role in human regeneration and potential therapeuticapplications. To address these challenges we leverage a comparative model of bone regeneration and scarformation within a single organism the mouse. Focusing on distal fingertip amputations (P3) resulting inregeneration and proximal amputations (P2) leading to scar formation we investigate macrophage subtypes andtheir impact on neighboring cells to promote bone and soft tissue regeneration. Our preliminary data identify aunique population of macrophages that associate with growing bone and express growth factors (i.e. BMPs)known to be essential for bone regeneration. These cells are found in regenerative injuries and not found in scar-forming injuries suggesting a potential role specific to regeneration. Moreover this population has a uniquemetabolic profile compared to macrophages found in scar-forming injuries suggesting a connection betweencellular metabolism and regenerative potential. This project will test the role of macrophages in guiding digitregeneration and their potential as therapeutic agents. In Aim 1 we will test if the unique metabolic and signalingprofile of P3-macrophages is essential for regeneration. Using mouse transgenic macrophage-depletion modelsand advanced analysis techniques combining single cell RNA sequencing and spatial transcriptomics we aim toidentify specific molecular signals macrophages use to instruct neighboring cells. We will additionally test therequirement for specific metabolic and signaling profiles by knocking out key proteins in macrophages anddetermining their influence on regeneration. In Aim 2 we will determine whether P3-macrophages can promotea regenerative environment during fibrotic scarring. Through cell isolation macrophage depletion and metabolicmanipulation we aim to explore the regenerative impact of P3-macrophages in a non-regenerative context. Inconclusion our project aims to unravel the intricate role of macrophages in regeneration using a mouse model.By identifying the specific functions and metabolic profiles of regenerative macrophages we hope to unlock thepotential of macrophages as therapeutic targets for engineering regeneration-permissive environments. Thisresearch provides valuable insights into how the body naturally harnesses macrophages to guide bone and softtissue regeneration and offers potential avenues for regenerative medicine.

project_terms:
Address;Amputation;Automobile Driving;Back;Biology;Blood Vessels;Bone Injury;Bone Marrow;Bone Regeneration;Bone Tissue;Cell Communication;Cell Separation;Cells;Cellular Metabolic Process;Cicatrix;Communication;Data;Defect;Distal;Elements;Engineering;Engraftment;Environment;Event;Fracture;Genetic Transcription;Glycolysis;Goals;Growth;Growth Factor;Heterogeneity;Histologic;Human;Human Biology;Immune;Individual;Inflammatory;Inflammatory Response;Injury;Knock-out;Ligands;Limb structure;Location;Macrophage;Mammals;Maps;Mediating;Metabolic;Metabolism;Methods;Modeling;Molecular;Mus;Muscle;Natural regeneration;Nerve;Organism;Osteoblasts;Outcome;Phalanx;Population;Process;Proteins;Radiology Specialty;Regenerative Medicine;Research;Role;Running;Signal Pathway;Signal Transduction;Skin;Techniques;Testing;Therapeutic;Therapeutic Agents;Tissues;Transgenic Mice;Transgenic Model;Transgenic Organisms;bone;comparative;digit regeneration;fatty acid oxidation;healing;in vitro testing;in vivo;insight;intercellular communication;metabolic profile;millimeter;morphogens;mouse model;novel;novel strategies;permissiveness;public health relevance;regeneration model;regeneration potential;regenerative;single-cell RNA sequencing;soft tissue;spatial transcriptomics;targeted treatment;therapeutic target;tissue regeneration;tool;transcriptomics

public_health_relevance:
PROJECT NARRATIVEUnderstanding the role of macrophages in tissue regeneration holds significant public health relevance as it canpave the way for groundbreaking advancements in regenerative medicine. By unraveling how macrophagesorchestrate the regrowth of tissues and create a favorable environment for regeneration we can potentiallydevelop targeted therapies that harness the body's natural healing processes. These novel approaches mayoffer new treatment options for individuals with amputation injuries or congenital limb defects promoting new boneregeneration and optimal healing.


application_id: 11223046
project_number: 7R21CA286376-02
project_title: Novel chemokine in the regulation of breast cancer metastasis
administering_ic: NCI
award_notice_date: 2025-04-15
opportunity_number: PA-24-254
application_type: 7
activity_code: R21
ic: CA
serial_number: 286376
program_official: BOURCIER, KATARZYNA
project_start_date: 2024-08-01
project_end_date: 2026-07-31
study_section: ZCA1-SRB-A(M1)S
contact_pi_person_id: 8546610
contact_pi: KARAN, DEV
other_pis: RUI, HALLGEIR
congressional_district: 03
department: UROLOGY
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 SummaryOur long-term goal is to understand the immunobiology of cancer and identify the molecular drivers thatpromote the metastatic progression of cancer. We discovered that a potent chemokine CCL24 isexpressed explicitly by aggressive estrogen receptor-negative breast cancer cells. Our preliminary datavalidated that the expression of CCL24 is significantly higher in breast cancer and that high CCL24mRNA levels in aggressive breast cancer is associated with poor prognosis. Permutation studiesrevealed that siRNA-mediated knockdown of CCL24 in overexpressing breast cancer cells promotedmesenchymal-to-epithelial transition (MET). CCL24 may promote cancer cell EMT and metastasis as aknown chemoattractant for immunosuppressor cells to further suppress antitumor immunity. Thereforewe hypothesize that the chemokine ligand CCL24 drives invasive features of breast cancer cellsleading to metastasis. Our specific aims are: 1) to determine the clinical significance of CCL24 inbreast cancer and its induction of EMT and unfavorable clinical outcomes; and 2) to determine theoncogenic function of CCL24 and therapeutic targeting of CCL24 in breast cancer. In parallel we willdetermine if CCL24 contributes to breast cancer metastasis by promoting the infiltration ofimmunosuppressive cells at the breast tumor site. This innovative concept explores previously unknownroles for CCL24 as a driver of metastatic progression of aggressive breast cancer. We expect to providepreclinical proof-of-concept of oncogenic function and therapeutic targeting of CCL24 in breast cancer.

project_terms:
Biological Assay;Breast Cancer Cell;Breast Cancer Patient;CCL24 gene;Cancer Etiology;Cancer cell line;Cell Proliferation;Cells;Chemotactic Factors;Data;Development;E-Cadherin;Estrogen receptor negative;Genetic;Goals;Health;Human;Immune;Immunocompetent;Immunosuppression;Immunosuppressive Agents;In Vitro;Infiltration;Interleukin-6;Invaded;Knock-out;Leucocytic infiltrate;Leukocyte Trafficking;Ligands;MCF10A cells;MCF7 cell;MDA MB 231;Malignant Breast Neoplasm;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of prostate;Mammary Neoplasms;Mediating;Messenger RNA;Molecular;N-Cadherin;Neoplasm Metastasis;Non-Malignant;Oncogenic;Patients;Prognosis;Progression-Free Survivals;Proteins;Regulation;Research;Role;Site;Small Interfering RNA;Specimen;Suppressor-Effector T-Lymphocytes;T-Lymphocyte;T47D;Therapeutic;Tumor Immunity;Tumor-associated macrophages;Unfavorable Clinical Outcome;United States;Woman;Women's mortality;aggressive breast cancer;breast cancer metastasis;breast cancer progression;cancer cell;cancer immunobiology;cell motility;chemokine;clinically significant;epithelial to mesenchymal transition;gene function;immune cell infiltrate;in vivo;innovation;knock-down;mouse model;novel;novel therapeutic intervention;overexpression;pharmacologic;pre-clinical;promoter;recruit;therapeutic target;trafficking;transcriptome sequencing;tumor;tumor microenvironment;tumor progression

public_health_relevance:
Project NarrativeBreast cancer is a leading cause of cancer deaths in women largely due to metastasis. We identified anincreased association of a novel chemokine ligand CCL24 with a poor prognosis in breast cancer patients.Therefore we propose determining the clinical significance oncogenic function and therapeutic targeting ofCCL24 in breast cancer.


application_id: 11222978
project_number: 3R41AG085737-01S1
project_title: Trans Spinal Delivery of a Targeted Nanoformulation of Curcuminoids to Treat AD
administering_ic: NIA
award_notice_date: 2025-03-12
opportunity_number: PA-20-272
application_type: 3
activity_code: R41
ic: AG
serial_number: 085737
suffix: S1
program_official: MARTIN, ZANE
project_start_date: 2024-09-25
project_end_date: 2025-08-31
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Technical Abstract Neurodegenerative disorders affect over 40 million people worldwide and most if not all are mediated byinflammation. Even though several drugs are approved by the FDA for treating neurological disorders such asAlzheimers disease (AD) their efficacy as AD therapeutics has not been realized as extremely low levels of thedrug reach the brain. The goal of this Phase I project is to develop an effective targeted delivery system for thebioactive curcuminoids curcumin (CUR) and bisdemethoxycurcumin (BDMC) to mitigate AD and potentially otherneuroinflammatory diseases. We will apply our extensive experience in exosomes drug delivery planttherapeutics and inflammatory responses for efficient targeted delivery of bioactive curcuminoids to themicroenvironment of the brain where progressive increase in inflammation amyloid plaque formation andneurofibrillary tangles ultimately leads to manifestation of AD. We hypothesize that the combined administrationof CUR and BDMC will be highly effective at ameliorating neuroinflammation and aberrant AD-related geneexpression returning these biomarkers to pre-disease levels due to synergistic action via different mechanisms.We also hypothesize that folic acid (FA)-functionalized exosomal formulations administered using a novel topicaltrans-spinal (t.s.) route will provide enhanced targeting to AD-related regions of the brain including the cortex andhippocampus. Exosomes cross the BBB efficiently and areas of the brain associated with AD have high levels offolate receptors (FRs). Thus t.s.-administered FA-ExoCUR/BDMC will deliver higher payload to the brain vs.conventional routes. Our hypotheses are supported by 1) effective drug loading of curcuminoids onto bovinecolostrum exosomes 2) higher levels (~5-fold brain) of curcuminoids in rodent tissues after oral treatment withExo-curcuminoids than free curcuminoids 3) FA-exosomes can increase drug delivery to the brain which containshigh expression of FRa 4) reduced NFB accumulation and decreased abundance of phosphorylated Tau (pTau)and amyloid precursor protein (APP) expression in brain lysates of mice treated orally with ExoCUR/BDMC inconcurrence with increased expression of brain-derived neurotrophic factors (BDNF) comparable to levels in age-matched untreated WT mice while free CUR/BDMC was ineffective and 5) higher brain accumulation of exosomesin mice treated via t.s. route vs. the traditional i.v. route. Investigators experienced in exosomes drug deliveryplant bioactives and animal models leveraging extensive experience of Dr. Robert Friedland in AD research willpursue the following specific aims: Aim 1. Optimize ExoCUR/BDMC formulations and determine biodistributionand toxicity in WT mice. Aim 2. Determine efficacy of FA-functionalized ExoCUR/BDMC formulations in AD mice.This project will provide proof-of-principle for the effectiveness of t.s.-delivered FA-ExoCUR/BDMC on themodulation of key molecular targets and cognitive function behavioral tests with AD progression. In Phase II wewill conduct dose-finding and longer-term early and late intervention studies using multiple rodent AD modelsimmunotoxicity etc. The t.s.-brain delivery could ultimately lead to the development of t.s. patches for AD.

project_terms:
Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease therapeutic;Amyloid beta-Protein Precursor;Animal Model;Anti-Inflammatory Agents;Area;Attenuated;Biodistribution;Biological Availability;Biological Markers;Brain;Brain region;Brain-Derived Neurotrophic Factor;Cattle;Colostrum;Curcumin;Development;Disease;Disease Progression;Dose;Drug Delivery Systems;Effectiveness;FDA approved;Folic Acid;Formulation;Fos-Related Antigens;Gene Expression;Goals;Hippocampus;Human Cell Line;Inflammation;Inflammatory Response;Intervention Studies;Mediating;Molecular Target;Mouse Cell Line;Mus;Nervous System Disorder;Neurodegenerative Disorders;Neurofibrillary Tangles;Oral;Persons;Pharmaceutical Preparations;Phase;Plants;Powder dose form;Research;Research Personnel;Rodent;Route;Senile Plaques;Spinal;Standardization;System;Testing;Tissues;Topical application;Toxic effect;behavior test;blood-brain barrier crossing;cognitive function;efficacy evaluation;exosome;experience;folate-binding protein;immunotoxicity;mouse model;nanoformulation;nanoparticle;neuroinflammation;novel;protein expression;public health relevance;receptor;targeted delivery;tau-1;treatment response

public_health_relevance:
Narrative (Public Health Relevance Statement) In the proposed project we will use a novel nano formulation of curcuminoids to mitigateneuroinflammation and attenuate neurological diseases including Alzheimers disease (AD). In our approachcurcuminoids known for their potent anti-inflammatory activity and activities inhibiting early brain markers ofAD including neurofibrillary tangles and amyloid plaque formation will be sequestered in exosomes (naturalnanoparticles) isolated from standardized bovine colostrum powder to increase bioavailability. The exosomeswill be decorated with folic acid whose receptors are expressed in high levels in the brain to target the brainsub tissues such as cortex and hippocampus and the formulation is delivered trans-spinally (t.s.) by topicalapplication for efficient brain delivery. The novel formulation will be optimized using mouse and human celllines assessed for toxicity and biodistribution and the efficacy of the targeted t.s. delivery system tested usinga mouse model of AD.


application_id: 11222964
project_number: 1R01AG095675-01
project_title: RNA modifications leading to pathophysiological translation of circRNAs in AD
administering_ic: NIA
award_notice_date: 2025-09-09
opportunity_number: RFA-AG-25-022
application_type: 1
activity_code: R01
ic: AG
serial_number: 095675
program_official: YAO, ALISON Q
project_start_date: 2025-09-15
project_end_date: 2030-08-31
study_section: Special Emphasis Panel[ZRG1 AN-N (55)]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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:
SummaryIn response to Deciphering the Impact of RNA Modifications on Brain Aging and AD/ADRD (RFA-AG-25-022) we will investigate the role of RNA modifications on the translation of circular RNAs in Alzheimers disease(AD). Circular RNAs (circRNAs) are cytosolic and metabolically stable allowing them to accumulate RNAmodifications. We reported that during AD progression in entorhinal cortex the deamination of adenosines toinosines (A>I modification) of circular RNAs correlates with Braak stages i.e. AD severity which was notobserved for mRNA. We also found that A>I modification result in the translation of circRNAs formed by theMAPT (microtubule associated protein tau) gene. The circRNA-encoded proteins promote aggregation of tauprotein. We found a similar role of RNA modification in the translation of circRNAs from the amyloid precursorprotein (APP) and presenlin1 (PSEN1) genes. We thus hypothesize that during AD progression circRNAs undergo increasing A>I modificationresulting in their translation generating proteins that promote tau aggregation. Other modifications like m6Acan interfere with or augment the translation of inosine-containing circRNAs. This central hypothesis will betested in three specific aims where we: (#1) Determine the mechanism of inosine mediated translation ofAD-relevant circular RNAs postulating that vigilin/HDLBP is an inosine reader promoting circRNA translation.We will further test the effect of AD-relevant RNA modifications on circRNA translation. We will next (#2)Determine the pathogenetic relevance of modification-dependent circRNA translation in human brainwhere we use human brain tissue RNAseq and nanopore sequencing polysome preparations and our circRNA-specific antisera to correlate circRNA modifications with circRNA translation and AD pathogenesis. Functionally(#3) we will Determine the role of circRNA encoded proteins in tau aggregation and test siRNAinterventions testing the contribution of eIF4B a protein that specifically interacts with circTau-encodedproteins and determining the contribution of circAPP and circPSEN1-encoded proteins to tau aggregation. This work is highly innovative testing the role of A>I modification in circular RNA translation which couldunveil a new proteome in AD. The studies are significant for AD as the circRNA encoded proteins representnew factors in AD possibly contributing to tau pathology. The work is feasible as circRNAs were shown to betranslated in human brain. This work is possible through a collaboration between an RNA biologist (Stamm PI)a specialist for translation (Wen Co-I) and a world-known dementia neuropathologist heading the brain bank(Nelson Co-I) who already published together.

project_terms:
Adenosine;Alzheimer's Disease;Alzheimer's disease related dementia;Amino Acid Sequence;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Automobile Driving;Binding;Biological Assay;Brain;Collaborations;Data;Deamination;Dementia;Disease Progression;Epigenetic Process;Genes;Genetic;Genetic Transcription;Human;Immune Sera;In Vitro;Inosine;Intervention;Kentucky;Lead;MAPT gene;Mediating;Messenger RNA;Metabolic;Methylation;Modification;Molecular;Neurofibrillary Tangles;Neurons;Open Reading Frames;Pathogenesis;Pathogenicity;Physiological;Polyribosomes;Positioning Attribute;Preparation;Proteins;Proteome;Publishing;RNA;RNA Splicing;RNA Stability;Reader;Reporting;Research;Ribosomal RNA;Ribosomes;Role;Severities;Severity of illness;Small Interfering RNA;Specialist;Tauopathies;Testing;Transcript;Transfection;Translating;Translations;Universities;Work;aging brain;base;brain tissue;circular RNA;eIF-4B;entorhinal cortex;induced pluripotent stem cell;innovation;insight;nanopore sequencing;neuropathology;novel;novel therapeutics;protein complex;response;ribosome profiling;tau Proteins;tau aggregation;therapeutic target;transcriptome sequencing;vigilin

public_health_relevance:
NarrativeCircular RNAs are covalently closed often human-specific RNAs. Adenosine to inosine RNA modifications thatincrease during Alzheimers disease (AD) lead to circRNA translation generating a so far unknown proteome.We will determine the molecular mechanism of inosine-dependent circular RNA translation the pathogenicrelevance of the novel proteins in human brain and determine their molecular functions.


application_id: 11222324
project_number: 3R01CA251478-05S1
project_title: Local Flavor Policies to Enhance Equity in Tobacco
administering_ic: NCI
award_notice_date: 2025-08-19
opportunity_number: PAR-18-675
application_type: 3
activity_code: R01
ic: CA
serial_number: 251478
suffix: S1
program_official: RODITIS, MARIA LEIA
project_start_date: 2021-04-08
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-RPHB-N(56)R]
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
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
project_abstract:
ABSTRACTPolicies restricting the sale of flavored tobacco products (FTP) are being enacted in localities around the US.We seek to expand the evidence base about the extent to which these policies decrease access to FTPs andexposure to flavored tobacco marketing and would likely reduce use of tobacco among youth and young adults.Additionally few studies examine the potential of these policies to reduce tobacco-related health disparitiesamong youth/young adult populations of color and those of lower socioeconomic status (SES). These vulnerablepopulations use flavored products at higher rates and FTPs are heavily marketed in communities where thesevulnerable groups live. Determining the impact of FTP policies overall and on populations of color and lower SESyouth/young adults in these communities can make sure that policies are structured to ensure equitable reachand reduce tobacco use disparities. The purpose of this study is to determine the impact of flavor policies onreducing exposure to and use of FTPs among vulnerable youth/young adults. Using the Policy ImplementationFramework and the Elaboration Likelihood Model as our theoretical guides we combine national local andindividual data to examine the equity impact of flavor policies around the US. To accomplish the study purposewe will conduct several aims. (1) We will use a longitudinal national dataset of youth and young adults (n=13892)followed for nine waves twice a year from 2014 to examine changes in tobacco marketing exposure and FTPand non-FTP use in those exposed to an FTP policy with no FTP policy exposure over time focusing ondifferences by race/ethnicity and SES. (2) We will compare marketing exposure to and appeal of FTP/non-FTPsbetween emerging adults in communities covered by flavor policy variants through ecological momentaryassessment (EMA) evaluating differences in outcomes by SES and race/ethnicity at the individual andneighborhood level. (3) Finally among EMA participants we will assess the predictive validity of exposure toFTP/non-FTP marketing exposure on use of FTP and non-FTPs at 6-month follow-up and evaluate whetherthese outcomes are associated with SES and race/ethnicity. For all of these activities we will partner withnational and local FTP policy experts who will disseminate lessons learned to communities who have or areconsidering an FTP policy. Achieving the aims of this R01 will expand the evidence base of the impacts of FTPpolicies on reducing tobacco use and potential equity impact of these policies to reduce tobacco and ultimatelycancer disparities.

project_terms:
Address;Advertising;Affect;Area;California;Cigarette;Code;Communities;County;Data;Data Collection;Data Set;Databases;Disparity;Ecological momentary assessment;Education;Electronic cigarette;Ensure;Equity;Ethnic Origin;Exposure to;Goals;Home;Income;Individual;Kentucky;Laws;Link;Longitudinal cohort;Longitudinal trends;Low income;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Menthol;Modeling;Neighborhoods;Outcome;Participant;Persuasive Communication;Policies;Population;Protocols documentation;Public Policy;Race;Reduce health disparities;Research;Resources;Respondent;Risk;Sales;Smokeless Tobacco;Socioeconomic Status;Statistical Data Interpretation;Structure;Testing;Time;Tobacco;Tobacco use;United States Food and Drug Administration;Universities;Variant;Vulnerable Populations;Youth;attributable mortality;cancer health disparity;cancer risk;cigarette smoking;cigarillos;cohort;cost;demographics;disparity reduction;emerging adult;evidence base;follow-up;health disparity;health equity;implementation framework;innovation;low socioeconomic status;neighborhood disadvantage;people of color;public policy on tobacco;racial difference;reduce tobacco use;theories;tobacco advertising;tobacco exposure;tobacco flavor;tobacco products;tobacco user;trend;vulnerable community;young adult

public_health_relevance:
PROJECT NARRATIVEThis project seeks to examine whether innovative local tobacco control policies restricting sales of flavoredtobacco products can reduce tobacco use and disparities in tobacco and ultimately cancer. The study willexamine trajectories of flavored tobacco use in a large longitudinal national cohort of youth and young adultsamong those exposed and not exposed to policy. It will also examine youth and young adult non-tobacco userexposure to tobacco marketing and subsequent tobacco use outcomes in real-time in eight communities withdifferent flavor policy variants and will have a particular focus on assessing differences in policy impact acrossvulnerable group status.


application_id: 11222245
project_number: 5P20GM121327-08
administering_ic: NIGMS
award_notice_date: 2023-12-20
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: GARTRELL, KYUNGSOOK
project_start_date: 2024-10-31
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3(C2)
subproject_number: 5644
contact_pi_person_id: 11465648
contact_pi: MOHRIN, MARY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Targeting SIRT7 Regulation of Mitochondrial Quality Control to Short Circuit Age-Related Diseases of the Hematopoietic System

project_abstract:
SIRT7 is a longevity regulator and integrator of many cell stress response pathways. SIRT7 expression is decreased with chronological age as such SIRT7 KO mice are short lived and mimic many facets of human aging such as hepatic steatosis cardiac dysfunction and a myeloid-skewed hematopoietic system. Here I aim to demonstrate that mitochondrial quality control (mitoQC) responses are dysregulated with age due to loss of SIRT7 and that this contributes to defects in the aged hematopoietic system such as clonal hematopoiesis. Clonal hematopoiesis is a pre-leukemic state driven by the outgrowth of hematopoietic stem and progenitor cell (HSPC) clones and is associated with an increased risk for acute myeloid leukemia as well as diseases of the periphery like cardiovascular disease due to the actions of HSPC progeny - tissue infiltrating innate immune cells. Targeting the SIRT7-mitoQC axis in the aged hematopoietic system will have far reaching effects as the hematopoietic system touches all tissues through immune surveillance and immune cells ability to take up residence in peripheral tissues.

project_terms:
Acute Myelocytic Leukemia;Age;Aging;Cancer Center;Cardiovascular Diseases;Cells;Cellular Stress;Chronology;Clone Cells;Defect;Disease;Fatty Liver;Hematopoiesis;Hematopoietic System;Hematopoietic stem cells;Human;Immune;Immunologic Surveillance;Infiltration;Kentucky;Knockout Mice;Longevity;Mitochondria;Myelogenous;Myocardial dysfunction;Pathway interactions;Peripheral;Preleukemia;Quality Control;Regulation;Risk;Tissues;Touch sensation;Universities;age-related disease;aged;biological adaptation to stress;residence;response;tumor metabolism


application_id: 11221456
project_number: 1R15GM160955-01
project_title: Mechanisms of Telomere Maintenance and Protection
administering_ic: NIGMS
award_notice_date: 2025-08-26
opportunity_number: PAR-24-152
application_type: 1
activity_code: R15
ic: GM
serial_number: 160955
program_official: VATAKIS, DIMITRIOS NIKOLAOS
project_start_date: 2025-09-01
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 CDB-N (81)]
contact_pi_person_id: 10153609
contact_pi: STEWART, JASON AARON
other_pis: Not Applicable
congressional_district: 02
department: BIOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Telomeres are repetitive DNA structures at the ends of eukaryotic chromosomes that prevent degradation andrecognition of the ends by the DNA repair machinery. The chromosome ends resemble DNA double-strandbreaks (DSBs) and therefore must be protected from unwanted repair that can lead to chromosome fusionsand other forms of chromosome instability. To distinguish telomeres from other regions of the genome telomeresare bound by protein complexes that shield the ends from the DNA damage response (DDR). The major telomereprotection complex is called shelterin. Our preliminary data point to a novel role of another telomere-associatedcomplex CST (CTC1-STN1-TEN1) in telomere protection. CST is a single-stranded DNA binding protein thatfunctions in telomere replication as well as DNA replication and repair. Mutations in CST cause the telomerebiology disorders Coats plus and dyskeratosis congenita and CST dysfunction has also been associated with avariety of cancers. Yet the cellular roles of CST and how they relate to human disease are still incompletelyunderstood. Previous work demonstrated that loss of CST leads to hyperextension of the telomeric G-rich single-stranded DNA overhang leading to the association of DNA repair and damage response factors. Surprisinglydespite the presence of these DDR factors telomeres remain mostly protected in cells lacking CST suggestinga novel mechanism of telomere protection. Preliminary data suggest that the DDR kinase ATR is necessary forthis protection. The overall goal of this proposal is to delineate the consequences of CST deletion on telomereprotection and genome stability and how CST deficiency leads to disease. Aim 1 will define the factors associatedwith telomeres in the absence of CST to identify how they remain protected. Aim 2 will identify whether CSTdisease mutations affect telomere protection and ATR signaling. This proposal will use a combination of well-established molecular and cellular assays that will allow us to delve into the mechanisms of telomere protection.Completion of these aims will significantly advance our understanding of chromosome end protection and howCST dysfunction promotes disease as well as provide important training experiences to undergraduate students.

project_terms:
Affect;Aging;Alzheimer's Disease;Back;Binding;Biology;CHEK1 gene;Cardiovascular Diseases;Cell Physiology;Cells;Cellular Assay;Chromosomal Instability;Chromosomes;Clinical Trials;Complex;DNA;DNA Damage;DNA Double Strand Break;DNA Primase;DNA Repair;DNA Structure;DNA biosynthesis;DNA-Directed DNA Polymerase;Data;Defect;Development;Disease;Dyskeratosis Congenita;Etiology;Exhibits;Functional disorder;Genetic Diseases;Genome;Genome Stability;Genomic Instability;Goals;Incidence;Malignant Neoplasms;Mammals;Mediating;Membrane;Minor;Molecular;Mutation;Nature;Nucleic Acids;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Physical condensation;Process;Proteins;Public Health;Pulmonary Fibrosis;Repetitive Sequence;Research;Role;SS DNA BP;Signal Transduction;Single-Stranded DNA;Structure;Telomerase;Telomere Maintenance;Telomere-Binding Proteins;Testing;Training;Work;age-related disease;cancer cell;chromosome fusion;exhaust;experience;human disease;inhibitor;insight;loss of function;novel;prevent;protein complex;protein function;recruit;repaired;replication stress;response;targeted cancer therapy;telomere;undergraduate student

public_health_relevance:
DNA breaks must be repaired to prevent mutations and instability that promote disease. However this processmust be tightly regulated to protect chromosome ends which resemble DNA breaks from unwanted repair thatleads to chromosome fusions. The proposed research is relevant to public health because it will define theprocesses that enable chromosome end protection and prevent genome instability a major driver of canceraging and disease.


application_id: 11221413
project_number: 1R21HL177760-01A1
administering_ic: NHLBI
award_notice_date: 2025-07-28
opportunity_number: PAR-23-036
application_type: 1
activity_code: R21
ic: HL
serial_number: 177760
suffix: A1
program_official: TATAW-AYUKETAH, GLADYS OROCK
project_start_date: 2025-08-01
project_end_date: 2027-07-31
study_section: Lifestyle and Health Behaviors Study Section[LHB]
contact_pi_person_id: 15794901
contact_pi: DUNCAN, MEREDITH
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Patterns of Long-term Cigarette Smoking Behavior on CVD Risk: Implications for Clinical Practice and Public Health

project_abstract:
Project Summary: The goal of the current study is to quantify cardiovascular disease (CVD) risk associatedwith smoking cessation and changes in smoking patterns among a diverse cohort of US adults. Individuals whocurrently smoke particularly those who smoke heavily or have smoked for a number of years may feel thatcessation is unattainable. For those who struggle to quit smoking substantial reduction in cigarettes per day(CPD) as a step toward smoking cessation may be a more achievable goal. However CPD reduction is notcommonly advocated in public health messaging and whether risk benefit is realized upon CPD reductionwithout cessation is debated. For smokers who do quit their CVD risk attributable to smoking takes at least 5years and potentially 10 to 15 years to attenuate to that of a never smoker. Whether the time-course of riskreduction differs by pack-years smoked remains unknown. Finally it is imperative that our risk assessmenttools accurately capture the impact of long-term smoking behaviors on CVD risk. However the American HeartAssociations newly released Predicting Risk of Cardiovascular Disease EVENTS (PREVENT) equationsdistinguish only between current and non-current smokers when estimating 10- and 30-year CVD risk (i.e.former and never smokers are combined into a single group) and neither years since quitting nor pack-yearssmoked are included. To this end we will incorporate data from six existing cohort studies to address theseknowledge gaps in a racially ethnically and socioeconomically diverse sample. First we will incorporaterepeated measures of smoking status and intensity to ascertain whether reduction in CPD results in decreasedCVD risk (Aim 1). Then we will estimate the number of years of cessation that are required for formersmokers risk to approximate that of a never smoker. We will also determine whether this time-course differs bypack-year smoked (Aim 2). Lastly we will determine whether adding an indicator of former smoking statuspack-years smoked and years since quitting to the PREVENT equations improves CVD risk prediction.Successful completion of the proposed research has implications for how physicians treat their currently andformerly smoking patients regarding CVD risk reduction which could decrease years of life lost due to cigarettesmoking. Findings may also impact public health messaging which could include information on lowering CVDrisk via smoking reduction on the path to full cessation.

project_terms:
Address;Adult;Advocate;American;American Heart Association;Assessment tool;Attenuated;Behavior;Benefits and Risks;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Cigarette;Classification;Clinical;Cohort Studies;Coronary Artery Risk Development in Young Adults Study;Data;Data Analyses;Data Pooling;Drops;Equation;Ethnic Origin;Event;Framingham Heart Study;Goals;Harm Reduction;Hispanic Community Health Study/Study of Latinos;Individual;Jackson Heart Study;Knowledge;Life Style Modification;Measures;Multi-Ethnic Study of Atherosclerosis;Not Hispanic or Latino;Onset of illness;Participant;Patients;Pattern;Performance;Physicians;Prevalence;Provider;Public Health;Race;Reasons for Geographic And Racial Differences in Stroke;Recording of previous events;Reporting;Research;Risk;Risk Assessment;Risk Estimate;Risk Factors;Risk Reduction;Sampling;Smoke;Smoker;Smoking;Smoking Behavior;Smoking History;Smoking Status;Testing;Time;United States;Update;Woman;attributable risk;cardiovascular disorder risk;cardiovascular risk factor;cigarette smoke;cigarette smoking;clinical practice;clinically significant;cohort;ethnic diversity;former smoker;hazard;improved;indexing;marginalized population;men;modifiable risk;never smoker;non-smoking;offspring;racial diversity;risk prediction;risk prediction tool;smoking cessation;socioeconomics;statistics;tool;years of life lost

public_health_relevance:
Project Narrative: In this project we will estimate the cardiovascular disease (CVD) risk associated withchanges in smoking behavior among a diverse group of US adults. Specifically we will determine: 1) thenumber of years a former smoker must be quit in order for their CVD risk to be the same as someone who hadnever smoked; and 2) whether current smokers can decrease their CVD risk by cutting down their cigarettessmoked per day. If our hypotheses are correct updated public health messaging could include information onlowering CVD risk via smoking reduction on the path to full smoking cessation and doctors could betterestimate their currently and formerly smoking patients CVD risk.


application_id: 11219054
project_number: 75N91024P00411-0-0-1
project_title: NCI PATTERNS OF CARE STUDY FY24 - DIAGNOSIS YEAR 2021 (PROSTATE CANCER AND OVARIAN CANCER)
administering_ic: NCI
project_start_date: 2024-05-01
project_end_date: 2025-04-30
contact_pi_person_id: 79747540
contact_pi: DURBIN, ERIC
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The National Cancer Institute (NCI) Patterns of Care (POC) studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. POC Studies are conducted periodically typically annually to satisfy a congressional directive (under Public Law 100-607 Sec. 413 (a)(2)(C) adopted on November 4 1988) to the NCI to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To satisfy the directive and to update and enhance the utility of the POC Studies a working group including representatives from the NCIs Divisions of Cancer Control and Population Sciences and Cancer Treatment and Diagnosis and a representative from the American Cancer Society was developed to review knowledge gaps in cancer therapy dissemination and to develop priority areas for study. The group reached a consensus that a gap remains regarding factors associated with guideline use of biomarker tests and targeted therapy. Furthermore the group determined there is limited information about the effects of the COVID-19 pandemic on cancer screening diagnosis treatment and receipt of supportive/palliative care among individuals diagnosed with cancer. For feasibility reasons the group also recommended that this POC Study be focused specifically on the patterns of care for patients newly diagnosed with prostate or ovarian cancer. This POC Study will also collect data on documentation of palliative care and patient financial impacts of the COVID-19 pandemic. Relevant information on cancer diagnosis cancer recurrence and metastasis patterns of care (e.g. utilization of biomarker testing specific cancer treatments supportive/palliative care) and patient financial stability shall be abstracted from medical records among patients aged 20 years or older who were diagnosed with prostate or ovarian cancer in 2021.

project_terms:
20 year old;Adjuvant Therapy;Adopted;Affect;Age;American Cancer Society;Area;Beds;Biological Markers;COVID-19 pandemic;COVID-19 pandemic effects;Cancer Patient;Characteristics;Communities;Congresses;Consensus;Data;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Guidelines;Healthcare Systems;Hospitals;Immunotherapy;Incidence;Individual;Inpatients;Insurance Coverage;Knowledge;Laws;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Medical;Medical Records;National Cancer Institute;Neoplasm Metastasis;Newly Diagnosed;Operative Surgical Procedures;Outpatients;Palliative Care;Patient Care;Patients;Pattern;Patterns of Care;Physicians;Physicians' Offices;Race;Radiation therapy;Recommendation;Records;Reporting;Screening for cancer;Systemic Therapy;Testing;Time;United States;Update;cancer care;cancer diagnosis;cancer recurrence;cancer therapy;chemotherapy;clinical practice;comorbidity;hormone therapy;pandemic potential;sex;targeted treatment;treatment pattern;working group


application_id: 11218757
project_number: 1R03CA286623-01A1
project_title: Health Communications for Adults Smoking Nondaily
administering_ic: NCI
award_notice_date: 2025-07-24
opportunity_number: PAR-23-058
application_type: 1
activity_code: R03
ic: CA
serial_number: 286623
suffix: A1
program_official: REYES-GUZMAN, CAROLYN
project_start_date: 2025-08-11
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZCA1 SRB-2 (M2)]
contact_pi_person_id: 78359142
contact_pi: SHOREY FENNELL, BETHANY
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 SUMMARYAdults smoking nondaily (ASN) make up approximately one-third of adults who currently use cigarettes in theU.S. and experience substantial risk of cancer respiratory and cardiovascular mortality. Yet ASN often do notperceive themselves as vulnerable to health consequences of smoking and are less likely than those smokingdaily to attend to or be persuaded by smoking health risk campaigns targeted to the general population adultswho smoke. It is critically important to develop smoking health risk messages targeted to ASN that areperceived as personally relevant and meaningfully influence key outcomes associated with smoking cessation.As the first step in a programmatic line of research designed to improve health communications for and smokingcessation outcomes among ASN we propose to develop and carefully evaluate theoretically-based smokinghealth communications targeted to ASN intended to increase knowledge worry risk perceptions motivationand intentions to quit. The Communication-Persuasion Matrix (CPM) offers an overarching conceptualframework for developing and evaluating targeted messages. We will pursue two aims. In Aim 1a guided by theCPM and empirical evidence that affect and social cues are especially strong predictors of smoking behavioramong ASN we will develop smoking cessation messages with content that varies on affective valence(positive vs. negative) and smoking consequences (social vs. health). Factors specifically relevant to ASN willbe targeted including the perception that they are not smokers and social cues for smoking. In Aim 1bLearner verification and revision procedures with ASN (N=20) will be used to evaluate the initial messages forcomprehension attractiveness acceptability and personal relevance. Messages will be modified in an iterativeprocess according to participant feedback throughout learner verification and revision. In Aim 2 in a 2x2factorial design the optimized messages from Aim 1 will be presented to ASN via an online panel (N=320) totest the effects of message affective valence (positive vs. negative) and consequences (social vs. health).Participants will be randomized to view one of four categories of messages: Positive/Health Positive/SocialNegative/ Health Negative/Social. Key outcomes will be assessed pre- and post-message exposure. Wehypothesize that positive (vs. negative) and social (vs. health) messages will produce greater increases inknowledge worry risk perceptions motivation and intentions to quit smoking among ASN. Identifyingunderlying components of effective messaging for this vulnerable group is especially impactful as findings caninform the development of future targeted messaging or smoking cessation campaigns. In the future we plan toconduct a fully powered RCT to evaluate the efficacy of the targeted messages at enhancing motivation to quitand examining quit attempts and tobacco treatment enrollment among ASN a substantial at risk andunderserved population of U.S. adults who smoke.

project_terms:
Adult;Affect;Affective;African American population;Attention;Behavior;Behavioral;Black race;Calibration;Cardiovascular Diseases;Cardiovascular system;Categories;Characteristics;Cognitive;Communication;Comprehension;Cues;Development;Elements;Enrollment;Feedback;Future;General Population;Goals;Health;Health behavior change;Hispanic;Individual;Intention;Intervention;Knowledge;Latino;Malignant Neoplasms;Mental Depression;Morbidity - disease rate;Motivation;Nicotine Dependence;Outcome;Output;Participant;Perception;Persuasive Communication;Phase;Procedures;Process;Randomized;Reporting;Research Design;Respiratory Disease;Risk;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Cessation Intervention;Smoking and Health Research;Stress;Testing;Tobacco;Tobacco-Related Carcinoma;Underserved Population;Vulnerable Populations;Work;cancer risk;cigarette smoke;cigarette smoking;design;efficacy evaluation;experience;health communication;improved;mortality;negative affect;respiratory;risk perception;smoking cessation;smoking cue;smoking prevalence;social;success;theories;tobacco control

public_health_relevance:
PROJECT NARRATIVEAdults smoking nondaily have substantial risk of experiencing tobacco-related cancer respiratory andcardiovascular morbidity and mortality yet are less likely to pay attention to general messages encouragingthem to quit smoking. In this study we will 1) develop messages specifically designed to be relevant to adultssmoking nondaily 2) refine the messages with input from adults smoking nondaily and 3) test whichmessages elements are most important and whether the messages increase risk perceptions and intentions toquit smoking. The ultimate goal of the study is to optimize messages for adults smoking nondaily to be used infuture interventions to increase smoking cessation treatment enrollment and quitting for this underservedgroup.


application_id: 11216814
project_number: 7R03DE033729-02
administering_ic: NIDCR
award_notice_date: 2025-03-05
opportunity_number: PA-24-254
application_type: 7
activity_code: R03
ic: DE
serial_number: 033729
program_official: GRISIUS, MARGARET
project_start_date: 2025-03-01
project_end_date: 2027-02-28
study_section: ZDE1-YM(09)
contact_pi_person_id: 14462851
contact_pi: JASMER, KIMBERLY J
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
budget_start_date: 2025-03-01
project_title:
lluminating the Role of the Novel G Protein-Coupled P2Y10 Receptor in Sjgrens Disease Pathophysiology

project_abstract:
Three G protein-coupled receptors (GPCRs) for lysophosphatidylserine (LysoPS) i.e. P2Y10 GPR174 and GPR34were recently identified. Studies in mice have uncovered immunomodulatory functions of LysoPS and associations withautoimmune conditions have been established including Graves disease Addisons disease and autoimmune thyroiddiseases. The P2Y10 receptor (P2Y10R) was initially identified as a member of the P2Y family of nucleotide receptorsbased on structural similarities. However the ability of nucleotide ligands to activate P2Y10R remains uncertain. Thisproject aims to address previous study limitations to determine P2Y10R ligand specificity. The pathophysiological andimmunomodulatory functions of LysoPS receptors vary with disease model and cell type which may be attributed to theLysoPS species present. Species of LysoPS have various fatty acid chains located at either the sn-1 or sn-2 position andchain length can dictate the immunological response based on preferential receptor binding. Sjgrens disease (SjD) is achronic inflammatory autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glandsresulting in dry eye and dry mouth respectively. Beyond glandular involvement SjD is a systemic disease that impactsmany exocrine and non-exocrine tissues with pulmonary manifestations observed in more than 20% of all SjD patients. Inaddition to genetic factors SjD is triggered by environmental exposures including various viral infections. Ourpreliminary data in humans and mice suggest an association between P2Y10R and the SjD phenotype. We found thatGPR174 P2RY10 and the LysoPS-producing enzyme phospholipase A1A (PLA1A) but not GPR34 are upregulated inparotid and minor salivary glands of SjD patients compared to non-SjD controls. P2Y10R and GPR174 receptors areexpressed predominantly in immune cells and lymphoid organs such as the spleen and bone marrow. P2Y10R expressiondepends on the Ets transcription factors Pu.1 and Spi-B known B cell receptor signaling mediators that promote B cellmaturation. B cells play an essential role in the pathogenesis of SjD. Indicators of B cell hyperactivity in SjD include theproduction of autoantibodies hypergammaglobulinemia and the development of B cell lymphomas. Single-cell RNA-sequencing (scRNA-seq) data from the minor salivary gland (MSG) biopsies of SjD and non-SjD subjects revealed thatP2RY10 is most abundant in B cells T cells and NK cells with lower expression in plasma cells and macrophages.Among these P2RY10 was most upregulated in T cells in SjD glands compared to controls. Though B cells have receivedmuch attention in the study of SjD T cells have garnered recent interest and are important to disease processes. Ourpreliminary data in mice indicate that P2Y10Rs are present in the submandibular glands of IL-14TG SjD-like mice athigher levels than age-matched wild-type C57BL/6 mice and can be activated by LysoPS. Spatial transcriptomic analysisrevealed that P2ry10 expression is localized to ectopic germinal centers in the IL-14TG submandibular gland. These datasuggest an association of P2Y10R with the SjD phenotype in humans and mice and warrant further investigation. Wepropose to use bioinformatic and in vivo techniques to elucidate the role of P2Y10R in SjD pathophysiology.Understanding the role of P2Y10R in SjD pathophysiology could establish a druggable target for SjD pharmacotherapy.

project_terms:
Ablation;Addison's disease;Address;Adenosine;Age;Attention;Attenuated;Autoantibodies;Autoimmune Diseases;B-Cell Antigen Receptor;B-Cell Development;B-Cell Lymphomas;B-Lymphocytes;Binding Proteins;Bioinformatics;Biological Assay;Biopsy;Bone Marrow;C57BL/6 Mouse;CD28 gene;CD4 Positive T Lymphocytes;Cell Communication;Cell Compartmentation;Cell Maturation;Cells;Chronic;Coupled;Coupling;Cytoplasm;Data;Data Set;Development;Disease;Environmental Exposure;Enzymes;Family;Fatty Acids;Female;Functional disorder;Future;G-Protein-Coupled Receptors;GTP-Binding Proteins;Genetic;Gland;Graves' Disease;Homologous Gene;Human;Hyperactivity;Hypergammaglobulinemia;Immune;Immune response;In Vitro;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Interferon Type II;Interstitial Lung Diseases;Investigation;Laboratories;Lacrimal gland structure;Length;Ligands;LoxP-flanked allele;Lung;Lymphocyte;Lymphocytic Infiltrate;Lysophosphatidic Acid Receptors;Lysophospholipids;Macrophage;Mediating;Mediator;Minor salivary gland structure;Modeling;Molecular;Mus;Natural Killer Cells;Neurodegenerative Disorders;Nucleotides;Ocular Pathology;Oral Pathology;P2X-receptor;P2Y2 receptor;Parotid Gland;Pathogenesis;Patients;Pattern;Pattern recognition receptor;Pharmaceutical Preparations;Pharmacotherapy;Phospholipase;Plasma Cells;Play;Population;Positioning Attribute;Process;Production;Pulmonary Inflammation;Receptor Activation;Receptor Signaling;Resolution;Role;Salivary;Salivary Glands;Sampling;Sialadenitis;Signal Transduction;Sjogren's Syndrome;Specificity;Specimen;Spleen;Structure of germinal center of lymph node;Submandibular gland;Systemic disease;T cell infiltration;T-Lymphocyte;Techniques;Testing;Time;Tissues;Transforming Growth Factor alpha;Upregulation;Virus Diseases;Woman;Xerostomia;antagonist;autoimmune exocrinopathy;autoimmune thyroid disease;cell injury;cell motility;cell type;chemokine;comparison control;cytokine;data modeling;design;differential expression;disease model;disease phenotype;disorder control;druggable target;eye dryness;immunoregulation;improved;in silico;in vivo;interest;lymphoid organ;lysophosphatidylserine;member;men;mouse model;new therapeutic target;novel;nucleotide receptor;overexpression;pharmacologic;prevent;proto-oncogene protein Spi-1;pulmonary;receptor;receptor binding;receptor expression;response;sexual dimorphism;single cell analysis;single-cell RNA sequencing;small molecule libraries;spatial transcriptomics;symptom management;transcriptomics;tripolyphosphate

public_health_relevance:
Three recently identified lysophosphatidylserine (LysoPS) receptors (i.e. P2Y10R GPR174 and GPR34) have beensuggested to elicit immunomodulatory effects in neurodegenerative and autoimmune diseases. The P2Y10 receptor(P2RY10) is overexpressed in the parotid and minor salivary glands of patients with Sjgrens disease (SjD) anautoimmune exocrinopathy that causes salivary and lacrimal gland dysfunction with specific upregulation observed insalivary gland T cells. Proposed studies are designed to systematically determine P2Y10R ligand specificity and G-protein coupling and investigate the contributions of P2Y10R to SjD pathophysiology in humans and mice usingbioinformatic and in vivo assays as a prelude to targeting the P2Y10R to prevent salivary gland dysfunction in SjDpatients.


application_id: 11215066
project_number: 1K99CA303792-01
project_title: Enhancing TIL efficacy in NSCLC through epigenetic reprogramming and computational modeling
administering_ic: NCI
award_notice_date: 2025-07-14
opportunity_number: PAR-23-286
application_type: 1
activity_code: K99
ic: CA
serial_number: 303792
program_official: RADAEV, SERGEY
project_start_date: 2025-07-14
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-U (M1)]
contact_pi_person_id: 78974528
contact_pi: PLAUGHER, DANIEL RAY
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:
ABSTRACTNovel therapeutic protocols are desperately needed to treat non-small cell lung cancer (NSCLC) the deadliestform of cancer world-wide. Immunotherapy is the standard-of-care for most NSCLC patients and has showngreat promise. However response rates are still strikingly low at just 20%. Alternatively utilizing a patients tumor-infiltrating lymphocytes (TIL) is proving to be a viable and highly personalized approach. Research: Hostile tumormicroenvironments (TME) contribute to T cell rejection in solid cancers and it is well known that the TME ofNSCLC influences immunotherapy responses. This project proposes Enhancing TIL efficacy in NSCLC throughepigenetic reprogramming and computational modeling. We recently found that inhibiting epigenetic enzymeEZH2 (EZH2i) is a promising mechanism to improve both TIL expansion and efficacy. Specifically EZH2i led toimproved anti-PD1 immunotherapy response upregulation of both major histocompatibility complexes greaterpro-T cell cytokine signaling and myeloid populations became more tumor-eliminating. Further several studiesshow that EZH2i limits regulatory T cells. Based on preliminary data we hypothesize that EZH2i will improveboth TIL expansion and infusion outcomes in NSCLC patients (Aim 1). Yet there are certainly mechanisms of Tcell suppression that EZH2i may not overcome. To address and identify these mechanisms mathematicalmodeling of cancer has risen as a viable method to analyze dynamical systems. Stochastic Boolean regulatorynetworks in particular provide a coarse-grained and mechanistic approach to study cellular processes that drivelong-term outcomes. Therefore we further hypothesize that modern sequencing data and methods frommathematical biology can discover alternative mechanisms of T cell suppression that will suggest novel targetsfor TIL-combination treatment (Aim 2). Candidate: Dr. Daniel Plaugher is an advanced early postdoctoral fellowin the University of Kentuckys NCI-designated Comprehensive Markey Cancer Center (MCC). He has extensivetraining in mathematical biology building dynamic models of cancer systems and has spent the last 1.5 yearsfully emersed in bench training. Further training in (1) cancer informatics (2) tumor immunology and (3) modernexperimental science will enhance his trajectory toward becoming an independent investigator.Mentors/Environment: Dr. Plaughers career development plan includes substantial mentorship didactic andnondidactic training and experiential learning at MCC. He will receive direct mentorship from Drs. ChristineBrainson (primary lung cancer biology) Ilhem Messaoudi (co-mentor immunology) and Chi Wang (co-mentorbioinformatics). He will be advised by Drs. Zhonglin Hao (thoracic oncology) Jinpeng Liu (computer science)and Daniel Abate-Daga (T cell biology). Overall the objectives of this application will advance lung cancerresearch both regionally and beyond by providing evidence for future R01 submissions and by supporting Dr.Plaughers training as an independent scientist to run a synergistic computational and experimental laboratory.

project_terms:
Abate;Active Learning;Address;Adoptive Cell Transfers;Antigen Presentation;Appalachian Region;Bioinformatics;Biopsy Specimen;CD8B1 gene;Cancer Biology;Cancer Center;Cancer Model;Cancer Patient;Cell Physiology;Cellular biology;Clinical Data;Combined Modality Therapy;Communication;Computer Models;Cytokine Signaling;Cytotoxic T-Lymphocytes;Data;Data Set;Development Plans;Disease Progression;EZH2 gene;Ensure;Environment;Enzymes;Epigenetic Process;Equation;Future;Goals;Grain;Homing;Human;Immune Evasion;Immune Targeting;Immune checkpoint inhibitor;Immunologic Markers;Immunology;Immunotherapy;In Vitro;Informatics;Infusion procedures;Interleukin-2;Kentucky;Learning;Libraries;Major Histocompatibility Complex;Malignant Neoplasms;Malignant neoplasm of lung;Mathematical Biology;Mathematics;Mentors;Mentorship;Methods;Modernization;Mus;Myelogenous;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;PD-1/PD-L1;Patients;Pattern;Phenotype;Population;Postdoctoral Fellow;Protocols documentation;Regulatory T-Lymphocyte;Research;Research Personnel;Resistance;Running;Sampling;Science;Scientist;Secure;Signal Transduction;Signal Transduction Pathway;Solid;System;Systems Analysis;T-Lymphocyte;Techniques;Testing;Therapeutic;Thoracic Oncology;Training;Tumor Expansion;Tumor-Infiltrating Lymphocytes;Universities;Upregulation;anti-PD1 antibodies;anti-cancer research;antitumor effect;career development;checkpoint inhibition;clinically relevant;computer science;control theory;deep sequencing;dynamic system;efficacy evaluation;efficacy testing;epigenetic therapy;experience;fighting;gene regulatory network;histone methyltransferase;immune cell infiltrate;improved;in vivo;in vivo evaluation;inhibitor;laboratory experiment;mathematical methods;mathematical model;neoantigens;neoplastic cell;novel;novel therapeutics;personalized approach;proliferation potential;resistance mechanism;responders and non-responders;response;side effect;skills;standard of care;theories;therapeutic target;treatment response;trend;tumor;tumor growth;tumor immunology;tumor microenvironment

public_health_relevance:
PROJECT NARRATIVEThe short-term goal of this K99/R00 application is to develop the PI as an independent investigator skilled incancer informatics tumor immunology and modern experimental science; the long-term goal is to enhancetumor-infiltrating lymphocyte (TIL) therapy in lung cancer patients. The proposed research will test the efficacyof epigenetic modulation paired TILs in lung cancer through in vivo and in vitro studies with de-identified humansamples. The project will also use modern sequencing data and methods from mathematical biology to discovermechanisms of T cell suppression and suggest novel targets for TIL-combination treatment.


application_id: 11212494
project_number: 1R21HD119324-01
project_title: SOX9: A Novel Mediator of the Ovulatory Process in the Human Ovary
administering_ic: NICHD
award_notice_date: 2025-08-27
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: HD
serial_number: 119324
program_official: TAYMANS, SUSAN
project_start_date: 2025-09-01
project_end_date: 2027-08-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
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:
Abstract Ovarian disorders in women including defects in ovulation and subsequent corpus luteum (CL)development account for up to 30% of all infertility cases. Understanding the mechanism underlying theseprocesses is critically important as this knowledge provides a foundation for our ability to aid or managefemale fertility. The mid-cycle gonadotropin surge triggers dramatic changes in the dominant follicleculminating in ovulation and transformation into the CL. One essential step elicited by the gonadotropin surgeis the induction of specific transcription factors that directly control the transcription of genes crucial forsuccessful ovulation and luteinization. However our knowledge of regulatory actions of LH/hCG-inducedovulatory transcription factors remains limited especially in humans. Our preliminary data shed light on SOX9 (sex-determining region Y (SRY)-box transcription factor 9) as acritical transcriptional regulator involved in periovulatory processes. It has long been accepted that SOX9 isexpressed at a low level or repressed in the developing ovary. This active suppression of SOX9 in granulosacells is crucial for maintaining ovarian phenotype. Challenging this belief our preliminary data show that SOX9expression is markedly up-regulated in granulosa cells of dominant follicles obtained from normally cyclingwomen after the LH surge. Furthermore our pilot study shows that SOX9 is a direct downstream-regulatedgene of progesterone/progesterone receptor (PGR) an essential mediator of the ovulatory process andregulates the expression of STAR and CYP11A1 and progesterone production in human granulosa/lutein cells.Based on these data we hypothesize that SOX9 is a human-specific ovulatory gene that plays a critical role inovulation and luteinization by regulating the expression of genes involved in the periovulatory process. Thishypothesis will be tested utilizing in vivo ovarian tissue samples obtained from normally cycling women duringvarious ovulatory phases and a primary human granulosa/lutein cell culture model that can recapitulate in vivochanges in ovulatory gene expression and hormone profiles. In Aim 1 we will determine the expression patternof SOX9 and its downstream genes in follicular cells isolated from dominant follicles and whole dominantfollicles obtained from normally cycling women throughout the periovulatory period. In Aim 2 we will identifySOX9-regulated downstream genes and assess the impact of SOX9 knockdown on granulosa/lutein cellfunction. The proposed is in line with R21 mechanisms as it will not only for the first time demonstrate theovulatory up-regulation of SOX9 in human ovulatory follicles but also enhance our understanding of how theLH surge/hCG - P4/PGR - SOX9 pathway controls the human-specific ovulatory process and luteinization inthe ovary. This fundamental knowledge could be directly applied to uncovering the molecular mechanismsunderlying anovulatory disorders or luteal insufficiency as well as developing strategies to improve themanagement of female fertility.

project_terms:
Automobile Driving;Belief;CYP11A1 gene;Cell Culture Techniques;Cell Physiology;Cell Separation;Cells;ChIP-seq;Data;Defect;Development;Event;Exploratory/Developmental Grant;Fertility;Foundations;Gene Expression;Genes;Genetic Transcription;Gonadal structure;Gonadotropins;Hormones;Hour;Human;Human Chorionic Gonadotropin;Infertility;Informatics;Knowledge;Lead;Life;Luteal Cells;Luteinization;Mediating;Mediator;Modeling;Molecular;Morphology;Mus;Oocytes;Ovarian;Ovarian Diseases;Ovarian Tissue;Ovary;Ovulation;Pathway interactions;Pattern;Phase;Phenotype;Pilot Projects;Play;Process;Production;Progesterone;Progesterone Receptors;Repression;Reproductive Health;Role;Rupture;Small Interfering RNA;Testing;Time;Tissue Sample;Tissues;Transcriptional Regulation;Upregulation;Woman;adenoviral mediated;analog;anovulatory disorder;corpus luteum;female fertility;granulosa cell;improved;in vivo;insight;knock-down;novel;sex;sex determination;single-cell RNA sequencing;small hairpin RNA;spatiotemporal;stem;transcription factor;transcriptomics

public_health_relevance:
NarrativeSuccessful ovulation and subsequent corpus luteum development are essential for female fertility. In thepresent proposal we will demonstrate for the first time that SOX9 plays a crucial role in ovulation and corpusluteum development in the human ovary. This fundamental Information will not only provide novel insights intothe mechanism(s) underlying ovulation and luteal formation but also be valuable for developing strategies toassist women with compromised reproductive health and infertility stemming from defects in the ovulatoryprocess and luteal development and manage fertility.


application_id: 11211278
project_number: 3R01CA251663-05S1
project_title: Targeting Mitochondrial Redox Capacity to Overcome Cancer Subtype that Regrowth After Radiation
administering_ic: NCI
award_notice_date: 2025-08-28
opportunity_number: PA-20-185
application_type: 3
activity_code: R01
ic: CA
serial_number: 251663
suffix: S1
program_official: PRASANNA, PAT G
project_start_date: 2021-04-01
project_end_date: 2027-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYRadiation therapy (RT) is widely used to treat localized prostate cancer (PCa). However cancer cells oftendevelop resistance to RT through unknown mechanisms resulting in cancer recurrence. To improve RT thereis a dire need to uncover cellular events that cause cells to become resistant. We previously demonstrated thatPCa heterogeneity particularly in prostate cancers with an abundant mitochondria subpopulation often surviveand regrow after RT (termed radiation resistant prostate cancer or RR-PCa). Elevation of mitochondrial massnumber reactive oxygen species (ROS) and biogenesis markers is acquired in RR-PCa cells. We furtherdemonstrated that knockdown of the mitochondrial biogenesis regulator TFAM (transcription factor Amitochondrial) significantly restored the sensitivity of RR-PCa cells to RT. Hence our overarching hypothesis isthat RT-activated mitochondrial biogenesis via ROS is an acquisition mechanism that drives PCa survival post-RT a premise that will undergo stringent examination in the proposed studies. ROS are known to directly andindirectly regulate mitochondrial homeostasis through fusion fission mitophagy and biogenesis. We screenedFDA-approved drugs in search of compounds that are nontoxic to normal cells and have the ability to raise thelevel of mitochondrial hydrogen peroxide (mtH2O2) in PCa cells while blocking mitochondrial protein translation.We found azithromycin (AZM) a macrolide antibiotic to be an effective prototype compound that possessesboth properties. We further demonstrated that AZM combined with RT enhances the death of PCa cells with anabundant mitochondrial subpopulation compared to AZM or RT alone. Thus we propose to advance our findingsand identify the mechanism(s) that effectively inhibit the survival of post-irradiated cancer cells to improve RTefficacy. The specific aims are: 1) to define the molecular mechanism(s) by which RT-activated mitochondrialbiogenesis promotes cell survival and metabolic adaptations of PCa cells with abundant mitochondria both invitro and in vivo; 2) to determine if overloading mtH2O2 to target inherent mitochondria and RT-acquiredmitochondria while blocking mitochondrial protein translation in RT-acquired mitochondria enhancesradiosensitivity of RR-PCa cells and 3) to improve RT using a mtH2O2 generator and a mitochondrial proteintranslation inhibitor AZM as prototype in an orthotopic mouse xenograft model and a patient-derived xenograftmodel of PCa with activated mitochondrial biogenesis. This study uses state-of-the-art platforms including thereverse phase protein array stable isotope-resolved metabolomics super-resolution microscopy with Imarissoftware TEMPOL-enhanced MRI imaging and a high resolution O2k-FluoRespirometer. The proposed studiesare expected to uncover novel molecular insights by which concurrently targeting mitochondrial redox capacityand mitochondrial biogenesis improve RT efficacy of RR-PCa.

project_terms:
Animal Model;Antibiotics;Azithromycin;Biochemical;Biogenesis;Cell Death;Cell Survival;Cells;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Computer software;Coupled;Cytoplasm;Data;Dose;Electron Transport;Enzymes;Event;Exhibits;External Beam Radiation Therapy;FDA approved;Failure;Growth;Homeostasis;Hydrogen Peroxide;Image;Impairment;In Vitro;Macrolides;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mitochondrial Proteins;Molecular;Mus;Normal Cell;Oxidation-Reduction;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Property;Prostate;Protein Array;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrence;Regulation;Research Design;Resistance;Resistance development;Resolution;Site;Testing;Therapeutic;Time;Translating;Translational Repression;Translations;Treatment Efficacy;Visualization;Xenograft Model;bioluminescence imaging;cancer cell;cancer heterogeneity;cancer recurrence;cancer subtypes;cancer survival;catalase;fractionated radiation;high risk;improved;in vivo;inhibitor;insight;knock-down;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;mortality;mtTF1 transcription factor;novel;novel therapeutics;overexpression;patient derived xenograft model;prevent;prostate cancer cell;prostate cancer model;prototype;radiation delivery;radiation resistance;radioresistant;response;stable isotope;success;superresolution microscopy;tempol;tumor;tumor growth;tumor heterogeneity

public_health_relevance:
PROJECT NARRATIVERadiation-resistant prostate cancer (RR-PCa) is highly unpredictable which frequently results in cancerrecurrence in many patients. This project aims to 1) establish the underlying mechanism(s) of mitochondrialbiogenesis that contribute to RR-PCa cell survival and metabolism and 2) determine if targeting inherentmitochondria and radiation-acquired mitochondria can overcome RR-PCa. The successful completion of thisproject will establish a new and significant therapeutic platform for making radiation therapy more effective.


application_id: 11211148
project_number: 5F31MD019997-02
administering_ic: NIMHD
award_notice_date: 2025-08-05
opportunity_number: PA-23-272
application_type: 5
activity_code: F31
ic: MD
serial_number: 019997
program_official: STINSON, NATHANIEL
project_start_date: 2024-09-03
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-F16-T(21)L]
contact_pi_person_id: 79490153
contact_pi: ROBERTS, MICHELLE KATHLEEN
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
budget_start_date: 2025-09-01
project_title:
From Survival to Living Well: A Socioecological Approach to Investigate Injury and Illness in Rural Appalachia

project_abstract:
ABSTRACTPeople with disabilities are significantly more likely to experience chronic conditions and are at risk of dying up to 20 years earlier than people without disabilities due to physical social psychological and financial challenges. Appalachian Kentucky a rural area with limited healthcare access has twice the U.S. rate of disability22.7% compared with 12.6% nationally. Rates of new or acquired disability are escalating as medical advances allow more people to survive hospitalization and live with disability yet we lack the knowledge to help people live well post-hospitalization. Specifically while formal medical care plays an invaluable role in saving the lives of people who experience an acute health event these survivors and their families are often left to manage the enduring challenges of living with acquired disability on their own. I propose a mixed methods ethnographic investigation to understand the nature of acquired disability including subsequent care throughout the life course in the rural communities of Appalachian Kentucky. Ethnographic studies enable a holisticpersonal environmental sociocultural and politicalperspective to understand individuals lived experiences and identify opportunities to reduce adverse health outcomes. Long-term health is intimately intertwined with broader cultural and structural factors that contribute to significant health challenges for rural disabled populations including informal (family and social relations) formal (health and human services) and institutional (policy and programs) forms of care. Consistent with the socioecological model I will identify multilevel factors impacting quality of life and long-term health and identify strategies to reduce stressors. Obtaining grounded insights on how disability amplifies existing challenges is necessary to inform health policy and structural interventions to improve quality of life and long-term health for people with disabilities. I propose two related aims: (1) to ethnographically investigate and describe experiences of acquired disability among those with disabilities family caregivers health and human service providers and policymakers and (2) to develop and verify a shared cultural model of disability describing the range of barriers facilitators and opportunities to help rural Appalachians live well with disability. To achieve these aims I will obtain rigorous training in rapid ethnographic assessment concept mapping culturally adapted interventions and grant writing to support my growth as an independent health equity researcher. A robust understanding of disability based on grounded experiences will inform future culturally adapted interventions to mitigate health challenges and improve the lives of people with disabilities and their families.

project_terms:
Acquired disability;Acute;Address;Affect;Appalachian Region;Caring;Chronic;Chronic Disease;Chronic Obstructive Pulmonary Disease;Communities;Complex;Death Rate;Development;Diabetes Mellitus;Disabilities experience;Disability outcome;Disabled Persons;Equipment;Ethnography;Event;Face;Family;Family Caregiver;Focus Groups;Formal caregiver;Future;Goals;Grant;Growth;Health;Health Care;Health Care Systems;Heart Diseases;Hospitalization;Human;Individual;Injury;Institution;Insurance;Intervention;Interview;Investigation;Kentucky;Knowledge;Left;Legal;Life Cycle Stages;Lived experience;Malignant Neoplasms;Medical;Mental Health;Methods;Modeling;Morbidity - disease rate;Nature;Outcome;Participant;Personal Satisfaction;Persons;Pharmaceutical Preparations;Play;Policies;Policy Maker;Politics;Premature Mortality;Prevalence;Preventive service;Quality of life;Reduce health disparities;Research;Research Methodology;Research Personnel;Resources;Risk;Risk Factors;Role;Rural;Rural Appalachia;Rural Community;Services;Social Change;Sorting;Stroke;Structure;Survivors;Training;Transportation;Unemployment;Writing;concept mapping;culturally appropriate intervention;disability;disabled;ethnographic method;experience;family management;follow-up;health care availability;health care quality;health equity;implementation intervention;improved;informal caregiver;informal caregiving;insight;low socioeconomic status;participant observation;physical conditioning;premature;programs;psychologic;psychosocial;public health relevance;quality of life improvement;rural area;rural dwellers;rural setting;service providers;social;social culture;stressor;structural determinants

public_health_relevance:
Public Health Relevance SectionPeople living in rural areas such as Appalachia are more likely to experience disability morbidity and premature mortality; despite the increasing prevalence of newly acquired disabilities and their negative impact on the well-being of rural residents we currently lack grounded perspectives on barriers and facilitators to optimal quality of life and health outcomes for people with disabilities. The proposed research will investigate diverse factors and circumstances that contributing to health challenges for rural disabled populations. This mixed methods research will expand knowledge of disability in Appalachia; identify gaps in health and human services; illuminate strategies to address individual interpersonal and community and policy-level challenges; and inform the future development and implementation of interventions across the socioecological model to improve the lives of people with disabilities and their families.


application_id: 11201249
project_number: 3R01ES027778-07S1
project_title: Mechanism for arsenic induced carcinogenesis
administering_ic: NIEHS
award_notice_date: 2024-12-17
opportunity_number: PA-23-189
application_type: 3
activity_code: R01
ic: ES
serial_number: 027778
suffix: S1
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-08-01
project_end_date: 2028-11-30
study_section: Environmental Determinants of Disease Study Section [EDD]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Arsenic exposure is a worldwide environmental health problem causing multiple chronic diseases includingcancer. Cancer results from mutations in and epigenetic modifications of oncogenes and tumor suppressorgenes. The molecular mechanisms driving arsenic (iAs)-induced carcinogenesis are likely a complex interplayof multiple factors contributing to yet unidentified genetic changes responsible for tumorigenesis. Onemechanism is the epigenetic effect of miRNA dysregulation. iAs-exposure induces chromosomal instability(CIN) and CIN contributes to carcinogenesis. We focused on mechanism and effects of overexpression of hsa-miR-186 on CIN in the previous funding period. miR-186 is an intronic miRNA and is overexpressed in iAs-induced squamous cell carcinoma (SCC). The parent gene encodes an alternative mRNA splicing factor that isdisrupted by iAs-exposure. miR-186 overexpression in human keratinocytes suppresses two mitotic regulatorsand gives rise to aneuploidy a hallmark of cancer. This investigation led to establishment of a new humankeratinocyte model for iAs-induced carcinogenesis using Ker-CT cells that is more amenable to karyotypeanalysis necessary to analyze CIN for leads into carcinogenic mutations. We identified 5 additional miRNAsthat are overexpressed in iAs-induced SCC and also in human keratinocytes (HaCaT) chronically exposed tolow dose iAs. These miRNAs are predicted to target multiple proteins also targeted by known oncogenicmiRNAs. This continuation application focuses on miRNAs dysregulated in iAs-induced SCC and proposes toidentify additional miR-186 targets contributing to CIN and to characterize the impact of the additional 5overexpressed miRNAs on carcinogenesis. The hypothesis underlying these studies is that dysregulation ofRNA metabolism contributes to iAs-induced carcinogenesis by modulating gene expression and inducing CIN.The specific aims are: 1) Determine the mechanism of hsa-miR-186 overexpression inducing aneuploidy andCIN in new Ker-CT model; 2) Characterize the new Ker-CT model of iAs-induced skin carcinogenesis; 3)Investigate role in cellular transformation of miRNAs common to SCC and arsenite-exposed HaCaT cells.Mutations in cancer genes in cells transformed by miR-186 overexpression and arsenic exposure will becharacterized providing information to fill a knowledge gap. Demonstrating that these miRNAs overexpressedin human iAs-induced SCC share targets with known oncogenic miRNAs will establish an epigeneticmechanism and be a major step forward in our understanding of the mechanism of iAs-inducedcarcinogenesis thus filling a critical knowledge gap in our understanding. The principles learned will provide atranslational framework for understanding the molecular mechanisms operative in iAs-induced carcinogenesisin other tissues and cell types. Identification of mutations in or epigenetic silencing of cancer genes inducedby iAs exposure will be a major step forward in our understanding of the mechanism of iAs-inducedcarcinogenesis.

project_terms:
Alternative Splicing;Aneuploidy;Arsenic;Arsenites;Automobile Driving;Cancer Etiology;Cell Culture Techniques;Cell Line;Cell model;Cells;Chromosomal Instability;Chronic;Chronic Disease;Clone Cells;Complex;DNA sequencing;Data;Development;Dose;Environmental Health;Epigenetic Process;Event;Exposure to;Funding;Gene Expression;Gene Fusion;Gene Targeting;Genes;Human;India;Investigation;Karyotype;Knowledge;Learning;Longitudinal Studies;Malignant Neoplasms;Messenger RNA;MicroRNAs;Mitotic;Modeling;Modification;Molecular;Mutation;Nature;Oncogenes;Oncogenic;Oncoproteins;Parents;Pathway interactions;Persons;Phenotype;Preparation;Proteins;Proteomics;RNA Splicing;RNA metabolism;Role;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;Tissue-Specific Gene Expression;Tissues;Tumor Suppressor Genes;Tumor Suppressor Proteins;Work;arsenic-induced carcinogenesis;carcinogenesis;carcinogenicity;cell transformation;cell type;drinking water;epigenetic silencing;exposed human population;fusion gene;gene induction;in vitro Model;insight;keratinocyte;mRNA Expression;metaplastic cell transformation;novel;overexpression;skin organogenesis;transcriptome sequencing;translational framework;tumor;tumorigenesis

public_health_relevance:
NarrativeSome microRNAs can act as oncogenes or tumor suppressors by suppressing the expression of tumorsuppressor or oncogene proteins. The proposed studies will determine whether microRNAs overexpressed inskin cancers caused by chronic arsenic exposure contribute to the development of skin cancer by targetingproteins in common with known oncogenic microRNAs.


application_id: 11198700
project_number: 1R16GM159630-01
project_title: Psychotropic compounds from wastewater contamination affect nervous system development
administering_ic: NIGMS
award_notice_date: 2025-08-05
opportunity_number: PAR-24-145
application_type: 1
activity_code: R16
ic: GM
serial_number: 159630
program_official: ZHOU, YANG
project_start_date: 2025-09-01
project_end_date: 2029-08-31
study_section: Special Emphasis Panel[ZGM1 RCB-T (SU)]
contact_pi_person_id: 11369515
contact_pi: WEINBERGER, DENA R
other_pis: Not Applicable
congressional_district: 01
department: BIOLOGY
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe receiving water bodies that are sources of drinking water are continuously contaminated with psychotropicdrugs  those that target the nervous system - through wastewater treatment facility effluent. Withoutmechanisms to remove or neutralize them these drugs can reach the drinking water cross maternal biologicalbarriers and alter embryonic gene expression. Is it not known how chronic exposure to the composite mixtureof these drugs including antidepressants and narcotics even at very low doses may represent a risk to humanhealth. Psychotropic medications are among the most commonly prescribed drugs in the U.S. Together withpsychotropic illicit drugs a significant portion of these medications and their active metabolites are dischargedinto the receiving water bodies. With the prevalence of drugs in wastewater ever-increasing so does the urgencyof understanding the risks. Our central hypothesis is that developmental exposure to low levels of psychoactivedrugs through contaminated water sources affects gene expression in the developing nervous system withbehavioral consequences. This proposed basic biomedical research will expose developing zebrafish to anenvironmentally-relevant combination of psychotropic compounds to evaluate the effects of this form of exposureon gene expression and function of nervous system. Quantitative RT-PCR and in situ hybridization will be usedto explore nervous system-specific changes in gene expression following drug exposure. A battery of larvalbehaviors ranging from basic locomotion to cognitive tasks will assess the functional consequences ofdevelopmental drug exposure. Finally sensitive behaviors will be used to evaluate potential synergism betweendrugs. By raising zebrafish in dosed water as a proxy for human prenatal exposure through contaminated waterthese experiments will identify sensitive behaviors and genes that are expressed in developing neural tissues.Strengthening the evidence that exposure to subtherapeutic levels of these drugs has adverse effects ondevelopment may inform intervention to remediation measures to reduce the risk to human health.

project_terms:
Address;Adverse effects;Affect;Age;Behavior;Behavioral;Biological;Biological Assay;Biological Models;Biomedical Research;Brain region;Chronic;Cocaine;Cognitive;Development;Dose;Drug Contamination;Drug Exposure;Drug Prescriptions;Drug Residues;Drug Synergism;Embryo;Embryonic Nervous System;Environment;Environmental Pollution;Environmental Risk Factor;Experimental Designs;Exposure to;First Generation College Students;Fluoxetine;Funding;Gene Expression;Genes;Health;Human;Illicit Drugs;Immune response;Immunity;In Situ Hybridization;Individual;Intervention;Knowledge;Larva;Life;Link;Locomotion;Low income;Measures;Methamphetamine;Narcotics;Nervous System;Nervous System Disorder;Nervous System Physiology;Neurodevelopmental Disorder;Neurologic Dysfunctions;Pharmaceutical Preparations;Prevalence;Protocols documentation;Proxy;Psychotropic Drugs;Quantitative Reverse Transcriptase PCR;Research;Risk;Risk Assessment;Risk Factors;Risk Reduction;Rural;Schizophrenia;Sensory;Source;Standardization;Stimulant;System;Testing;Therapeutic;Tissues;Water;Work;Zebrafish;anti-depressive agents;behavior change;behavior measurement;behavior test;cognitive task;contaminated drinking water;contaminated water;cytokine;drinking water;drug action;experimental study;exposed human population;exposure route;gene function;minimal risk;nervous system development;neural;novel strategies;prenatal;prenatal exposure;primarily undergraduate institution;remediation;response;synergism;tool;transcriptome sequencing;undergraduate student

public_health_relevance:
NarrativeWide ranges of drugs with overlapping neural targets contaminate our drinking water sources and wehypothesize that this route of exposure affects gene expression in brain regions with functional consequences.By raising zebrafish in dosed water as a proxy for prenatal human exposure through contaminated drinkingwater undergraduate-led projects will identify behaviors and genes that are sensitive to this type of sub-therapeutic potentially synergistic and chronic exposure.


application_id: 11198644
project_number: 1S15OD039798-01
project_title: Modernization of Sterilization Equipment in the UK Todd Vivarium
administering_ic: OD
award_notice_date: 2025-08-13
opportunity_number: PAR-24-259
application_type: 1
activity_code: S15
ic: OD
serial_number: 039798
program_official: SPECTOR, JEFFREY O
project_start_date: 2025-08-15
project_end_date: 2026-08-14
study_section: Special Emphasis Panel[ZRG1 KUDS-S (90)]
contact_pi_person_id: 8666992
contact_pi: KINCER, JEANIE F.
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract:The conduct of quality biomedical research is dependent upon the availability of rodents that are free of severalimportant diseases. Thus the cage wash facility of a vivarium is essential for ensuring the prevention of bothcross-contamination of sensitive animal models and outbreaks of opportunistic infections in immune-deficientstrains. This proposal requests a modern eco-friendly dry heat sterilizer which will substantially enhance theoperations of the universitys Division of Laboratory Animal Resources specifically the research-supportingfunctions that advance facility operations to accommodate a rapidly expanding biomedical research enterprisethrough enhanced throughput increased capacity for housing sensitive rodent models improved biosecurityfor animal colonies and innovative green technologies for savings in energy and water. Completed foroccupancy in February 2010 the Lee T. Todd Jr. animal facility was designed to provide a daily inventory ofup to 2000 sterile mouse cages with appropriate autoclave capacity to meet this demand out of a total 11000IVC cages. The initial sterile cage capacity was sufficient to maintain rodents in a rigorously defined microflorastatus following rederivation as well as to support immune deficient mouse models however the increasingnumber of researchers and mice in the West Research Complex is outstripping this capacity. Since the ToddBuildings opening dry heat sterilizers have begun to be used more frequently in animal facilities instead oftraditional bulk autoclaves for sterilizing rodent cages bedding and feed presenting a unique opportunity toexplore more innovative solutions. These more-modern sterilizers have less-complex technology resulting inconsiderably fewer maintenance requirements; lower initial project costs to deploy; lower operational costs;and lower infrastructure costs. Smaller less demanding autoclaves can be used for sterilization of other items(e.g water bottles) to maximize the higher efficiency of the dry heat units. In order for UKs researchers torealize these advantages the aim of this proposal is to modernize the sterilization equipment within the ToddBuilding animal facility by installing a Gruenberg Steri-Dry dry heat sterilizer and a smaller autoclave.Modernizing the current cage sterilization system in this facility will allow the UKs researchers to continuefostering cutting-edge discovery and innovation. Notably the new equipment will provide much neededinfrastructure to support improve and expand the research of UKs National Cancer Institute-designatedComprehensive Cancer Care Center NIH-funded Centers of Biomedical Research Excellence (COBRE) andnumerous additional NIH-funded programs and investigators. In addition the modernization of this cage washequipment is a critical component of UKs Research Strategic Plan to enhance NIH-funded biomedicalresearch and support health focused research programs that benefit both Kentuckians and populations beyondthe Commonwealth of Kentucky.

project_terms:
Alzheimer's Disease;Animal Experimentation;Animal Model;Area;Beds;Biomedical Research;Centers of Research Excellence;Complex;Derivation procedure;Disease;Disease Outbreaks;Dryness;Ensure;Equipment;Equipment and supply inventories;Fostering;Friends;Funding;Health;Housing;Infrastructure;Kentucky;Laboratory Animals;Maintenance;Malignant Neoplasms;Metabolic Diseases;Modernization;Mus;National Cancer Institute;Nervous System Disorder;Opportunistic Infections;Population;Prevention;Request for Proposals;Research;Research Personnel;Research Support;Rodent;Rodent Model;Savings;Sterility;Sterilization;Strategic Planning;System;Technology;United States National Institutes of Health;Universities;Water;animal colony;animal facility;animal resource;biosecurity;cancer care;cost;design;immunodeficiency;improved;innovation;microbiota;mouse model;operation;programs

public_health_relevance:
Project NarrativeResearch in the Todd Building main vivarium is concentrated in the areas of cancer metabolicdiseases Alzheimer's disease and neurologic disease. The cage wash facility of a vivarium isessential in ensuring the prevention of both cross-contamination of sensitive animal models andoutbreaks of opportunistic infections in immune-deficient strains. By obtaining a modern eco-friendly dry heat sterilizer we would be ensuring that we are providing a controlled andconsistent microenvironment to support meaningful animal research.


application_id: 11198552
project_number: 1R25CA302429-01
project_title: Markey STRONG Scholars Program
administering_ic: NCI
award_notice_date: 2025-08-04
opportunity_number: PAR-23-277
application_type: 1
activity_code: R25
ic: CA
serial_number: 302429
program_official: JAKOWLEW, SONIA B
project_start_date: 2025-08-01
project_end_date: 2030-07-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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:
Kentucky has the highest rates of cancer incidence and mortality in the nation that stem from significant health socioeconomic and education challenges that are prevalent throughout the state. To address and reverse these trends a transformational approach to selecting educating and training our next generation of researchers and medical care practitioners is needed. To create a better informed and educated scientific workforce that can address the unique challenges of our population the Markey Science Training in Research Oncology Networking and professional Growth (STRONG) Scholars Program will leverage the exceptional research educational and career development resources at the University of Kentuckys Markey Cancer Center to culturally adapt its undergraduate summer research experience in partnership with stakeholders throughout the university. The STRONG Scholars Program will engage undergraduate STEM-M students in transdisciplinary mentored research experiences cancer clinical care observational experiences cancer education networking and professional career development activities that include soft skills critical for professional success. The objective of the program is to advance the scholars knowledge critical thinking skills technical experimental skills responsible/ethical conduct of research and networking abilities to advance their career and allow them to confidently contribute their talents to our fight to end cancer mortality. The overarching goal of this program is to improve our undergraduate research training experience by reimagining how the selection education and training of our next generation of researchers and medical care practitioners thus ensuring these individuals are positioned well to impact change. The goals and objectives of this program will be accomplished through four Specific Aims including: 1) To develop participants scientific research knowledge and research self-efficacy through faculty mentored research training experiences; 2) To cultivate participants knowledge of cancer cancer health challenges cancer research methods and cancer clinical care through interactive lectures scientific communication workshops and clinical shadowing opportunities; 3) To enhance participants professional development through thematic workshops roundtable discussions networking and personalized coaching and mentoring; and 4) To evaluate the effectiveness of the program and its components through quantitative and qualitative assessment methods and longitudinal tracking of participants academic and professional careers. Ultimately the program will build on a solid foundation to create a new paradigm for enhancing cancer-focused research and educational experiences to foster a resilient confident and informed next generation of cancer researchers and medical professionals that will participate in improving our knowledge of cancer treatment options and survival outcomes that will eventually eliminate cancer health challenges and save lives.

project_terms:
Address;Affect;American Cancer Society;COVID-19 pandemic;Cancer Center;Cancer Patient;Caring;Clinical;Communication;Communities;Creativeness;Critical Thinking;Death Rate;Dedications;Development;Education;Educational workshop;Ensure;Environment;Ethics;Evaluation;Family;Fostering;Foundations;Goals;Grant;Growth;Health;Health Care;Height;Hereditary Malignant Neoplasm;Incidence;Individual;Kentucky;Knowledge;Li-Fraumeni Syndrome;Malignant Neoplasms;Medical;Medicine;Mentors;Methods;Mission;Oncology;Participant;Pathway interactions;Population;Positioning Attribute;Program Effectiveness;Program Evaluation;Program Reviews;Research;Research Methodology;Research Personnel;Research Training;Resource Development;Scholars Program;Science;Scientist;Self Efficacy;Solid;Students;Syndrome;Talents;Thinking;Training;Training and Education;Universities;Voice;Work;anti-cancer research;cancer education;career;career development;clinical care;cohort;design;effectiveness evaluation;experience;faculty mentor;fighting;improved;innovation;lectures;low socioeconomic status;mortality;next generation;novel;novel strategies;programs;research education experience;resilience;skills;socioeconomics;stem;success;summer research;survival outcome;trend;undergraduate research;undergraduate student;undergraduate summer research

public_health_relevance:
Kentucky has the highest cancer incidence and mortality rates in the nation that derive from the states prevalent health socioeconomic and educational challenges. To help reverse these trends The Markey Science Training in Research Oncology Networking and professional Growth (STRONG) Scholars Program will provide transformative mentored cancer research experiences for individuals from the communities most severely impacted by cancer with the goal of creating a more resilient knowledgeable and innovative workforce in cancer research that is ready to effect change.


application_id: 11197683
project_number: 75N93024D00036-0-759302400001-1
project_title: Pre-Clinical Models of Infectious Diseases
project_abstract: This contract provides for Pre-Clinical Models of Infectious Diseases activities.
administering_ic: NIAID
project_start_date: 2024-07-15
project_end_date: 2031-07-14
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_terms:
Contracts;Development;Modeling;Pre-Clinical Model;Reagent;infectious disease model;medical countermeasure


application_id: 11197323
project_number: 1R35GM159612-01
administering_ic: NIGMS
award_notice_date: 2025-08-06
opportunity_number: PAR-23-145
application_type: 1
activity_code: R35
ic: GM
serial_number: 159612
program_official: NIE, ZHONGZHEN
project_start_date: 2025-08-07
project_end_date: 2030-07-31
study_section: Maximizing Investigators’ Research Award B Study Section[MRAB]
contact_pi_person_id: 14354764
contact_pi: RADKA, CHRISTOPHER DAVID
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-07
project_title:
Targeting Membrane Environments: The Role of Oleate Hydratase (OhyA) in Lipid-Protein Interactions Across Microbial Communities

project_abstract:
PROJECT SUMMARY/ABSTRACTMembrane integrity and function in biological systems heavily rely on lipid-protein interactions particularly therole of proteins in concentrating signaling molecules within cellular membranes. Oleate hydratase (OhyA) is amicrobial enzyme crucial in modifying unsaturated fatty acids (UFA) within cell membranes transforming theminto anti-inflammatory hydroxy fatty acids (hFA). This enzymatic activity is pivotal for various physiologicalprocesses including gut health maintenance and immune response modulation. Despite its importance themolecular mechanisms underpinning OhyA's membrane interaction and catalytic function especially inpathogenic and commensal bacteria remain unclear.Our research aims to elucidate the fundamental aspects of OhyA biology focusing on three areas: investigationof how OhyA acquires UFA substrates from the membrane understanding how bacteria utilize OhyA anddistribute hFA to support colonization and immune modulation and exploring the catalytic mechanisms of OhyAvariants lacking typical functional domains. Our multidisciplinary approach leverages advanced structuralbiology lipidomics and genetic techniques to uncover novel insights into microbial physiology and protein-membrane interactions. This innovative framework promises significant contributions to both fundamentalscience and applied biotechnology.Characterizing OhyA and its role in lipid metabolism and immune modulation is pivotal for understandingbacterial pathogenesis and commensalism. Insights gained will inform biotechnological advancementspotentially facilitating the development of novel therapeutic strategies targeting microbial lipid metabolism.Our recent advances include solving crystal structures of OhyAliposome complexes and identifying membrane-targeting domains developing robust lipidomics pipelines for hFA quantification in biological samples andestablishing PPAR alpha as a key target for immunomodulatory hFA signaling. Our future investigations willexpand on these foundations: defining the ecological relevance of OhyA in intestinal microbiomes using diversemurine models determining the molecular details of OhyA-membrane interactions across bacterial taxa andelucidating catalytic mechanisms of unusual OhyA variants and their implications for enzyme engineering.In summary our research program aims to advance understanding of OhyA-mediated lipid metabolism inmicrobial communities paving the way for innovations in microbiome science and biotechnological applications.

project_terms:
Address;Anatomy;Anti-Inflammatory Agents;Area;Bacteria;Bacterial Physiology;Biological;Biology;Biotechnology;Cell membrane;Cellular Membrane;Complex;Development;Ecology;Engineering;Environment;Enzymes;Fatty Acids;Foundations;Future;Genetic Techniques;Human;Immune response;Inflammation;Intervention;Investigation;Knowledge;Lipids;Liposomes;Maintenance;Mediating;Membrane;Membrane Proteins;Metabolic Diseases;Microbial Physiology;Molecular;Oleates;PPAR alpha;Pathogenesis;Physiological Processes;Proteins;Research;Role;Sampling;Science;Signal Transduction;Signaling Molecule;Structure;Symbiosis;Therapeutic;Unsaturated Fatty Acids;Variant;biological systems;commensal bacteria;grasp;gut health;gut microbiome;health application;host-microbe interactions;hydroxy fatty acid;immunoregulation;innovation;insight;interdisciplinary approach;lipid metabolism;lipidomics;microbial;microbial community;microbiome research;mouse model;novel;novel therapeutic intervention;pathogenic bacteria;programs;structural biology

public_health_relevance:
PROJECT NARRATIVEThe research on oleate hydratase (OhyA) promises significant contributions to our understanding of bacterialphysiology and human health applications. By elucidating how OhyA interacts with bacterial membranes toaccess and modify fatty acids this study addresses fundamental questions about protein targeting andenzymatic function in host lipid-rich environments. This knowledge will enhance our grasp of microbial ecologyand host-microbe interactions within diverse anatomical sites and also holds the potential for developing novelbiocatalysts and therapeutic strategies aimed at modulating inflammation and metabolic disorders throughtargeted lipid interventions.


application_id: 11197045
project_number: 1R16DK147815-01
project_title: Elucidating the mechanisms of Glis3-regulated development in the pancreas and kidney
administering_ic: NIDDK
award_notice_date: 2025-09-12
opportunity_number: PAR-24-144
application_type: 1
activity_code: R16
ic: DK
serial_number: 147815
program_official: BRUNSKILL, ERIC WAYNE
project_start_date: 2025-09-15
project_end_date: 2029-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-X (SF)]
contact_pi_person_id: 11381044
contact_pi: ZERUTH, GARY T
other_pis: Not Applicable
congressional_district: 01
department: BIOLOGY
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryEmbryonic development is orchestrated through complex networks of genes that specify cell fates and choreograph themigration and reorganization of cells into tissues. Mutations within developmental genes can both give rise to birth defectsand increase susceptibility to diseases later in life. The transcription factor Gli-similar 3 (Glis3) has been found to beimportant during embryological development and mutations within the GLIS3 locus have been implicated in the developmentof several diseases including diabetes Alzheimers disease and cancer. Currently little is known about the specific rolesGlis3 plays during development or how divergence from its normal function promotes disease at the molecular level.In this proposal experiments are described intended to characterize pancreatic and renal development in the glis3EX4del/EX4delmutant zebrafish line that lacks functional glis3 expression. In Specific Aim 1 we will characterize pancreatic developmentin glis3 knockout fish to determine what role glis3 plays in directing development of the pancreatic ducts and the specificationof secondary islets that emerge from the ductal epithelium. The experiments described in Specific Aim 2 are designed toexamine the mechanisms by which loss of glis3 expression results in cystic kidneys. Particular emphasis will be placed oncharacterizing the association between glis3 and the mechano-sensory organelle known as the primary cilium. Finally inSpecific Aim 3 plans are described to gain a better understanding of the specific cell types that express glis3 duringdevelopment and how loss of glis3 expression alters gene expression in the developing zebrafish by conducting scRNA-seq analysis.The research described in this proposal will be conducted at a regional comprehensive university that serves apredominately rural economically underdeveloped community for whom access to scientific research is traditionallyrestricted. The research will be completed with extensive support from undergraduate researchers who will gain theopportunity to co-author manuscripts and present findings at local state and national meetings.Broadly the completion of the studies outlined in this proposal will increase our understanding of how Glis3 specifies cellfates during development and may help shed light on how Glis3 mutations lead to diseases in humans such as diabetesmellitus and polycystic kidney disease. Furthermore a greater understanding of the mechanisms that regulate pancreaticand renal development is likely to be achieved including a more thorough knowledge of the transcription factor networksthat direct cell fates and tissue organization. Ultimately completion of the research described may lead to the establishmentof a complementary zebrafish model for the study of human disease.

project_terms:
Alzheimer's Disease;Bilateral;Blood Glucose;Brain;CRISPR/Cas technology;Carrier Proteins;Cell Lineage;Cells;Characteristics;Cilia;Communities;Complex;Congenital Abnormality;Cretinism;Cystic kidney;Data;Defect;Development;Developmental Gene;Diabetes Mellitus;Disease;Dorsal;Duct (organ) structure;Ductal Epithelium;Embryo;Embryonic Development;Endocrine;Endoderm;Event;Exhibits;Family member;Fishes;Gene Expression;Gene Expression Profile;Genes;Genetic Techniques;Goals;Hepatopancreas;Hormones;Human;Human Development;Hyperglycemia;Hypothyroidism;Impairment;Islets of Langerhans;Kidney;Kinesin;Knock-out;Knowledge;Larva;Lead;Length;Malignant Neoplasms;Manuscripts;Mediating;Microcephaly;Modeling;Molecular;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Organ;Organelles;Pancreas;Pancreatic Bud;Pancreatic duct;Pathology;Pattern;Phenotype;Play;Polycystic Kidney Diseases;Predisposition;Pronephric structure;Reporting;Research;Research Personnel;Role;Rural;Signal Transduction;Specific qualifier value;Study models;System;Tissues;Universities;Visualization;WNT Signaling Pathway;Zebrafish;cell fate specification;cell type;cilium biogenesis;clinically significant;design;differential expression;experimental study;functional loss;gene network;genome wide association study;glucose metabolism;human disease;insight;islet;later life;loss of function mutation;meetings;migration;model organism;mutant;neonatal diabetes mellitus;notch protein;novel therapeutics;offspring;pancreas development;protein transport;single-cell RNA sequencing;stem cells;trafficking;transcription factor;transcriptome sequencing;type I and type II diabetes;undergraduate student;zebrafish development

public_health_relevance:
Project NarrativeGLIS3 mutations in humans are associated with a number of pathologies including polycystic kidney disease congenitalhypothyroidism and diabetes mellitus. In this project a zebrafish mutant deficient in glis3 is used as a model organism togain a better understanding of pancreatic and renal development and function. Given the similarities between zebrafishand human development the results of this study may eventually lead to the facilitation of novel therapies to treatdiabetes and polycystic kidney disease.


application_id: 11196752
project_number: 5R01DA061996-02
administering_ic: NIDA
award_notice_date: 2025-07-11
opportunity_number: RFA-DA-22-040
application_type: 5
activity_code: R01
ic: DA
serial_number: 061996
program_official: JENKINS, RICHARD A
project_start_date: 2024-09-30
project_end_date: 2029-07-31
study_section: ZDA1-TXT-E(A1)R
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
budget_start_date: 2025-08-01
project_title:
Optimizing PrEP Care Delivery through Adaptive Intervention Strategies for Underserved Rural People who Inject Drugs

project_abstract:
ABSTRACTKentuckys HIV epidemic displays an especially profound and disproportionate impact among people whoinject drugs (PWID): 14.8% of males and 54.2% of females newly diagnosed with HIV in 2021 have aninjection drug use-related transmission factor far exceeding the national average for this exposure category.A central pillar of Ending the HIV Epidemic (EHE) is the prevention of new HIV infections through scale up ofPre-Exposure Prophylaxis (PrEP) in key populations including PWID. For PWID PrEP uptake remainsseverely limited and no evidence-based PrEP interventions specifically targeted for PWID are available. In ourR34 in KYs Appalachian region we successfully implemented two brief low-intensity interventions topromote linkage to co-located PrEP care in rural syringe service programs (SSPs) including a newly adaptedstrengths-based case management (SBCM-PrEP) intervention designed to address multi-level barriers toPrEP initiation. Our pilot trial has demonstrated proof of concept for integrated PrEP care withinrurally-located SSPs and high acceptability among PWID: 96% of PWID participants entered the PrEPcare cascade by attending at least one PrEP intervention session and 86% completed an initial PrEP clinicalvisit and point of care testing for PrEP eligibility. Nevertheless just 51% returned for test results and 28%progressed to PrEP prescription indicating that augmented intervention support is required to optimize PrEPuptake. Building on this strong foundation the proposed study will deploy stepped-care adaptive interventionsin three rural SSPs in a Sequential Multiple Assignment Randomized Trial (SMART) design to test the optimalintervention pathways for PrEP uptake defined as PrEP initiation (measured by dispensed prescription for oralPrEP) and persistence in PrEP care (measured by refill verification and biomarker confirmation). The SpecificAims are to: 1: Compare the relative effectiveness of adaptive interventions (AIs) that begin with Peer-ledSBCM-PrEP versus those that begin with CDC PrEP education plus text messaging (TM) on patient-level PrEPcare outcomes (initiation and persistence) at 1- 3- and 6-months; 2: Estimate and rank the effectiveness of thefour embedded AIs on PrEP care outcomes at 3- and 6-months: (1) CDC PrEP education continue TM forresponders add mobile outreach for non-responders (NR); (2) CDC PrEP education continue TM forresponders add peer transitional SBCM for NR; (3) Peer-led SBCM continue TM for responders add mobileoutreach for NR; (4) Peer-led SBCM continue TM for responders add peer transitional SBCM for NR; and 3:Across interventions examine the effects of age baseline injection frequency perceived HIV risk PrEPinterest SSP utilization patterns and other factors in predicting PrEP care outcomes at 1- 3- and 6-months toinform optimally-tailored intervention strategy recommendations for PWID subgroups. Directly informed by ourpilot trial our SMART design is poised to identify the optimal combination and sequencing of interventioncomponents required to achieve the greatest likelihood of PrEP initiation.

project_terms:
Address;Adoption;Appalachian Region;Biological Markers;Caring;Case Management;Categories;Clinical;Communities;Consensus;Consultations;County;Data;Disparity;Drug user;Education;Effectiveness;Eligibility Determination;Epidemic;Female;Foundations;Frequencies;Goals;HIV;HIV Infections;HIV diagnosis;HIV risk;Home;Injecting drug user;Injections;Intervention;Intervention Strategies;Interview;Kentucky;Knowledge;Measures;Needle-Exchange Programs;Newly Diagnosed;Oral;Participant;Pathway interactions;Patients;Pattern;Population;Poverty;Prevention;Recommendation;Reporting;Rural;Rural Appalachia;Rural Population;Sequential Multiple Assignment Randomized Trial;Services;Subgroup;Test Result;Testing;Text Messaging;Visit;access restrictions;adaptive intervention;age effect;care delivery;care outcomes;community advisory board;efficacy testing;evidence base;experience;housing instability;injection drug use;interest;male;medical specialties;novel;outreach;peer;pilot trial;point of care testing;pre-exposure prophylaxis;primary care setting;relative effectiveness;response;risk perception;rural area;rural underserved;scale up;social stigma;therapy design;transmission process;trial design;uptake

public_health_relevance:
PROJECT NARRATIVEKentucky (KY) is a high priority Ending the HIV Epidemic (EHE) jurisdiction due to heavy rural HIV burden andexceptionally high rates of new HIV diagnoses driven by injection drug use. A central pillar of EHE is theprevention of new HIV infections through scale up of Pre-Exposure Prophylaxis (PrEP) in people who injectdrugs (PWID). The proposed study will deploy a novel stepped-care intervention within rurally-located syringeservice programs (SSPs) and conduct a robust test of efficacy on PrEP initiation and persistence among ruralPWID which is critical for achieving progress toward EHE goals.


