# projects

application_id: 11162387
project_number: 5R01CA279455-03
project_title: Pdcd4-Rictor Interaction in Suppression of Lung Tumorigenesis
administering_ic: NCI
award_notice_date: 2025-08-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 279455
program_official: FORRY, SUZANNE L
project_start_date: 2023-09-20
project_end_date: 2028-08-31
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 8737920
contact_pi: YANG, HSIN-SHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractLung cancer is the leading cause of cancer-related deaths in the United States. The high mortality rate is notonly due to the lack of effective early detection but also due to poor tumor response to currently availabletherapies. These underscore the urgent need to better understand the biological events and mechanism of lungcancer suppression as is the need for important new therapeutic approaches that specifically target theseprocesses to improve survival rates. Lung cancer is mainly divided into two types: small cell lung cancer (SCLC)and non-small cell lung cancer (NSCLC) the latter of which accounts for 80-85% of all cases. A new subset oflung cancer in both SCLC and NSCLC was recently identified in which Rapamycin-insensitive companion ofmTOR (Rictor) gene is amplified. Rictor is an essential component of the mammalian target of rapamycincomplex 2 (mTORC2) and is required for mTORC2 complex activity and integrity. Activation of mTORC2 resultsin promotion of cancer cell proliferation and survival. This application builds on exciting preliminary data thatProgrammed cell death 4 (Pdcd4) bound with Rictor through a Rictor binding domain (RBD) to inhibit mTORC2activity 6-phosphofructo-2-kinase/fructose-26-biphosphatase 3 (PFKFB3) level cell proliferation and colonyformation. In addition a peptide containing the RBD specifically inhibits mTORC2 but not mTORC1. Our datafurther demonstrated that the RBD peptide suppressed NSCLC proliferation in cultured cells and nude mice. Thecentral hypothesis is that Pdcd4-Rictor binding specifically inhibits mTORC2 to preferentially suppressproliferation in Rictor-elevated NSCLC via induction of proteasomal degradation of PFKFB3. To test thishypothesis three specific aims are proposed: i) Delineate the mechanism of how Pdcd4-Rictor binding interfereswith mTORC2 activity to suppress tumor growth in NSCLC; ii) Dissect how Pdcd4-Rictor-mTORC2 axis impactsPFKFB3 stability and metabolic pathways; iii) Demonstrate that mTORC2-specific inhibition by RBD peptidepreferentially suppresses the growth of Rictor-elevated NSCLC to improve survival rate. The accomplishment ofthe proposed study will not only uncover novel regulatory mechanisms of mTORC2 activity and PFKFB3expression by Pdcd4 but also reveal the importance of mTORC2-specific inhibition by RBD peptide on NSCLCtumorigenesis. The expected findings will guide us to develop new strategies that are particularly relevant toprecision medicine approaches for NSCLC patients with elevated Rictor.

project_terms:
6-Phosphofructo-2-kinase;Acetylation;Apoptosis;Binding;Biological;Biological Assay;Cancer Etiology;Cancer Patient;Cause of Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Companions;Complex;Cultured Cells;DNA Sequence Alteration;Data;Death Rate;Drug Kinetics;Early Diagnosis;Event;Exhibits;FRAP1 gene;Feedback;Fructose;Gene Amplification;Genes;Genetic;Genetic Transcription;Glycolysis;Growth;In Vitro;Inhibition of Cell Proliferation;Invaded;Investigation;Knock-out;Laboratories;Malignant neoplasm of lung;Maps;Mediating;Metabolic Pathway;Mutation Analysis;Neoplasm Metastasis;New Agents;Non-Small-Cell Lung Carcinoma;Nude Mice;Outcome Study;Patients;Penetration;Peptides;Phosphorylation;Phosphorylation Site;Phosphotransferases;Process;Prognosis;Proliferating;Proteasome Inhibitor;Proteins;Regulation;Reporting;Resistance;Role;Signal Transduction;Sirolimus;Site;Subgroup;Survival Rate;Tertiary Protein Structure;Testing;Therapeutic;Tumor Suppressor Proteins;Ubiquitination;United States;Upregulation;Woman;Work;Xenograft procedure;cancer cell;cancer diagnosis;cancer type;improved;in vivo;inhibitor;knock-down;lung cancer cell;lung tumorigenesis;men;metabolomics;migration;multicatalytic endopeptidase complex;mutant;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;precision medicine;prevent;research clinical testing;response;small cell lung carcinoma;therapy resistant;tumor;tumor growth;tumorigenesis;ubiquitin-protein ligase

public_health_relevance:
Project NarrativeLung cancer is the most commonly diagnosed cancer and the first leading cause of death in both men andwomen in the United Sates. In this proposal we intend to understand of how Pdcd4 a tumor suppressor bindswith Rictor an important protein in suppression of the lung cancer cells. This work will provide new strategiesfor lung cancer with Rictor elevation therapeutics and potentially develop new agents for treatment of this typeof lung cancer.


application_id: 11161576
project_number: 5UC7AI180309-03
project_title: UofL RBL Pandemic Preparedness and Response Integrated Research Core
administering_ic: NIAID
award_notice_date: 2025-08-13
opportunity_number: RFA-AI-22-075
application_type: 5
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: ZAI1-SJ-W
subproject_number: 9959
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY: PANDEMIC PREPAREDNESS AND RESPONSE INTEGRATED RESEARCH SERVICES COREThe Pandemic Preparedness and Response Integrated Research Services Core (PaPR Core) shall support allRisk Group 3 (RG3) pathogen studies conducted at the University of Louisville (UofL) Regional BiocontainmentLaboratory (RBL). In alignment with the NIAID Pandemic Preparedness Mission the PaPR Core shall serveinvestigators at UofL our regional academic and industrial partners collaborating investigators in the NBL/RBLnetwork and other investigators who wish to avail of our facilities and expertise. The PaPR Core supports fundedresearch programs by providing scientific expertise on study design labor to support execution of both in vitroand in vivo BSL-3 studies and data analysis and interpretation services that culminate in issuing acomprehensive study report to the sponsor investigator. The PaPR Core shall operate on a cost-recoverybusiness model with revenue re-invested in core services. The aims of the PaPR Core are to: (1) Supportcontinuous refinement of RG3 pathogen infection models established at UofL RBL.; (2) Support continuousrefinement of RG3 pathogen infection models established at UofL RBL; (3) Enable investigations on the impactof aging and chronic metabolic disease on RG3 pathogen infections; and (4) Enable studies on the impact ofenvironmental toxicant exposure on RG3 pathogen infections.

project_terms:
Aging;Alcoholic Liver Diseases;Ally;Alpha Virus;Animal Model;Arthritogenic;Attention;Autopsy;Blood Chemical Analysis;Businesses;COVID-19;Cardiometabolic Disease;Centers of Research Excellence;Chronic;Chronic Disease;Clinical;Collaborations;Communicable Diseases;Communities;Data;Data Analyses;Development;Disease;Disease Outcome;Elderly;Emerging Communicable Diseases;Ensure;Environmental Exposure;Environmental Impact;Environmental Medicine;Funding;Health;Hematology;Immunology;In Vitro;Industrialization;Infection;Investigation;Investigational Drugs;Investments;Japanese encephalitis virus;Laboratories;Measurement;Metabolic;Metabolic Diseases;Mission;Modeling;National Institute of Allergy and Infectious Disease;Outcome;Outcome Study;Pathogenesis;Pathology;Persons;Pharmacodynamics;Physiological;Positron;Positron-Emission Tomography;Powassan virus;Recovery;Reporting;Reproducibility;Research;Research Design;Research Personnel;Risk;SARS-CoV-2 infection;Scanning;Semliki forest virus;Service delivery model;Services;System;Testing;Toxic Environmental Substances;Toxicant exposure;Translational Research;United States National Institutes of Health;Universities;Viral Pathogenesis;Virus;Virus Diseases;Vulnerable Populations;West Nile virus;Whole Body Plethysmography;Workforce Development;X-Ray Computed Tomography;biocontainment facility;chikungunya;cost;environmental toxicology;future pandemic;global environment;good laboratory practice;in vivo;in vivo Model;in vivo imaging;infectious disease model;instrument;instrumentation;medical countermeasure;mouse model;operation;pandemic potential;pandemic preparedness;pandemic response;pathogen;programs;pulmonary function


application_id: 11161574
project_number: 5UC7AI180309-03
project_title: UofL RBL BSL3 Practices and Workforce Development Core
administering_ic: NIAID
award_notice_date: 2025-08-13
opportunity_number: RFA-AI-22-075
application_type: 5
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: ZAI1-SJ-W
subproject_number: 9958
contact_pi_person_id: 7016711
contact_pi: SEVERSON, WILLIAM E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY: BSL-3 PRACTICES AND WORKFORCE DEVELOPMENT COREThe BSL-3 Practices and Workforce Development Core (BSL-3 PWD) shall develop and maintain SOPsbiosafety and biosecurity plans and provide training for BSL-3 best practices to ensure a safe and secure workenvironment within the University of Louisville (UofL) Regional Biocontainment Laboratory (RBL). The BSL-3PWD Core will support the RBLs mission to provide a regional resource to facilitate research goals forbiodefense emerging infectious diseases and pandemic preparedness and response. The Core will provideBSL-3 practices training to investigators at UofL regional academic investigators with BSL-3 facilities andspecialized biosafety and biocontainment professionals and tradesmen who support the operations the UofLRBL and the RBL network. The specific aims of the BSL-3 PWD core to: (1) Provide laboratorians and personneltraining for BSL-3 best practices to ensure a safe and secure work environment within the RBL and support theRBLs mission; (2) Develop and maintain Standard Operating Procedures (SOPs) for personnel working in theBSL-3/ABSL-3 space in the RBL (3) Provide select agent training for handling of select agents inventory andaccountability; (4) Provide Operations and Maintenance training for specialized biosafety and biocontainmentprofessionals and tradespeople who support the operations of the RBL; and (5) Provide biosafety education andtraining for removal of materials and equipment from the BSL-3 policies for shipping and receiving materialsand waste management.

project_terms:
Accountability;Aromatase;Biological;Computer software;Dedications;Development;Emerging Communicable Diseases;Ensure;Environment;Equipment;Equipment and supply inventories;Evaluation;Excision;Exposure to;Goals;Hazardous Substances;Human Resources;Individual;Laboratories;Maintenance;Mentors;Mission;National Institute of Allergy and Infectious Disease;Policies;Principal Investigator;Procedures;Process;Protective Devices;Reporting;Research;Research Personnel;Resource Sharing;Resources;Secure;Security;Services;Shipping;Specialist;Toxin;Training;Training Programs;Training and Education;Universities;Update;Waste Management;Workforce Development;animal facility;biocontainment facility;biodefense;biosafety level 3 facility;biosecurity;meetings;microorganism;operation;pandemic preparedness;pandemic response;professional atmosphere;programs;wasting


application_id: 11161572
project_number: 5UC7AI180309-03
project_title: UofL RBL BSL3 Facility Management Maintenance and Operations Core
administering_ic: NIAID
award_notice_date: 2025-08-13
opportunity_number: RFA-AI-22-075
application_type: 5
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: ZAI1-SJ-W
subproject_number: 9957
contact_pi_person_id: 79041956
contact_pi: STEFFEN, MARLENE CLARKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY: Facility Management Maintenance and Operations (FMMO) CoreThe Center for Predictive Medicine (CPM) Regional Biocontainment Lab at the University of Louisville wasdesigned and constructed following established guidelines to provide a safe facility for the trained and qualifiedpersonnel to work with hazardous pathogens while protecting themselves the community and environment. Inorder to assure that the structure and specialized content within hold up to the exceptional standards over theyears a highly skilled and dedicated team of individuals from all walks of life e.g. project management technicaltrades biosafety animal welfare security business services information technology and senior scientificprofessionals to name a few must combine their expertise to reach this goal. The CPM Facility OperationsManager is paramount in the success of the management maintenance and operations 24/7/365. Theestablished activities processes and workflows are based on risk assessment and communicated to allstakeholders. Preventive maintenance is the strategy employed to make certain preparedness is the foundationfor fulfilling the CPM mission. Each facet (management maintenance and operations) is essential to thereliability longevity and purpose set forth in 2009 and have an impeccable record to affirm its efficacy.In addition personnel must be familiar with the standard operating procedures safety protocols security accessmeasures emergency procedures BSL-3/ABSL-3 practices and are trained and educated annually to reviewrefresh and reinforce the basis of proper steps to safely complete their assigned tasks.Collaboration and communication with law enforcement Homeland Security FBI public health agenciesgovernment entities university and local subject matter experts other groups in the NBL/RBL Networkinspectors and service technicians all enhance the outcome.Based on our historical successes the contributions (impact commitment involvement dedication) of theFMMO Core provide the necessary assets for our expert scientists to be at the leading edge of infectiousdiseases research and readiness to respond for another pandemic.

project_terms:
Address;Administrator;Animal Welfare;Area;Businesses;Calibration;Certification;Collaborations;Communication;Communities;Containment;Contractor;Decontamination;Dedications;Development;Disinfectants;Emergency Situation;Ensure;Environment;Environmental Health;Equipment;Foundations;Gases;Goals;Government;Guidelines;Human Resources;IACUC;Individual;Infectious Diseases Research;Information Technology;Infrastructure;Law Enforcement;Life;Life Cycle Stages;Longevity;Maintenance;Measures;Medicine;Mission;Monitor;Motion;Names;Outcome;Pathogenicity;Persons;Phase;Preventive;Procedures;Process;Protocols documentation;Public Health;Publishing;Qualifying;Readiness;Recommendation;Regulation;Research;Research Personnel;Resources;Risk Assessment;Role;Running;Safety;Schedule;Scientist;Security;Services;Specialist;Structure;Surface;System;Testing;Time;Training;Universities;Update;Veterinarians;Walking;Work;Workforce Development;animal care;biocontainment facility;biosafety level 3 facility;biosecurity;chlorine dioxide;comparative;continuous monitoring;design;design and construction;experience;insight;intrusion detection system;member;operation;pandemic disease;pandemic preparedness;pathogen;repaired;research study;skills;success


application_id: 11161571
project_number: 5UC7AI180309-03
project_title: UofL RBL Operations Workforce Development and Pandemic Preparedness Research
administering_ic: NIAID
award_notice_date: 2025-08-13
opportunity_number: RFA-AI-22-075
application_type: 5
activity_code: UC7
ic: AI
serial_number: 180309
program_official: DIAZ SAN SEGUNDO, FAYNA C
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: ZAI1-SJ-W(S1)
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY (OVERALL):The University of Louisville Regional Biocontainment Laboratory (RBL) is operated by the University Center forPredictive Medicine for Biodefense and Emerging Infectious Diseases (CPM). The RBL is a regional resourcethat facilitates translational research to develop diagnostics prognostics therapeutics and vaccines to mitigatebiodefense and emerging infectious disease threats. Our Center operates the only BSL-3 and ABSL-3 facilitiescurrently operating in the Commonwealth of Kentucky. The CPM mandate is to prepare for and respond to publichealth emergencies such as the COVID-19 pandemic.The broad long-range objectives and goals of the University of Louisville (UofL) CPM RBL are:1. To offer state-of-the-art research services to the regional and national biomedical research community to learn from past pandemics and biological warfare experiences and effectively predict and mitigate future emerging infectious disease threats.2. To manage maintain and operate the UofL RBL to serve the national and regional need for biocontainment facilities suitable for research on Risk Group 3 pathogens and other biothreats.3. To follow a philosophy of continuous improvement in BSL-3 and ABSL-3 work practices and to ensure that all personnel who need to access BSL-3 and ABSL-3 containment laboratories are appropriately trained and prepared to serve the national and regional need for biocontainment research professionals.To achieve these aims we propose to establish three collaborative Cores. The Facilities ManagementMaintenance and Operations Core (FMMO Core) is responsible for ensuring that the facility is always availableto meet the research and emergency preparedness mission of the RBL. The BSL-3 Practices and WorkforceDevelopment Core (BSL-3PWD Core) formalizes our mentor-mentee training plan to ensure our laboratory isstaffed with BSL-3 research professionals who are proficient at biocontainment research professionals. This coreresponds to the reality that response to rapidly emerging public health emergencies like COVID-19 is limited bythe number of available BSL-3 trained and experienced research professionals. Our Pandemic Preparednessand Response Integrated Research Core (PaPR Core) responds to the substantially increased requests for ourBSL-3 research services by organizing an integrated full-service BSL-3 research support function to supportinvestigator needs. These cores will work in unison to achieve the CPM mission: to prepare for and respond topublic health emergencies like the COVID-19 pandemic.

project_terms:
Attention;Biological Warfare;Biomedical Research;Biotechnology;COVID-19;COVID-19 pandemic;COVID-19 patient;China;Clinical Trials;Communities;Containment;Creativeness;Crowns;Dedications;Diagnostic;Disease Outbreaks;Economics;Emerging Communicable Diseases;Ensure;Federal Government;Funding Opportunities;Future;Goals;Health Care Facility;Health Services Research;Hospitals;Hour;Human Resources;Industry;Infection;Infectious disease threat;Institution;International;Investigational New Drug Application;Kentucky;Laboratories;Leadership;Learning;Maintenance;Managed Care;Medicine;Mentors;Mission;Modeling;National Center for Advancing Translational Sciences;National Institute of Diabetes and Digestive and Kidney Diseases;Nose;Patients;Philosophy;Play;Public Health;Research;Research Personnel;Research Support;Resources;Rest;Reverse Transcriptase Polymerase Chain Reaction;Risk;Role;Scientist;Serology test;Services;System;Talents;Techniques;Testing;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;University resources;Vaccines;Work;Workforce Development;biocontainment facility;biodefense;biothreat;cohort;emergency preparedness;experience;improved;laboratory experience;medical countermeasure;metropolitan;novel;novel coronavirus;operation;pandemic disease;pandemic preparedness;pandemic response;pathogen;previous pandemic;prognostic;prophylactic;public health emergency;recruit;response;service organization;skills;wastewater surveillance

public_health_relevance:
NARRATIVE (OVERALL):The University of Louisville Regional Biocontainment Laboratory (RBL) is a regional resource that facilitatestranslational research to develop diagnostics therapeutics and vaccines to mitigate biodefense and emerginginfectious disease threats. We propose to establish three cores that will work in unison to achieve the RBLmission to prepare and respond to public health emergencies like pandemics. The cores will be responsible forfacility management and operations; for training laboratory workers in safe BSL-3 work practices; and foroperating a full-service research support function for scientists who need to use the RBL.


application_id: 11161538
project_number: 5R01CA276284-04
project_title: Mechanism of double-negative T cells in antitumor immunity to breast cancer
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PA-20-185
application_type: 5
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:
Abstract: Breast cancer (BC) the most common cancer globally as of 2021 and accounting for 12% of all newannual cancer cases worldwide is the most commonly diagnosed cancer among American women. Based onthe expression of estrogen receptor alpha (ER) progesterone receptor (PR) and human epidermal growthfactor receptor 2 (HER2) breast cancer can be classified into three major subtypes: luminal subtype (ERa/PR+HER2-) HER2+ subtype (ERa/HR- HER2+) and triple-negative subtype (TNBC ERa/HR- HER2-). All types ofBC have metastatic potential. TNBC is the deadliest form. Chemoresistance is a major obstacle to therapeuticefficacy. Once chemoresistance develops metastatic BC is incurable. Cancer immunotherapy has achievedunprecedented success in treating many types of advanced cancers including TNBC. However the responserate of BC patients to cancer immunotherapy is low because of the poor tumor infiltration of tumor-infiltratinglymphocytes (TIL). Developing more effective cancer immunotherapy approaches is critical to treating and curingTNBC patients. Using a T cell receptor (TCR)-alpha deficient Ja281 KO mouse model we found that transferringthymocytes into Ja281 KO mice could completely inhibit EO771 and Py8119 TNBC growth in these cell-transferred mice. We further found that the cell transfer-induced antitumor immunity was mediated by tissue-resident +CD4-CD8- double-negative T (DN T) cells formed from the transplanted donor population anddepended on host NK cells. Deciphering the underlying mechanism will allow us to develop a powerfulimmunotherapy approach for TNBC treatment. The long-term goal of our research is to develop newimmunotherapeutic regimens for cancer treatment. The objective of this project is to decode the mechanism ofDN T cell antitumor immunity to TNBC. Our central hypothesis is that DN T cells initiate antitumor immunity andinteract with NK cells to control TNBC growth and to shape tumor microenvironment (TME) and that a populationof immunoinhibitory T cells modulate DN T cell antitumor function. We will test this hypothesis by pursuing thefollowing three specific aims: Aim 1: Determine how tissue-resident DN T cells are generated and how theymediate antitumor immunity using the Ja281 KO mouse model. Aim 2. Determine the antitumor function oftissue-resident DN T/NK cell axis. Aim 3: Define the immunoregulatory cells that govern tissue-resident DN Tcell generation and their antitumor function. The finding that tissue-resident DN T cells can inhibit TNBC growthand eradicate breast cancer is novel. The completion of the proposed research will not only greatly advance ourknowledge of DN T cells in antitumor immunity but also allow us to develop more effective approaches for TNBCimmunotherapy.

project_terms:
Accounting;Advanced Malignant Neoplasm;American;Antitumor Response;Biology;Breast Cancer Patient;Breast Cancer Treatment;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Chemoresistance;Classification;Clinical;Combination immunotherapy;Complex;Data;Dendritic Cells;Development;Disease;Donor person;EO771;ESR1 gene;Early treatment;Epidermal Growth Factor Receptor;Exhibits;Family;Foundations;Generations;Goals;Growth;Human;Immune;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Infiltration;Knockout Mice;Knowledge;Lymphoma;Macrophage;Malignant Breast Neoplasm;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Melanoma;Metastatic breast cancer;Methods;Modeling;Molecular;Mucous Membrane;Mus;Natural Killer Cells;Natural Killer T cell;Non-Small-Cell Lung Carcinoma;Patients;Play;Population;Pre-Clinical Model;Progesterone Receptors;Regimen;Regulatory T-Lymphocyte;Reporting;Research;Resistance development;Role;Shapes;Solid;T cell response;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;T-cell receptor repertoire;Testing;Tissues;Treatment Efficacy;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Wild Type Mouse;Woman;anti-PD1 antibodies;anti-tumor immune response;antitumor effect;cancer diagnosis;cancer immunotherapy;cancer therapy;chemotherapy;immunogenic;immunoregulation;improved;improved outcome;innovation;mouse model;novel;response;success;survival outcome;thymocyte;triple-negative invasive breast carcinoma;tumor;tumor immunology;tumor microenvironment;tumor progression

public_health_relevance:
Project narrativeBreast cancers are poorly immunogenic which significantly hampers breast cancerimmunotherapy. The finding that DN T cells can inhibit tripe-negative breast cancer growth isnovel and has not been explored. Deciphering the cellular and molecular mechanism of how DNT cells orchestrate antitumor immune response in breast cancer will fundamentally advance ourknowledge in tumor immunology and allow us to develop more effective DN T cell-based cancerimmunotherapy for breast cancer treatment.


application_id: 11160885
project_number: 2R01AA028735-07
administering_ic: NIAAA
award_notice_date: 2025-09-18
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: AA
serial_number: 028735
program_official: LIN, LI
project_start_date: 2020-09-01
project_end_date: 2026-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: VARLAMOV, OLEG
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-09-20
project_title:
Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

project_abstract:
SUMMARYAlcohol misuse is prevalent in the United States with 10.5% of people ages 12 or older suffering from alcoholuse disorder (AUD) in 2021. Chronic alcohol consumption (CAC) is associated with adverse health outcomesincluding increased incidence of infectious diseases alcoholic liver disease cancer cardiovascular disease aswell as impaired wound and bone healing. These findings suggest alcohol misuse negatively impacts the immunesystem and particularly monocytes and macrophages which play critical roles in tissue homeostasis andantimicrobial defense. During the previous funding cycle we showed that CAC is associated with elevatedsecretion of proinflammatory cytokines and impaired host defense in circulating monocytes and tissue residentmacrophages. Importantly this phenotype was also observed in bone marrow myeloid progenitor cells and weshowed that CAC leads to vascular remodeling of the bone marrow niche characterized by a reduction ofprimitive hematopoietic stem and progenitor cells (HSPC) as well as a shift in localization of HSPC from anadipose to a perivascular niche. Moreover we reported shifts in cell states chromatin accessibility and histonemarks with CAC. These findings indicate CAC shifts transcriptional functional and epigenetic profiles ofmonocytes to a hyper-inflammatory state but the mechanisms by which CAC alters specific subsets of monocytesand their bone marrow progenitors remain poorly understood. To address this knowledge gap we will continueto leverage a well-established macaque model of voluntary ethanol self-administration that recapitulates thehallmarks of alcohol drinking in humans to test the central hypothesis that dysregulation of the gut microbiotacoupled with the loss of barrier integrity due to chronic alcohol consumption leads to translocation ofmicrobial products that reprogram monocytes and HSPC towards a hyperinflammatory response withreduced functional capacity. The novelty of this renewal application lies in the systems biology approach thatintegrates metabolomic and functional data with transcriptional and epigenetic readouts at the single cell level inmonocytes and their bone marrow progenitors. Completion of the proposed experiments will uncover themolecular mechanisms underlying the detrimental effect of CAC on monocytes and their progenitors thusenabling a better understanding of the etiology of chronic inflammation caused by CAC.

project_terms:
16S ribosomal RNA sequencing;ATAC-seq;Abstinence;Activities of Daily Living;Acute Respiratory Distress Syndrome;Address;Adipocytes;Age;Alcohol consumption;Alcoholic Liver Diseases;Bioinformatics;Biological Assay;Biology;Biometry;Blood Vessels;Bone Marrow;Bone Marrow Stem Cell;Cardiovascular Diseases;Cell Nucleus;Cells;Chromatin;Chronic;Colon;Communicable Diseases;Coupled;Data;Endotoxemia;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Ethanol;Etiology;Flow Cytometry;Funding;Genes;Genetic Transcription;Health;Hematopoietic stem cells;Histology;Histones;Homeostasis;Host Defense;Human;Immune;Immune system;Impaired wound healing;Impairment;Incidence;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Intestinal permeability;Investigation;Knowledge;Lead;Liquid substance;Macaca;Macrophage;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mesenchymal Stem Cells;Metagenomics;Mitochondria;Modeling;Molecular;Myeloid Progenitor Cells;Outcome;Persons;Phenotype;Play;Predisposition;Promoter Regions;Reporting;Rest;Role;Self Administration;Severities;Shotguns;Systems Biology;Testing;Tissues;United States;Vascular remodeling;Work;adverse outcome;alcohol craving;alcohol misuse;alcohol use disorder;antimicrobial;bacterial community;bone fracture repair;bone healing;chromatin remodeling;chronic alcohol ingestion;cytokine;dysbiosis;experimental study;gut dysbiosis;gut microbiota;hematopoietic differentiation;histone modification;ileum;intestinal barrier;metabolome;metabolomics;microbial;microbial products;monocyte;nonhuman primate models;novel therapeutics;organ repair;progenitor;programs;response;single-cell RNA sequencing;spatial transcriptomics;stem cell population;transcriptome sequencing

public_health_relevance:
NARRATIVEAlcohol misuse is prevalent in the United States and chronic alcohol consumption (CAC) is associated withsignificant adverse health outcomes including heightened susceptibility to infections and impaired wound andbone healing. These data suggest alcohol misuse negatively impacts the immune system. Using a well-established macaque model of voluntary ethanol self-administration that recapitulates the hallmarks of alcoholdrinking in humans we will investigate the role of CAC-induced alterations in the gut microbiota in reprogrammingmonocytes and hematopoietic stem cells towards a hyperinflammatory response with reduced functionalcapacity.


application_id: 11160751
project_number: 5R01DK133195-03
project_title: Targeting urinary tract dysfunctions after spinal cord injury with epidural stimulation
administering_ic: NIDDK
award_notice_date: 2025-07-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 133195
program_official: MULLINS, CHRISTOPHER V
project_start_date: 2023-09-15
project_end_date: 2026-06-30
study_section: Kidney and Urological Systems Function and Dysfunction Study Section[KUFD]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
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:
(PLEASE KEEP IN WORD DO NOT PDF)AbstractSpinal cord epidural stimulation (scES) which creates an electrical field directly over the spinal cord has shown early promise for the restoration of voluntary and reflex control of the lower urinary tract (LUT) among individuals with spinal cord injuries (SCI). A major advantage of the proposed multi-electrode array over the Interstim system and transcutaneous approach is the versatility of the multi-electrode and the ability to activate multiple structures and functions simultaneously with a single electrode placement and device. The goal of this pre-clinical research is to optimize scES for functional benefits and identify mechanism(s) to better facilitate daily management and improve quality of life. It is hypothesized that effective scES for both bladder storage and emptying occurs when initiated chronically post-SCI through activation of spinal bladder circuits including neurons within the dorsal commissure superficial dorsal horn sacral parasympathetic nucleus and Onufs nucleus with the requirement of intact hypogastric/pelvic/pudendal nerves and with greater effectiveness when given in combination with locomotor training. For Aim 1 previously identified optimal parameters will be used to identify neural components of the spinal networks contributing to scES-induced LUT effects with different chronicitys post-SCI in urethane-anesthetized rats using two approaches: a) Fos protein induction (a marker for postsynaptic activation of spinal neurons) and b) select peripheral nerve transections. Examining the contributing spinal central regions activated with scES and key peripheral components for different aspects of LUT function will provide novel targets for further development and refinement of epidural arrays and controllers. For Aim 2 the impact of scES on LUT functions in SCI rats after treatment with differing periodicities of locomotor training will be examined to address the potential added benefit of a combinatory approach (neuromodulation with rehabilitation). A sub-aim examines the underlying Fos induced central neural components as plasticity is likely induced with training. Both aims will also include bladder histology/molecular biology assessments re the effects of chronicity/training. These studies will significantly move the SCI field forward by providing optimal parameters and locations for targeting LUT function that will be key for advancing the existing technology.

project_terms:
Acute;Address;Aftercare;Anesthesia procedures;Ataxia;Bilateral;Biological Markers;Bladder;Bladder Tissue;Cell Nucleus;Cells;Chronic;Clinical Trials;Clinical effectiveness;Commissure;Contusions;Development;Devices;Dorsal;Effectiveness;Electrodes;FOS Protein;Functional disorder;Goals;Health;Health Care Costs;Histology;Hour;Human;Immune;Individual;Location;Locomotor training;Lower urinary tract;Maintenance;Maps;Mediating;Modeling;Molecular Biology;Motor;Nerve;Neurons;Outcome;Pattern;Pelvis;Peripheral;Rattus;Recommendation;Reflex action;Reflex control;Rehabilitation therapy;Source;Sphincter;Spinal;Spinal Cord;Spinal Cord Tract;Spinal cord injury;Structure;Synapses;System;Technology;Training;Urethane;Urinary tract;chemokine;cholinergic;clinically relevant;design;dorsal horn;electric field;experimental study;functional outcomes;gray matter;improved;multi-electrode arrays;nerve transection;neural;neurological rehabilitation;neuroregulation;novel;peripheral nerve transection;postsynaptic;pre-clinical research;preclinical study;pressure;quality of life improvement;response;response to injury;restoration;timeline;treadmill;urologic

public_health_relevance:
Spinal cord epidural stimulation which creates an electrical field directly over the spinal cord has shown early promise with clinical effectiveness for restoration of voluntary and reflex control of the lower urinary tract. The goal of this pre-clinical research is to optimize epidural stimulation alone and in combination with neurorehabilitation for functional urological benefits and identify mechanism(s) to better facilitate daily management and improve quality of life for those with spinal cord injuries.


application_id: 11160743
project_number: 4K23DE031807-03
administering_ic: NIDCR
award_notice_date: 2025-08-15
opportunity_number: PA-20-206
application_type: 4
activity_code: K23
ic: DE
serial_number: 031807
program_official: FUQUA, CHANTEL FAYSAN
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: ZDE1-AC(04)
contact_pi_person_id: 11936065
contact_pi: BOGGERO, IAN ANDRES
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
arra_indicator: N
budget_start_date: 2025-09-01
project_title:
Initial Evidence for a Brief Psychological Telehealth Intervention for Patients with Chronic Masticatory Muscle Pain

project_abstract:
Chronic masticatory muscle pain disorders (MMPD) affect between 5-12% of the population are the secondmost common musculoskeletal pain conditions after chronic low back pain and are associated withmanagement costs of over $4 billion per year presenting a serious public health issue. Multidisciplinary carecombining dental care with psychological interventions appears to offer the best prognosis. Physical self-regulation (PSR) is a brief two-session psychological intervention that has been shown to lead to long-termreductions in pain intensity over standard dental care alone in patients with chronic MMPD. Unfortunatelytreatment utilization for PSR is low when it is offered in-person with fewer than 50% of eligible patientschoosing to begin treatment. Offering PSR over telehealth (PSR-TH) may help address this issue withpreliminary data demonstrating >80% treatment utilization for PSR-TH. A full-scale trial is needed to test theefficacy of PSR-TH and 1) determine if PSR-TH effects are due to the intervention itself or to nonspecifictreatment effects and 2) determine moderators and mediators of treatment effects. However additional dataare needed before such a trial can be conducted. The goal of this proposal is to obtain data to support a futurefull-scale Phase II efficacy trial by achieving the following specific aims. First PSR-TH and a controlintervention need to be formally piloted in patients with MMPD to determine recruitment and retention ratesinterventionist fidelity and patient-reported acceptability credibility and burden of the interventions (Aim 1).Second we need to identify potential moderators and mediators of PSR-TH so that we can focus onthoroughly assessing those specific variables in the future trial (Aim 2). Treatment-seeking females withchronic MMPD will be randomly assigned to two 50-min telehealth sessions of PSR-TH or a controlintervention (N=52/group) and will provide biopsychosocial moderator data (week 0) treatment feasibility dataimmediately following the intervention (week 3) mediation data two weeks following the intervention (week 5)and outcome data (pain intensity pain interference and quality of life) two weeks and three months followingthe intervention (weeks 5 and 15). We hypothesize that both PSR-TH and the control intervention willdemonstrate strong feasibility (i.e. recruitment of at least 1 participant per week >75% retention >95%interventionist fidelity and adequate acceptability credibility and burden). We also hypothesize that specificbiopsychosocial variables will moderate PSR-related changes in outcomes and that PSR-TH-related changesin perceived control over pain self-efficacy coping parafunctional habits and relaxation will mediate treatmenteffects. In addition to supporting a future efficacy trial of PSR-TH the proposed project will leverage myprevious training a collaborative environment at the University of Kentucky and the expertise of world-renownmentors to provide me training in clinical research assessment of moderators and mediators in orofacial painand leadership of research teams giving me the skills for a successful independent clinical research career.

project_terms:
Address;Adult;Affect;Age;Awareness;COVID-19 pandemic;Caring;Chronic;Chronic low back pain;Clinical;Clinical Research;Continuity of Patient Care;Data;Dental;Dental Care;Disease;Educational process of instructing;Eligibility Determination;Exercise;Fatigue;Female;Financial Hardship;Future;Goals;Habits;Individual;Informal Social Control;Intervention;Kentucky;Knowledge;Leadership;Literature;Loneliness;Manuals;Masticatory muscles;Mediating;Mediation;Mediator;Medical;Mental Health;Mentors;Muscle relaxation phase;Musculoskeletal Pain;Myalgia;Orofacial Pain;Outcome;Pain;Pain Disorder;Pain intensity;Pain interference;Pain management;Participant;Patients;Persistent pain;Persons;Phase;Population;Prognosis;Public Health;Publishing;Quality of life;Randomized;Readiness;Relaxation;Reporting;Research;Research Personnel;Self Efficacy;Social support;Standardization;Stress;Symptoms;Testing;Training;Universities;active control;anxiety symptoms;biopsychosocial;biopsychosocial factor;career;career development;chronic pain;chronic painful condition;collaborative environment;comorbidity;coping;cost;depressive symptoms;design;efficacy testing;efficacy trial;intervention effect;multidisciplinary;pain catastrophizing;pain outcome;pain reduction;post intervention;psychologic;quality of life improvement;recruit;research and development;research study;retention rate;satisfaction;skills;sleep quality;social;telehealth;treatment effect;women patients

public_health_relevance:
PROJECT NARRATIVEChronic masticatory muscle pain disorders (MMPD) affect between 5-12% of the adult population and are themost common cause of chronic non-odontogenic orofacial pain. Combining standard dental care with brieftelehealth psychological interventions offers hope for reducing negative pain outcomes and improving quality oflife in this population but few such interventions exist. The proposed submission will generate data to supporta future full-scale Phase II efficacy trial of a brief telehealth psychological intervention for MMPD potentiallyleading to an efficacious widely implementable and disseminatable treatment option for patients with chronicMMPD.


application_id: 11159367
project_number: 5F31HL174069-02
project_title: The Role of Emergency Granulopoiesis in Wound Healing after Myocardial Infarction
administering_ic: NHLBI
award_notice_date: 2025-07-10
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: HL
serial_number: 174069
program_official: CHEON, YEWON
project_start_date: 2024-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-F10A-K(20)L]
contact_pi_person_id: 77801950
contact_pi: STEPHAN, JONAH
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Myocardial infarction (MI) wound healing is accomplished through scar formation initiated by an acuteinflammatory response. The post-MI inflammatory phase is marked by a dramatic recruitment of neutrophils tothe heart where they become activated. Studies within the clinic have demonstrated that increased quantitiesof circulating neutrophils serve as a predictor of death and adverse prognoses. Studies have demonstratedthat elimination of this neutrophil response prior to MI delays scar formation and contributes to worsening heartfailure. These two narratives indicate that although increased quantities of neutrophils may contribute topathogenesis of heart failure a certain number are required for appropriate scar formation. Either side of thisbalance could contribute to worsened cardiac function. Due to their short lifespan the body must maintain thenumber of circulating neutrophils through steady-state granulopoiesis. However in circumstances of immunechallenge (such as in MI) the enhanced demand for neutrophil production is met through a reactive processknown as emergency granulopoiesis. Whether or not neutrophils produced through emergency granulopoiesisexhibit different character or function has not been investigated previously and presents a gap in currentunderstanding. Additionally how any altered neutrophil function may contribute to the pathogenesis of heartfailure post-MI is unknown. We hypothesize that neutrophils produced via emergency granulopoiesis exhibitaltered functions which contribute to the pathogenesis of heart failure. This project seeks to determine ifemergency granulopoiesis produces neutrophils with aberrant secretory function and if emergencygranulopoiesis contributes to post-MI heart failure. The objectives of the proposed research are 1) to determineif MI-induced emergency granulopoiesis gives rise to neutrophils with differential functionality and 2) todetermine if emergency granulopoiesis delays scar formation and contributes to heart failure post-MI.Successful completion of the proposed research will contribute to the knowledge of neutrophil function insituations of inflammatory stress such as after MI and the role of neutrophils in post-MI scar formation.Additionally identification of differential functions and their role in the pathogenesis of heart failure couldpresent avenues of study for future identification of therapeutic targets facilitating post-MI recovery.

project_terms:
Acceleration;Acute;Adverse effects;Attention;Biological Markers;Biology;Bone Marrow;Cardiac;Cells;Cessation of life;Cicatrix;Circulation;Clinic;Clinical;Collagen;Cytoplasmic Granules;Data;Deposition;Echocardiography;Emergency Situation;Emergency response;Enzyme-Linked Immunosorbent Assay;Equilibrium;Exhibits;Extracellular Matrix;Faculty;Fellowship;Fibroblasts;Fibrosis;Flow Cytometry;Functional disorder;Future;Granulopoiesis;Heart;Heart failure;Histologic;Immune;Immune system;Immunophenotyping;Impaired wound healing;Impairment;In Vitro;Infarction;Infection;Inflammation;Inflammatory;Inflammatory Response;Kinetics;Knowledge;Left;Left ventricular structure;Macrophage;Measures;Mediating;Mus;Myocardial Infarction;Myocardial rupture;Myocarditis;Myocardium;Neutrophil Infiltration;Outcome;Pathogenesis;Phase;Phenotype;Physiology;Play;Population;Positioning Attribute;Postdoctoral Fellow;Preparation;Process;Production;Prognosis;Proliferating;Pump;Recovery;Research;Role;Segmented Neutrophil;Side;Stress;Technical Expertise;Testing;Tissues;Training Programs;Universities;Ventricular;Ventricular Function;chemokine;cytokine;healing;heart function;immune cell infiltrate;life span;member;neutrophil;novel;peripheral blood;recruit;response;single-cell RNA sequencing;skills;stem cells;therapeutic target;tissue injury;transcription factor;transcriptomics;wound healing

public_health_relevance:
After a heart attack the immune system plays a critical role in the bodys healing process. This project seeks todetermine if specific modes of immune cell production can determine their function and contribute to heartfailure after a heart attack.


application_id: 11159060
project_number: 1R01DA063069-01
project_title: Targeting Immune Inflammation in Cocaine Use Disorder: A Human Laboratory Study with Pentoxifylline
administering_ic: NIDA
award_notice_date: 2025-06-27
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: DA
serial_number: 063069
program_official: FOSTER, KATRINA L
project_start_date: 2025-07-01
project_end_date: 2028-02-29
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTCocaine use disorder is a persistent public health concern. Despite strides in our understanding of theneurobiological underpinnings of cocaine addiction in preclinical models a limited amount of research hastranslated those findings to clinical populations. Such translation is crucial to identify neurobiologicaldisruptions that contribute to the problems posed by cocaine use disorder and to guide treatment based onthose findings. The field has long recognized the critical role of the glutamate system in cocaine use.Specifically a wealth of data indicate that cocaine produces profound changes in the brain glutamate systemresulting in impaired glutamate homeostasis. Targeting this mechanism has some promise for treating cocaineuse disorder but results have been inconsistent suggesting other strategies are needed to address brainglutamate changes due to cocaine use. Emerging preclinical research indicates that neuroimmune signalingmediates brain glutamate changes observed following drug exposure but very little clinical research hasevaluated whether targeting neuroimmune signaling affects response to cocaine or if this strategy is apromising treatment approach. Preclinical research has shown that phosphodiesterase inhibitors ameliorateneuroimmune perturbations following stimulant use at least in part through glutamatergic mechanisms.Further they selectively reduce the reinforcing effects of cocaine the development of cocaine sensitization andreinstatement to cocaine seeking. Most of the phosphodiesterase inhibitors tested preclinically are notavailable for use in humans however. Pentoxifylline a xanthine derivative and phosphodiesterase inhibitor thatis used clinically to treat muscle pain in individuals with peripheral artery disease is structurally similar to andproduces anti-inflammatory effects like the phosphodiesterase inhibitors tested preclinically. Thus theoverarching goal of this study is to translate preclinical findings that used phosphodiesterase inhibitors toameliorate neuroimmune perturbations and reduce cocaine intake to the human laboratory. We seek todemonstrate pentoxifylline reduces cocaine self-administration and abuse-related effects in individuals withcocaine use disorder. We will also evaluate safety and tolerability of pentoxifylline and cocaine combinationsand determine whether pentoxifylline affects immune biomarkers. This research will directly translate findingsfrom preclinical research and provide strong clinical evidence that pentoxifylline reduces the reinforcing andother abuse-related effects of cocaine while also ameliorating immune perturbations associated with cocaineuse. In addition this work has key basic science implications about neuroimmune mechanisms underlying thepharmacodynamic effects of cocaine in humans.

project_terms:
Acetylcysteine;Address;Admission activity;Adverse event;Affect;American;Antiinflammatory Effect;Attenuated;Basic Science;Biological Assay;Blood;Blood specimen;Brain;Brain-Derived Neurotrophic Factor;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Dependence;Cocaine use disorder;Data;Development;Dose;Double-Blind Method;Drug Exposure;Enrollment;Enzyme-Linked Immunosorbent Assay;Female;Glutamates;Goals;Homeostasis;Human;Immune;Immune Targeting;Immunologic Markers;Impairment;Individual;Inflammation;Inpatients;Intake;Interleukin-6;Intravenous;Laboratories;Laboratory Study;Maintenance;Measures;Mediating;Motivation;Myalgia;Neurobiology;Neuroimmune;Neuroimmunomodulation;Outcome Study;Pentoxifylline;Peripheral arterial disease;Pharmacodynamics;Pharmacotherapy;Phosphodiesterase Inhibitors;Physiological Effects of Drugs;Placebo Control;Population;Pre-Clinical Model;Preclinical Testing;Preclinical data;Public Health;Reporting;Research;Role;Safety;Sampling;Sex Differences;Signal Transduction;System;TNF gene;Time;Translating;Translations;Underserved Population;Work;Xanthines;blood-brain barrier crossing;cocaine overdose;cocaine seeking;cocaine self-administration;cocaine sensitization;cocaine use;cytokine;design;diagnostic criteria;experimental study;human subject;improved;male;meetings;neurotrophic factor;novel;pre-clinical research;reinforcer;response;sex;side effect;stimulant use;uptake

public_health_relevance:
PROJECT NARRATIVECocaine produces profound changes in neuroimmune signaling and that affects downstream glutamatefunction which may present a target for novel cocaine use disorder (CUD) pharmacotherapies. We propose arigorous human laboratory study to determine whether ameliorating disrupted neuroimmune signaling throughtreatment with a phosphodiesterase inhibitor reduces cocaine intake and other abuse-related effects.


application_id: 11158674
project_number: 5U01DK074007-19
administering_ic: NIDDK
award_notice_date: 2025-08-01
opportunity_number: RFA-DK-20-504
application_type: 5
activity_code: U01
ic: DK
serial_number: 074007
program_official: SHEA-DONOHUE, TEREZ
project_start_date: 2006-04-15
project_end_date: 2027-07-31
study_section: ZDK1-GRB-9(M2)S
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-01
project_title:
U of L Clinical Center to Investigate the Pathogenesis Etiology and Treatment of Gastroparesis through the NIDDK Gastroparesis Consortium

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

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

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


application_id: 11158661
project_number: 5R01CA258421-05
project_title: Gold-derived therapeutic compounds for disease application
administering_ic: NCI
award_notice_date: 2025-08-05
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 258421
program_official: FU, YALI
project_start_date: 2021-08-04
project_end_date: 2026-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 11956743
contact_pi: AWUAH, SAMUEL GORMAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT. Gold-derived anticancer compounds are promising therapeutic agents fordisease applications including cancer. Triple negative breast cancer (TNBC) is an aggressive clinical subtypeof breast cancer that lacks effective therapy. Approximately 66% of all breast cancer deaths are TNBC-relatedhence pragmatic treatment options are sorely needed. Our research program seeks to harness the unique spatialproperties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for new targetedtherapeutic regimen to eliminate TNBC. We have developed gold compound libraries with different scaffolds anddistinct mode of action in TNBC cells including modulating mitochondrial biogenesis and morphology. Thecompounds display high potency in the nanomolar range with >30-fold selectivity to cancer cells over normalcells. Comparative profiling using the NCI-60 screen confirmed toxicity of a lead compound AuPhos against apanel of breast cancer including TNBC. Preliminary maximum tolerated dose studies in BALB/c mice suggestthat different classes of gold compounds can be well tolerated in animals. Additionally AuPhos exerts profoundantitumor effect and prevents liver metastasis in the metastatic 4T1 TNBC mouse model. Mechanism of actionstudies suggest that the gold compounds target different mitochondrial processes including mitochondrialbiogenesis or morphology. We hypothesize that synthetic modification of the gold scaffold will enable thedevelopment of a suite of gold-based drugs that are targeted to different mitochondrial locales and biologicaltargets to eliminate TNBC. We will test the hypothesis in this project via the following aims: Aim 1) optimizechemically and functionally diverse gold anticancer agents; Aim 2) Delineate the mechanism of gold-basedmodulation of mitochondrial function; and Aim 3) Determine the therapeutic index of optimized gold compoundsin TNBC mouse models. The outcomes of this project will 1) provide novel gold-based compounds with specificityfor mitochondrial function to eliminate TNBC; 2) delineate the mechanism of TNBC inhibition by the developedgold-based compounds; and 3) establish in vivo efficacy and pharmacodynamics of gold anticancer agents.Critically the compounds generated will provide impetus for targeted therapies for TNBC which is an unmetneed.

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

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


application_id: 11158618
project_number: 5R01CA274981-03
project_title: The PLOD2/succinate axis in cancer cell plasticity and stemness
administering_ic: NCI
award_notice_date: 2025-08-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 274981
program_official: AULT, GRACE S
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: Biochemical and Cellular Oncogenesis Study Section[BCO]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractTumor cells in TNBC tissue exhibit enhanced cell plasticity and stemness which is crucial for cancer metastasis.Metabolic and epigenetic reprogramming plays crucial roles in the regulation of cell plasticity. Succinate is anintermediate metabolite of the tricarboxylic acid (TCA) cycle. Aberrant accumulation of succinate has beendetected in many cancers. However the cellular function and regulation of succinate in breast cancerdevelopment and progression have not been well investigated. We showed that the epithelial-to-mesenchymaltransition (EMT) was associated with profound changes in metabolites including elevation of cytoplasmicsuccinate. Importantly treatment with the membrane permeable succinate was sufficient to induce mesenchymalphenotypes enhance cancer cell stemness and colonization and reduce DNA hydroxymethylation and genetranscription in mammary epithelial cells. Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2)catalyzes lysine hydroxylation in endoplasmic reticulum and generates succinate as another product. We foundthat PLOD2 expression was induced in cancer cells in TNBC tissue and increased PLOD2 expression correlateswith poor prognosis and high chances of cancer metastasis. Silence of PLOD2 in cancer cells significant reducedcancer cell colonization and metastasis. PLOD2 expression was induced during EMT and associated withelevation of cytoplasmic succinate levels. Using gain- and loss-of function approaches we showed thatincreased PLOD2 expression is necessary and sufficient to enhance the accumulation of cytoplasmic succinate.Importantly silencing PLOD2 in breast cancer cells inhibited cancer cell stemness. The overall objective of thisproject is to define roles of the PLOD2/succinate axis in regulating cancer cell plasticity and stemness and toevaluate biological activity of the new PLOD2 inhibitor in suppressing TNBC progression and metastasis. Thecentral hypothesis of this proposal is that PLOD2-induced succinate accumulation enhances cancer cellplasticity and metastasis by reducing DNA hydroxymethylation; therefore targeting the PLOD2/succinate axis isa potential strategy to halt TNBC progression and metastasis. To test this hypothesis we propose the followingaims: Aim 1. Elucidate the molecular and cellular mechanisms by which succinate enhances cancer cell plasticityand stemness. Aim 2. Define roles of the PLOD2/succinate axis in regulating breast cancer progression. Aim 3.Evaluate the potential of targeting PLOD2 to suppress breast cancer metastasis. Successfully completion of theproject will reveal novel function of collagen hydroxylation enzymes in regulating succinate-associated epigeneticreprogramming and identify PLOD2 as a potential therapeutic target to suppress breast cancer metastasis.

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

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


application_id: 11146701
project_number: 5P30CA177558-13
project_title: Shared Resource Management
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5472
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Management of Shared Resource Facilities (SRF) fosters the execution of strategic science goals of theMarkey Cancer Center (MCC). Since their inception MCC SRFs have benefitted from strong and experiencedleadership significant investment and support from MCC and the University of Kentucky utilization of uniqueprocesses to facilitate effective delivery and coordination of services and governance by evaluation andoversight from advisory committees and the MCC Directors Council. The aims of SRF Management are to: 1)Promote state-of-the-art technology methodologic and content expertise to foster MCC scientific strategiesacross three Research Programs; 2) Conduct rigorous monitoring and evaluation processes and supportfinancial health for stability of SRF infrastructure and 3) Facilitate robust and stable access to MCC sharedresources through innovative initiatives. The SRFs received improved ratings from NCIs 2018 site visit andhave exhibited continued growth in breadth of services depth of skills and service provision aligned with theresearch direction of MCCs programs. In addition SRF management was guided by a culture of integratedand collaborative relationships with MCC researchers with formalized processes for hand-offs among SRFsfacilitating enhanced support and the bi-directional continuum of MCC research from basic science to clinicand into the community. MCC is supported by seven established SRFs: Biospecimen Procurement andTranslational Pathology (BPTP) Biostatistics and Bioinformatics (BB) Cancer Research Informatics (CRI)Flow Cytometry and Immune Monitoring (FCIM) Redox Metabolism (RM) with Oncogenomics (OG) andPatient-Oriented and Population Sciences (POP) as new fully operational facilities in this application resultingfrom rigorous SRF management evaluation processes and advisory committee recommendations andapproval. SRFs are led by Dr. Heidi Weiss (TO) Associate Director for Shared Resources; she is assisted byDr. Thrse Bocklage (MCO) Assistant Director for Shared Resources the SRF Management Office and MCCAdministration. MCC has invested $8.3M in SRF enhancements since 2018. SRF usage is robust evident byhigh numbers of users; SRFs also appropriately prioritize their services evident by the percent of users from2018-2022 who are MCC members: BB (156 users 79%) BPTP (150 users 61%) CRI (161 users 65%)FCIM (87 users 61%) OG (61 users 69%) POP (34 users 71%) and RM (72 users 68%). MCC ResearchProgram members heavily utilize SRFs as follows: 84% of Molecular and Cellular Oncology 85% ofTranslational Oncology and 82% of Cancer Prevention and Control. The total number of MCC members usingall SRFs remains consistently high (151 and 171 over MCCs first two CCSG cycles respectively). Fiscalmanagement and business planning from MCC Administration ensure SRF income mechanisms and financialprocesses are robust and appropriate. These management strategies and consequent value-added metricsdemonstrate the critical role of SRFs and their direct contributions to MCCs mission.

project_terms:
Advisory Committees;Affect;Applications Grants;Assessment tool;Basic Science;Bioinformatics;Biometry;Budgets;Businesses;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Prevention Intervention;Cancer Therapy Evaluation Program;Clinic;Clinical Research;Clinical Trials;Communication;Communities;Comprehensive Cancer Center;Decision Making;Dedications;Dissemination and Implementation;Documentation;Electronics;Ensure;Evaluation;Evidence based intervention;Exhibits;Financial Support;Flow Cytometry;Fostering;Funding;Genomics;Goals;Growth;Health;Health Insurance Portability and Accountability Act;Human Resources;Immunologic Monitoring;Improve Access;Income;Informatics;Infrastructure;Institution;Investigation;Investments;Kentucky;Laboratories;Lead;Leadership;Marketing;Measurement;Metabolism;Methodology;Mission;Modeling;Modification;Molecular;Monitor;NCI Center for Cancer Research;Office Management;Oncology;Outcome;Oxidation-Reduction;Pathology;Peer Review Grants;Performance;Population Intervention;Population Sciences;Population Study;Process;Productivity;Recommendation;Reporting;Research;Research Personnel;Resource Sharing;Resources;Role;Science;Screening for cancer;Secure;Service provision;Services;Site Visit;Strategic Planning;System;Technical Expertise;Technology;Therapeutic Trials;Tobacco;Training;Training and Education;Universities;Work;anti-cancer research;biomarker driven;cancer genomics;cancer prevention;cancer research center director;cellular oncology;community based research;continuous monitoring;cost;cost effective;cost effectiveness;data sharing;epidemiology study;experience;implementation facilitation;improved;innovation;instrumentation;member;molecular oncology;oncology program;operation;patient oriented;programs;service coordination;skills;survivorship;targeted treatment;tool;translational oncology;translational study;treatment program

public_health_relevance:
Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements.


application_id: 11146700
project_number: 5P30CA177558-13
project_title: Protocol Review and Monitoring System
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5471
contact_pi_person_id: 1926108
contact_pi: ANTHONY, LOWELL B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT In accordance with CCSG guidelines the Markey Cancer Center (MCC) has established appropriate mechanisms for ensuring rigorous scientific oversight of cancer clinical trials through the Protocol Review and Monitoring System (PRMS). Protocols undergo initial scientific review by Clinical Care and Research Teams (CCARTs) including assessment of relevance to the patient population fit within the portfolio and interest of investigators. In 2019 the MCC formalized first-stage review by CCARTs expanding structure and function and enhancing communication with the Protocol Review and Monitoring Committee (PRMC). Following CCART approval review for operational feasibility is completed by the Feasibility Review Committee. The goal of these reviews is to ensure that only the highest quality trials are submitted to the PRMC. The MCC PRMC is responsible for independent peer-review of scientific merit feasibility and prioritization of new protocols. Following activation PRMC monitors protocols for ongoing scientific progress and has ultimate authority to suspend or close protocols that do not meet MCC scientific standards. The Specific Aims of the PRMS are: 1) Optimize the PRMS structure and process for sufficient size and breadth of expertise to conduct a critical rigorous and fair scientific review of all institutional cancer-related research protocols involving human subjects; 2) Ensure that clinical trials conducted at MCC support and enable the scientific mission of the center are relevant to patients in the catchment area including those from understudied populations; 3) Safeguard the scientific integrity feasibility and prioritization of all cancer-related interventional clinical research of the MCC and apply rigorous scientific review criteria in a consistent and objective manner; 4) Oversee the progress and performance of all interventional cancer clinical trials to ensure their continued scientific merit and accomplishment of the scientific goals of the protocol and the MCC. Highlights during the funding period include incorporation of first-stage reviews into PRMS framework enhanced member education expanded representation in key scientific areas and strengthened quorum expectations. From 2019 to 2021 the CCARTs reviewed 409 clinical trials for potential opening approved 294 (72%) and declined 115 (28%); the Feasibility Review Committee declined 20 (4%) due to lack of feasibility. From 2019 to 2021 the PRMC reviewed and/or prioritized 239 new protocols of which 230 were approved and 9 were disapproved. In the past three years the PRMC reviewed 552 active protocols for scientific progress closing 29 protocols due to low accrual or a change in scientific merit. The PRMC continuously assesses its own performance. In 2021 median time from PRMC submission to approval was 8 days overall (7 national 8 industry 24 institutional). As the MCC has matured the PRMS has continued to optimize the first- and second-stage review and to increase scientific rigor objectivity and scrutiny of each trials relevance to our population in order to ensure MCC brings the highest quality clinical research to Kentuckians.

project_terms:
Area;Basic Science;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Catchment Area;Charge;Clinical Cancer Center;Clinical Oncology;Clinical Protocols;Clinical Research;Clinical Trials;Committee Members;Communication;Conduct Clinical Trials;Data;Discipline;Disease;Education;Electronics;Ensure;Evaluation;Faculty;Funding;Goals;Guidelines;Individual;Industry;Institution;Institutional Review Boards;Intervention;Intervention Studies;Kentucky;Laboratory Research;Malignant Neoplasms;Mission;Modification;Monitor;Observational Study;Outcome;Pathology;Patients;Peer Review;Performance;Pharmacology;Policies;Population;Population Heterogeneity;Prevention;Process;Protocols documentation;Radiology Specialty;Recommendation;Reporting;Research;Research Personnel;Resources;Review Committee;Safety;Scientific Advances and Accomplishments;Structure;System;Time;Underserved Population;Universities;Vulnerable Populations;authority;cancer clinical trial;cancer prevention;cancer research center director;clinical care;clinical translation;clinically relevant;community engagement;expectation;human subject;innovation;interest;member;mid-career faculty;patient population;professor;success;trial enrollment

public_health_relevance:
Project Narrative Not applicable. This document is attached to satisfy electronic submission requirements.


application_id: 11146697
project_number: 5P30CA177558-13
project_title: Community Outreach and Engagement
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5470
contact_pi_person_id: 8310976
contact_pi: HULL, PAMELA CARMEN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The University of Kentucky (UK) Markey Cancer Center (MCC) embraces the entire Commonwealth of Kentucky as its catchment area. Despite notable recent advances Kentucky has the highest all-site cancer incidence and mortality in the U.S. With a 47-year history the goal of MCC Community Outreach and Engagement (COE) is to engage communities practitioners and researchers in mutually beneficial collaborations to reduce cancer incidence and mortality. MCCs long-standing COE programs include regionally-based community outreach management of the states cancer coalition and policy efforts and the MCC Affiliate Network (MCCAN) MCCs innovative clinical outreach program with 19 community-based (non-UK) hospitals across the state. Since 2018 MCC made strategic investments to enhance COE strengths and further integrate research and cancer control. COEs previous needs assessment shaped the FY19-23 MCC Research Priorities. Key accomplishments include conducting the 2021 Kentucky Cancer Needs Assessment (KY CNA) launching new research engagement initiatives (e.g. Community Impact Ambassadors as Research Program liaisons Research Advocacy Program Clinical Trial Referral Ambassadors internal COE funding) and cancer control activities with extensive reach (e.g. training/technical assistance policy changes individual education facilitating access to services). Building on existing efforts and FY24-28 MCC Research Priorities COE Specific Aims are to: 1) Monitor cancer rates in Kentucky and identify community-driven priorities. In addition to monitoring cancer rates and conducting the next KY CNA in 2026 each year COE will carry out a focused needs assessment to address data gaps and underserved populations identified in the 2021 KY CNA. 2) Foster impactful research that responds to community needs. COE will expand the Research Advocacy Program with a training module for basic and clinical researchers and Rapid Feedback Sessions. COE will add two new strategies to facilitate clinical trial participation: providing appropriate patient and community education including testimonial videos and assisting studies accrue patients from all backgrounds through consultations and research advocate feedback. 3) Disseminate and implement sustainable guidelines practices and policies. COE is currently using the 2021 KY CNA to guide development of the states new five-year Cancer Action Plan. Next COE will assess its portfolio of community cancer control programs to strategically realign them with the new state plan to address gaps leverage partnership opportunities and maximize impact. IMPACT: COE has made important advances in synergizing MCC research and cancer control efforts with statewide partners and significant contributions to population-level improvements in colon and lung cancer screening and outcomes and smoking. COE is poised to further accelerate MCC impact.

project_terms:
Acceleration;Address;Advocacy;Advocate;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Communities;Community Health Education;Community Outreach;Consultations;Data;Development;Education;Electronics;Feedback;Fostering;Funding;Goals;Guidelines;Health Services Accessibility;Hospitals;Incidence;Individual;Investments;Kentucky;Malignant Neoplasms;Monitor;NCI Center for Cancer Research;Needs Assessment;Outcome;Patient Education;Patients;Policies;Population;Recording of previous events;Research;Research Personnel;Research Priority;Screening for cancer;Shapes;Smoking;Training;Training Activity;Underserved Population;Universities;cancer site;colon cancer screening;community engagement;improved;innovation;lung cancer screening;mortality;outreach program;programs

public_health_relevance:
Project Narrative Not applicable. This document is attached to satisfy electronic submission requirements.


application_id: 11146694
project_number: 5P30CA177558-13
project_title: Clinical Protocol and Data Management
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5469
contact_pi_person_id: 6772940
contact_pi: ARNOLD, SUSANNE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) Clinical Protocol and Data Management (CPDM) facilitates all clinical cancer research at the University of Kentucky. CPDMs Specific Aims are: 1) To provide comprehensive centralized support for MCC clinical research activities; 2) To ensure the safety compliance and quality of all clinical cancer research performed at the center and MCCs Research Network (MCCRN) in accordance with the Data Safety and Monitoring Plan and NCI requirements; 3) To integrate all efforts of the Cancer Center to provide clinical trial access to all MCC patients including women racial/ethnic minorities understudied populations and individuals across the lifespan; and 4) To provide ongoing education and training services for CPDM and MCCRN staff and faculty that enhance teams and lead to increased engagement with MCCs catchment population. The CPDM facilitates clinical research through the Clinical Research Offices four units (72 FTEs) Protocol Development Teams (10 FTE) a Quality Assurance Program (5 FTE) and MCCRN (11 FTE) which provide centralized expertise for development coordination and execution of trials. In 2022 the Clinical Research Office managed 369 active trials211 cooperative group 113 industry sponsored and 45 investigator-initiated (12 investigational new drug-enabling). MCCs statewide infrastructure supports research referral and accrual within the catchment area. As the CPDM has matured the center increased clinical research engagement to 98 of Kentuckys 120 counties with 18753 total accruals (8857 interventional; 9896 non-interventional 2018-2022). The Quality Assurance Program and Audit Committee function independently from other CPDM components to support education safety and quality of trial conduct. All cancer trials are guided by MCCs Data and Safety Monitoring Plan which provides oversight in accordance with NCI CCSG requirements. The Data and Safety Monitoring Committee ensures patient safety and protocol compliance by staff and investigators. MCC leaders investigators and staff promote the inclusion of women racial/ethnic minorities and Appalachian Kentucky residents in clinical cancer research in alignment with CCSG guidelines. Enhanced efforts have increased trial participation to reflect this patient population focusing on important cancers such as lung and prostate. In alignment with NIH policies MCC strives for inclusion of individuals across the lifespan in clinical research. In 2021 40% of therapeutic trial accruals were adults 65 or older surpassing national averages. Cancer care for children is provided by one of two comprehensive pediatric oncology programs in the state. MCC is the first center in the region to offer germline testing to all pediatric oncology patients supported by the Molecular Tumor Board interpretation of results.

project_terms:
Adult;Appalachian Region;Cancer Center;Cancer Center Support Grant;Catchment Area;Child Care;Clinical;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Clinical Trials;County;Data;Development;Education;Electronics;Ensure;Faculty;Guidelines;Individual;Industry;Infrastructure;Intervention;Investigational Drugs;Kentucky;Lung;Malignant Neoplasms;Molecular;Monitor;NCI Center for Cancer Research;Office Management;Patients;Pediatric Oncology;Policies;Population;Prostate;Protocol Compliance;Research Activity;Research Personnel;Research Support;Safety;Services;Therapeutic Trials;Training and Education;United States National Institutes of Health;Universities;Woman;anti-cancer research;cancer care;data management;ethnic minority;germline testing;human old age (65+);life span;oncology program;patient oriented;patient population;patient safety;programs;protocol development;quality assurance;racial minority;tumor

public_health_relevance:
Project Narrative Not applicable. This document is attached to satisfy electronic submission requirements.


application_id: 11146693
project_number: 5P30CA177558-13
project_title: Developmental Funds
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5468
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT CCSG Developmental Funds are a vital mechanism for furthering the strategic mission and vision of the Markey Cancer Center (MCC) through pilot funding to MCC members and support of emerging Shared Resource Facilities. During the current funding period Developmental Funds helped support 17 basic clinical population and translational cancer research pilot projects from MCCs Molecular and Cellular Oncology Cancer Prevention and Control and Translational Oncology Research Programs stimulating a high return on investment of $15.16 per CCSG dollar. These projects have fostered five new extramurally funded grants and have opened clinical trials that accrued 241 new participants. In close alignment with MCCs scientific direction 14 of the 17 projects are on topics that correspond to the centers FY19-23 Research Priorities for the current funding period. Outside of the routine CCSG pilot award process MCC also elected to use Developmental Funds to support two interdisciplinary teams of researchers who ultimately successfully applied for a CCSG Supplement designed to foster the development of multiproject research programs. Developmental Funds were also invested in two developing Shared Resource Facilities (Oncogenomics and Patient-Oriented and Population Sciences) which have supported research projects from all three MCC programs and after careful annual evaluation have been approved by the MCC Directors Council as fully functioning resources presented as such in this CCSG application. Leveraged with philanthropic investment and institutional support Developmental Funds will also be strategically allocated during the upcoming funding period to address two Specific Aims: 1) Cultivate innovative and collaborative science through the use of pilot grants in areas that align with MCCs FY24-28 Strategic Plan and Research Priorities and reflect the scientific aims of MCCs three Research Programs; and 2) Foster deeper collaboration across the UK campus through strategic partnerships to fund innovative pilot awards and ensuring the continuation of community input through the CCSG pilot review process. To achieve these aims MCC requests $150000 per year in Developmental Funds allowing the center to achieve several key objectives outlined in the Strategic Plan including fostering research that aligns with its research priorities expanding transdisciplinary opportunities for research teams and increasing clinical studies that are informed by MCC basic research. MCC will also continue partnerships with other major research centers across campus allowing cancer research to have an impact far beyond what MCC alone can achieve and will foster the maturity of a new process by which Community Advisory Board members directly contribute to the CCSG pilot reviews allowing community input to inform and influence funding decisions.

project_terms:
Address;Area;Award;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Development;Electronics;Ensure;Evaluation;Extramural Activities;Fostering;Funding;Grant;Institution;Investments;Kentucky;Mission;Participant;Pilot Projects;Population;Population Sciences;Process;Program Research Project Grants;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Resource Sharing;Resources;Science;Strategic Planning;Universities;Vision;anti-cancer research;cancer genomics;cancer prevention;cancer research center director;cellular oncology;community advisory board;design;innovation;member;molecular oncology;patient oriented;programs;translational cancer research;translational oncology


application_id: 11146692
project_number: 5P30CA177558-13
project_title: Leadership Planning and Evaluation
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5467
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT B. Mark Evers MD (TO) Director of the Markey Cancer Center (MCC) is assisted by eight Senior Leaders who support activities in cancer research outreach education and training clinical care and administration. With the exception of some notable additions during this reporting period that have expanded the effectiveness and expertise of the Senior Leadership team this highly experienced group of leaders has worked together since 2009 overseeing MCCs initial NCI designation in 2013 a successful renewal application in 2018 the preparations for this renewal and quest for Comprehensive Cancer Center status as well as a future five-year outlook in the form of MCCs FY24-28 Strategic Plan. MCCs Senior Leaders leverage all available resources at the University of Kentucky state and national levels to further their cohesive plan to fulfill MCCs mission to reduce cancer incidence and mortality with a focus on Kentucky through research prevention treatment education and community engagement. To that end MCCs Leadership Planning and Evaluation efforts are centered around the following Specific Aims: 1) Implement and execute MCCs FY24-28 Strategic Plan and lead MCC based on the opportunities and needs of the statewide catchment area and in tandem with institutional and NCI priorities; 2) Lead the ongoing planning and evaluation of the center coordinating and responding to internal and external reviews; and 3) Ensure the appropriate resources and infrastructure to foster success across all areas of MCCs Strategic Plan including the success of MCCs Research Programs Shared Resources clinical and translational scientific endeavors and outreach and mentoring initiatives. MCCs planning and evaluation efforts sustaining its substantial growth since 2018 are accomplished through External and Internal Advisory Boards that meet regularly the Directors Council and committees that provide both the Director and Senior Leadership ongoing guidance and support. Future directions for the center are guided by plans outlined in MCCs FY24-28 Strategic Plan which was constructed through an extensive review and vetting process with input from key internal and external stakeholders. The plan is a living document and roadmap to guide the next five years of excellence in key pillars of activity across the center: 1) basic research 2) clinical translation 3) cancer prevention and control 4) cancer education and mentoring 5) community outreach and engagement and 6) clinical care. These pillars are reinforced by strong institutional support philanthropy Shared Resource Facilities and administration all of which work in tandem to support a cancer center poised to continue its trajectory of increasing contributions to cancer research training education and outreach.

project_terms:
Area;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Clinical;Community Outreach;Comprehensive Cancer Center;Education;Effectiveness;Electronics;Ensure;Evaluation;Fostering;Future;Growth;Incidence;Infrastructure;Institution;Kentucky;Lead;Leadership;Malignant Neoplasms;Mentors;Mission;NCI Center for Cancer Research;Preparation;Prevention;Process;Reporting;Research;Resource Sharing;Resources;Strategic Planning;Training;Training and Education;Universities;Work;anti-cancer research;cancer education;cancer prevention;clinical care;clinical translation;community engagement;experience;mortality;outreach;programs;success


application_id: 11146690
project_number: 5P30CA177558-13
project_title: Translational Oncology Research Program
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5466
contact_pi_person_id: 6772940
contact_pi: ARNOLD, SUSANNE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Centers (MCC) Translational Oncology (TO) Research Program is scientifically focused on identifying novel targets discovering new anticancer agents and devices and leading catchment-relevant clinical trials to decrease cancer incidence and mortality in Kentucky and the nation. The overarching theme of the TO Program is to use precision medicine to enhance patient outcomes through three Specific Aims: 1) Identify and validate mechanistic targets of cancer 2) Discover re-design and develop new anticancer agents and devices and 3) Develop and lead biomarker directed catchment-relevant clinical trials. Currently 33 ongoing translational studies are evaluating molecular targets and mediators of cancer. Since 2018 38 new drugs novel combinations and repurposed anticancer agents and devices have been developed with a focus on identified mutations and phenotypes as informed by COE catchment area data. TO is a cross-disciplinary program with 67 investigators from four colleges and 16 departments producing research awards of approximately $10M in annual direct costs a 68% increase from 2017 including $1.8M from the NCI and $3.4M from other NIH agencies. Members have published 613 manuscripts (2018 to 2022) of which 148 (24%) are inter-programmatic 169 (28%) are intra-programmatic 344 (56%) are inter-institutional and 13% of which have an impact factor >10. TO members lead 26 new therapeutic interventional investigator-initiated trials (IITs) a 53% increase since the previous funding period (17 IITs 2013-2017). These IITs have enrolled 870 patients (2018-2022) a 111% increase in IIT accruals (413 patients 2013-2017) with 52% of participants from Appalachia. In addition TO investigators enrolled 12689 individuals to the programs interventional and non-interventional trials compared to 8571 from 2013-2017 a 48% increase. TO Program members are international leaders in target discovery and validation have national and international collaborations and hold leadership roles in the National Cancer Institutes Experimental Therapeutics Clinical Trials Network the Oncology Research Information Exchange Network and Onco-Array Networks and the MCC-led Global Cancer Consortium. The TO Program fosters continuous collaboration among MCC program members to inform and advance MCC basic science into the clinic. A notable example is translating early identification of the biomarker FASN to an ongoing colorectal cancer trial. The TO Program has a cohesive and collaborative team focused on translating MCC scientific discoveries into safe and effective anticancer treatments with a demonstrated depth and breadth of impact in MCCs catchment area nationally and internationally.

project_terms:
Address;Antineoplastic Agents;Appalachian Region;Area;Award;Basic Science;Biological Markers;Biological Models;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Clinic;Clinical;Clinical Oncology;Clinical Trials;Clinical Trials Network;Collaborations;Colorectal Cancer;Communities;Community Outreach;Data;Development;Devices;Diet;Direct Costs;Disparity;EIF4EBP1 gene;Early Therapeutic-Clinical Trials Network;Early identification;Electronics;Enrollment;FASN gene;Fostering;Funding;Future;Genomics;Goals;Gold Compounds;Incidence;Individual;Infrastructure;Institution;Interdisciplinary Study;International;Intestinal Hormones;Investigational Drugs;Investigational Therapies;Kentucky;Lead;Leadership;Malignant Neoplasms;Manuscripts;Mediator;Mission;Molecular;Molecular Target;Multi-Institutional Clinical Trial;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Nursing Faculty;Obesity;Oncology;Participant;Patient-Focused Outcomes;Patients;Peer Review;Pharmaceutical Preparations;Phase;Phenotype;Population;Preclinical data;Prostate;Public Policy;Publications;Publishing;Radiopharmaceuticals;Research;Research Personnel;Research Priority;Resources;Role;Ruthenium Compounds;Science;Strategic Planning;Structure;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Translating;Translations;United States National Institutes of Health;Universities;Validation;anti-cancer treatment;cancer care;cancer prevention;cancer therapy;cellular oncology;clinical development;clinical translation;clinical trial enrollment;clinically relevant;college;community engagement;cross disciplinary program;design;drug repurposing;early phase clinical trial;ethnic disparity;genome resource;inhibitor;insight;inter-institutional;intervention program;investigator-initiated trial;member;molecular oncology;mortality;next generation sequencing;novel;novel anticancer drug;novel therapeutic intervention;novel therapeutics;oncology program;phase 1 study;pre-clinical;precision medicine;preclinical development;programs;racial disparity;recruit;repository;translational goal;translational oncology;translational pipeline;translational study;treatment trial;tumor;working group


application_id: 11146688
project_number: 5P30CA177558-13
project_title: Molecular and Cellular Oncology Research Program
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5465
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The goal of the Molecular and Cellular Oncology (MCO) Research Program is to gain a comprehensive understanding of basic mechanisms driving cancer initiation progression metastasis and therapeutic resistance to facilitate development of novel and rational approaches for cancer prevention and therapy. MCO research efforts are central to the overall Markey Cancer Center (MCC) mission to reduce cancer rates in Kentucky through research prevention treatment education and community engagement. MCO investigators determine signaling genetic epigenetic and metabolic mechanisms that promote cancer development fuel tumor progression and contribute to therapeutic resistance. To achieve its goal MCO proposes three inter-related aims: 1) Identify aberrant signaling networks and critical interactions of tumor cells with their microenvironment to delineate molecular mechanisms that drive tumor initiation progression and metastasis and resistance; 2) Determine the contribution of metabolic reprogramming and epigenetic dysregulation to define novel pathways promoting cancer cell survival and adaptation; 3) Delineate the mechanisms by which dysregulation of redox signaling promotes genomic instability therapeutic resistance and normal tissue toxicity. The 54 members of the MCO Program are experts in cancer cell signaling tumor microenvironment cancer metabolism epigenetic regulation and redox biology who hail from 16 departments in the Colleges of Medicine; Engineering; Arts and Sciences; and Agriculture Food and Environment reflecting diverse disciplinary perspectives. Cancer-related MCO funding is nearly $10.3M in annual direct costs and 53% of MCO peer-reviewed funding is from the NCI. Members have published 320 manuscripts (July 2018June 2022) of which 106 (33%) are inter-programmatic 81 (25%) are intra-programmatic and 195 (61%) are inter-institutional. The program is co-led by three researchers with expertise in each of the three programmatic areas. Dr. Rina Plattner (an expert in oncogenic kinase signaling and tumor metastasis) Dr. Binhua Peter Zhou (a specialist in epigenetic and metabolic reprogramming of epithelial-mesenchymal transition) and Dr. Tianyan Gao (an expert in protein phosphatases and mitochondrial regulation of cancer stem cells) bring together expertise in cancer signaling (Plattner Aim 1) epigenetics and metabolism (Zhou Aim 2) and redox biology and mitochondrial bioenergetics (Gao Aim 3). In addition to their scientific leadership each offers significant strengths in clinical translation junior faculty mentoring communications among MCC Research Programs and expertise on the MCC catchment area. By leveraging comprehensive program strengths the MCO Program collectively provides a rich environment to facilitate multidisciplinary collaboration and builds a productive pipeline for translation of MCO science into the clinic.

project_terms:
Address;Adhesions;Agriculture;Area;Arts;Automobile Driving;Bioenergetics;Biogenesis;Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Caregivers;Catchment Area;Cell Proliferation;Cell Survival;Chromatin;Clinic;Clinical Trials;Collaborations;Colorectal Cancer;Communication;Community Outreach;DNA Repair;Development;Direct Costs;Disparity;Education;Electronics;Engineering;Ensure;Environment;Enzymes;Epigenetic Process;Epithelium;Extracellular Matrix Proteins;FASN gene;FDA approved;Food;Funding;Future;Genetic;Genomic Instability;Goals;Heart Injuries;Incidence;Interdisciplinary Study;Intervention;Invaded;Joints;Kentucky;Leadership;Maintenance;Malignant - descriptor;Malignant Neoplasms;Manuscripts;Medicine;Mesenchymal;Metabolic;Metabolism;Metastatic Melanoma;Mission;Mitochondria;Modeling;Molecular;NCI Center for Cancer Research;Neoplasm Metastasis;Normal tissue morphology;Oncogenic;Oxidation-Reduction;Pathway interactions;Patients;Peer Review;Phosphoric Monoester Hydrolases;Phosphotransferases;Prevention;Production;Productivity;Protein Kinase;Protein phosphatase;Publications;Publishing;Reactive Oxygen Species;Recurrence;Regulation;Research;Research Personnel;Research Priority;Resistance;Science;Signal Transduction;Signaling Molecule;Specialist;Stress;Survivors;Tissues;Toxic effect;Translating;Treatment Efficacy;Universities;Vulnerable Populations;base;cancer cell;cancer health disparity;cancer initiation;cancer prevention;cancer stem cell;cancer therapy;cellular oncology;clinical translation;college;community engagement;diagnostic biomarker;epigenetic regulation;extracellular vesicles;faculty mentor;immune checkpoint blockade;inter-institutional;member;microbiome;molecular oncology;mortality;multidisciplinary;neoplastic cell;novel;novel therapeutic intervention;oncology program;programs;recruit;stem cell biology;therapeutic target;therapy resistant;tissue injury;translational oncology;translational pipeline;tumor;tumor immunology;tumor initiation;tumor metabolism;tumor microenvironment;tumor progression


application_id: 11146686
project_number: 5P30CA177558-13
project_title: Cancer Prevention and Control Research Program
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5464
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Markey Cancer Centers (MCC) Cancer Prevention and Control (CP) Research Program fosters high-impact population-based and community-engaged research with the overarching goal of reducing cancer incidence and mortality in Kentucky. CP research spans the population science translation pipeline from advancing understanding of risk factors and intervention targets to developing and testing new interventions to studying the process of dissemination and implementation of interventions into practice. Impactful scientific contributions include research into patient survival in oropharyngeal cancer timely regulatory and policy research on novel smokeless tobacco products trials of innovative interventions to reduce carcinogenic environmental exposures trials of interventions to promote quality of life outcomes among rural cancer survivors and community implementation trials to prevent hepatitis C transmission and implement cancer prevention and screening guidelines in communities throughout Kentucky and Appalachia. CP impact also extends to public health policy within Kentucky and nationally and in advancing standards of care related to tobacco cessation and lung cancer screening. The CP Program combines these strengths to address three Aims: Advance the understanding of risk factors and intervention targets for cancer prevention and control (Aim 1); Develop and test the efficacy of interventions across the cancer control continuum (Aim 2); Study the dissemination and implementation of interventions (Aim 3). The CP Program has been transformed by substantial strategic investments that have led to new leadership and by the infusion of multiple recruitments that have expanded the breadth and depth of program research combined with the continued success of long-standing program members. The programs peer-reviewed funding has increased by 50% and NCI funding has grown dramatically by 567% to now comprise 33% of peer-reviewed funding compared to 7% in 2017. The maturation of the program is evident in a 24% increase in clinical trial accrual and by the awarding of NCI P01 and UH3 multi-investigator inter-institutional grants and an NCI T32 focused on rural cancer. CP investigators are highly engaged with and responsive to the needs of MCCs catchment area residents and are engaged in inter-programmatic research that addresses MCCs catchment research priorities in collaboration with Community Outreach and Engagement. Thus the CP Program is integral to achieving the overall MCC mission to reduce cancer in Kentucky through research prevention treatment education and community engagement.

project_terms:
Address;Appalachian Region;Award;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research Program;Cancer Survivor;Caring;Catchment Area;Clinical Trials;Communities;Community Outreach;Dissemination and Implementation;Education;Electronics;Environmental Exposure;Fostering;Funding;Goals;Grant;Health Policy;Hepatitis C Transmission;Incidence;Infusion procedures;Intervention;Intervention Trial;Investments;Kentucky;Leadership;Malignant Neoplasms;Mission;Outcome;Patients;Peer Review;Policy Research;Population Sciences;Prevention;Prevention Guidelines;Process;Public Health;Quality of life;Research;Research Personnel;Research Priority;Risk Factors;Rural;Smokeless Tobacco;Testing;Tobacco Use Cessation;Treatment Efficacy;Universities;cancer prevention;carcinogenicity;community collaboration;community engaged research;community engagement;efficacy testing;implementation intervention;implementation trial;innovation;inter-institutional;lung cancer screening;malignant oropharynx neoplasm;member;mortality;novel;population based;prevent;programs;recruit;screening guidelines;success;tobacco products;translational pipeline


application_id: 11146684
project_number: 5F31AI178999-03
project_title: Defining the impact of Extracellular Vesicles on inflammation during pneumonic plague
administering_ic: NIAID
award_notice_date: 2025-08-28
opportunity_number: PA-21-052
application_type: 5
activity_code: F31
ic: AI
serial_number: 178999
program_official: MOITRA, KAROBI
project_start_date: 2023-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-F07A-B(20)L]
contact_pi_person_id: 77802022
contact_pi: SHENEMAN, KATELYN RENEE
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/ABSTRACTDuring infection immune cells rely on communication to productively target and eliminate invading pathogens.Extracellular vesicles (EVs) are one key mediator of intercellular communication between immune cells. Thesemembrane-bound vesicles contain proteins lipids and nucleic acids that represent the inflammatory state of agiven cell. Upon release these EVs can fuse with other immune cells establishing biochemical communicationbetween cells and amplifying the inflammatory response to augment pathogen clearance. Yersinia pestis is theetiologic agent of the human disease known as plague. A hallmark of this disease is the sophisticatedsuppression of the host immune system in a biphasic manner. During acute infection Y. pestis utilizes its type 3secretion system (T3SS) to inject effector proteins into host cells which disrupt signaling pathways essential forbacterial clearance. Thus acute infection is hallmarked by the maintenance of a non-inflammatory environmentin which the bacteria can proliferate without host intervention. The second stage of infection the pro-inflammatory phase begins 36-48 hours post-infection in which the host begins to successfully mount animmune response against the pathogen. However the bacterial load ultimately overwhelms the host delayedresponses at which point the host may succumb to infection. Previous work has demonstrated that thegeneration of this non-inflammatory environment during acute infection is essential for Y. pestis virulence. Whilenumerous studies have highlighted the importance of suppressing phagocytosis exocytosis and otherantibacterial responses there is a gap in knowledge of how Y. pestis manipulates the EV response and how thisimpacts intercellular communication. Preliminary studies suggest that Y. pestis can manipulate the proteinspackaged into EVs by neutrophils in vitro. These data support the hypothesis that Y. pestis disrupts EVsproduction during infection to alter inflammation. The studies presented here will expand on our preliminary databy delineating the in vivo EV response during pneumonic plague (Aim 1) and defining the impact of EVs onimmune modulation (Aim 2). These studies will be the first to investigate the role of EV-mediated intracellularcommunication during plague. Therefore completion of these aims will significantly improve our understandingof how. Y. pestis exploits EV trafficking to manipulate the host immune response.

project_terms:
Antibacterial Response;Bacteria;Bacterial Infections;Binding;Biochemical;Cells;Communication;Data;Dependence;Development;Disease;Disease Progression;Endocytosis Inhibition;Environment;Etiology;Exocytosis;Generations;Goals;Hour;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Intervention;Invaded;Knowledge;Lipids;Lung infections;Maintenance;Mediating;Mediator;Membrane;Neutrophil Infiltration;Nucleic Acids;Organism;Outcome;Pathogenesis;Pathway interactions;Phagocytes;Phagocytosis;Phase;Plague;Play;Pneumonic Plague;Population;Production;Productivity;Proliferating;Protein Secretion;Proteins;Pulmonary Inflammation;Role;Signal Pathway;Testing;Time;Tissues;Type III Secretion System Pathway;Vesicle;Virulence;Work;Yersinia pestis;acute infection;antimicrobial;cell type;cytokine;extracellular vesicles;human disease;immunoregulation;improved;in vivo;in vivo evaluation;intercellular communication;mutant;neutrophil;new therapeutic target;pathogen;pulmonary;response;tool;trafficking

public_health_relevance:
PROJECT NARRATIVEYersinia pestis the etiologic agent of the plague has refined mechanisms to manipulate the host immuneresponse and suppress inflammation. This project will define the impact of disrupting extracellular vesicletrafficking and illustrate how this manipulation contributes to disease pathogenesis. Understanding thesemechanisms of immune subversion is essential for the development of novel targeted therapeutics.


application_id: 11146680
project_number: 5P30CA177558-13
project_title: Cancer Research Training and Education Coordination
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5462
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) at the University of Kentucky collectively delivers highly successful training programs spanning from K-12 to faculty level through the Cancer Research Training and Education Coordination (CRTEC) component. MCCs CRTEC programs and activities are structured around specific aims to: 1) Generate early interest in cancer-related careers; 2) Promote education and career development of graduate and postdoctoral cancer researchers; and 3) Foster research faculty career development in basic population and clinical/translational sciences. Key education activities address the academic challenges across rural Appalachian Kentucky through support from five grants that include an NCI Youth Enjoy Science R25 program. These efforts complement impactful structured academic and research training at the graduate postdoctoral and medical residency levels including three NCI-funded T32 training grants. Through new initiatives such as the recently funded NCI T32 and undergraduate research programs MCCs CRTEC component expands its comprehensive training reach to implement bold initiatives that complement well-established and emerging state-of-the-art cancer curricula and enrich MCC Research Programs. The establishment of sustainable NIH-funded Centers of Biomedical Research Excellence awards with dedicated cancer themes and associated junior faculty mentorship augment MCCs long-standing American Cancer Society Institutional Research Grant support for early-stage faculty and effective team-based faculty mentorship mechanisms across basic population and clinical research levels that are significantly expanding MCCs extramural funding base. Further targeted mentorship of early career clinical investigators through mechanisms such as the Clinical Trials Boot Camp fosters the development of investigator-initiated trials that translate MCC science to the clinic. The MCC Affiliate Network provides an effective conduit for multi-faceted statewide training of health care professionals in state-of-the-art cancer care which is needed to address cancer rates within Kentucky and the region. A rich cadre of seminars symposia meetings and career enrichment activities facilitate successful career development for all individuals engaged in cancer research and clinical practice. The MCCs collective efforts draw on vital institutional training resources to achieve the overarching goals of this program which are to guide cohesive growth and coordinate transdisciplinary education and mentoring endeavors across the MCC and integrate them with efforts campus-wide and nationally. Through coordination supported by MCCs Cancer Center Support Grant this comprehensive program will continue to evolve innovative curricula and strategically linked initiatives to prepare trainees and faculty for evolving cancer career opportunities.

project_terms:
Academic Training;Address;American Cancer Society;Award;Basic Science;Cancer Center;Cancer Center Support Grant;Centers of Research Excellence;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Complement;Dedications;Development;Education;Education Projects;Educational Activities;Educational Curriculum;Electronics;Evolution;Extramural Activities;Faculty;Fostering;Funding;Goals;Grant;Growth;Health Professional;High School Student;Individual;Institution;Kentucky;Link;Malignant Neoplasms;Medical Residency;Mentors;Mentorship;Middle School Student;NCI Center for Cancer Research;Population;Population Research;Postdoctoral Fellow;Research Personnel;Research Project Grants;Research Training;Resources;Rural Appalachia;Science;Structure;Training;Training Programs;Training and Education;Translating;Translational Research;United States National Institutes of Health;Universities;Youth;anti-cancer research;base;cancer care;career;career development;clinical practice;educational atmosphere;health training;high school;innovation;interest;investigator-initiated trial;meetings;programs;research faculty;symposium;undergraduate research experience;undergraduate student


application_id: 11146676
project_number: 5P30CA177558-13
project_title: Cancer Center Administration
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F
subproject_number: 5461
contact_pi_person_id: 78871078
contact_pi: ROGERS, JENNIFER F
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Markey Cancer Center (MCC) Administration provides efficient administrative support to MCCs Director Senior Leadership Research Program leaders Shared Resource Facility (SRF) directors and MCC members. Administration fosters exceptional science and impact through the following Specific Aims: 1) Lead MCCs planning and evaluation efforts; 2) Foster collaboration through inter- and intra-programmatic activities and investing in and leveraging resources and infrastructure; 3) Support MCCs comprehensive research education and community outreach activities; and 4) Support sustainability and business planning. During the current reporting period Administration has facilitated member science through: 1) creating a new FY24-28 MCC Strategic Plan which is coupled with a $64.4M financial commitment and investment from UK Leadership in the cancer center; 2) assisting in the restructuring of MCCs Research Programs; 3) expanding MCCs Research Communications Office in key areas to continue robust support of CCSG-related activity; 4) driving a 128% expansion of MCCs Clinical Protocol and Data Management teams which paved the way for a 56% increase in accruals to interventional treatment trials; 5) overseeing a 78% expansion of MCCs physical space which has grown from 128587 sq. ft. to 228237 sq. ft. since 2009; 6) facilitating all MCCs pilot and seed award programs which have awarded $2.2M to investigators since 2018; 7) streamlining the membership application and review process; and 8) improving MCCs internal and external communication channels ranging from upgrades to MCCs public-facing website to establishing new channels for internal communication among staff leaders. To enhance cancer focus Administration created and implemented a center-wide policy on determining cancer-relatedness of all grants and contracts listed on Data Table 2. Together these efforts supported an increase in peer-reviewed funding of $11.1M since 2017 and the addition of 66 new cancer center members. Over the coming five years Administration will work closely with the MCC Director and Senior Leaders to: 1) implement and evaluate the centers FY24-28 Strategic Plan; 2) implement the planned expansion of MCCs capabilities to lead multi-site clinical trials which represents a $2.2M commitment from the center to build out this new competency; 3) expand MCCs faculty and staff recruitment and retention practices; 4) expand reporting and analysis capabilities and achieve greater efficiency through the implementation of CCSG data and electronic regulatory systems; and 5) facilitate planning efforts for an advanced ambulatory building site work for which is slated to begin in late fall 2022. Through robust planning and evaluation efforts Administration will lead the alignment of MCC functions in support of the centers Comprehensive Cancer Center status.

project_terms:
Administrative Efficiency;Area;Automobile Driving;Award;Businesses;Cancer Center;Cancer Center Support Grant;Clinical Cancer Center;Clinical Data;Clinical Protocols;Collaborations;Communication;Community Outreach;Competence;Comprehensive Cancer Center;Contracts;Coupled;Data;Education and Outreach;Electronics;Evaluation;Faculty;Fostering;Funding;Grant;Infrastructure;Intervention;Investments;Kentucky;Lead;Leadership;Malignant Neoplasms;Multi-Institutional Clinical Trial;NCI Center for Cancer Research;Peer Review;Policies;Process;Reporting;Research;Research Personnel;Resource Sharing;Resources;Science;Site;Strategic Planning;System;Universities;Work;cancer research center director;data management;falls;improved;member;programs;recruit;square foot;treatment trial;web site


application_id: 11146675
project_number: 5P30CA177558-13
project_title: University of Kentucky Markey Cancer Center Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2025-09-05
opportunity_number: PAR-21-321
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1-RTRB-F(M1)
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Markey Cancer Center (MCC) is a university-based matrix cancer center at the University of Kentucky (UK) with a mission to reduce cancer incidence and mortality with a focus on Kentucky through research prevention treatment education and community engagement. As the only National Cancer Institute (NCI)-designated Cancer Center in the state the MCC is vital to Kentucky the U.S. leader for highest all-site cancer incidence and mortality. Notably recognition of the extraordinary disease rates in Kentuckys populations as a significant underpinning of that national ranking shapes the MCC vision and goals and drives its unique focus on prevalent cancers and cancer risk factors in the catchment population. Over $569M in state institutional and philanthropic investment since 2009 has supported significant research and resource expansion propelling new faculty recruitment program development clinical and shared resource space renovations new state-of-the art instrumentation and statewide education and community outreach. MCCs 159 members align with one of three MCC Research Programs: Cancer Prevention and Control Molecular and Cellular Oncology and Translational Oncology and are supported by seven Shared Resource Facilities that facilitate cutting-edge research via robust infrastructure specialized expertise and advanced methods: Biospecimen Procurement and Translational Pathology Biostatistics and Bioinformatics Cancer Research Informatics Flow Cytometry and Immune Monitoring Oncogenomics Patient-Oriented and Population Sciences and Redox Metabolism. Significant achievements in this funding period include an increased research depth and breadth as indicated by increased total cancer-relevant funding (41%) peer-reviewed funding (35%) and NCI funding (55%). Expanded transdisciplinary collaborations driven in part through a strategic focus on precision medicine and a more streamlined translational pipeline resulted in 26 new therapeutic trials 8 concepts or devices in Phase I or II clinical trials 10 agents or devices undergoing in vivo validation 43 patent applications and 17 patents during the current funding periodall based on MCC science. In collaboration with other U.S. and international cancer centers the number of U- and P-series grants awarded to the MCC increased by 80%. The number of member publications increased by 28% (total of 1093) with 62% of the publications with cancer investigators at other institutions. Expanded education and training initiatives include a new NCI T32 focused on rural cancer health a new NCI R25 Youth Enjoy Science award to engage Appalachian students in cancer research and two new training programs. With unique research strengths and integrated statewide community outreach and engagement MCCs programs provide robust capacity to deliver transformative interventional research to Kentuckys underserved populations thereby contributing to national efforts to conquer cancer through discovery and clinical translation cancer prevention and community outreach.

project_terms:
Acceleration;Achievement;Address;Appalachian Region;Award;Basic Science;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Clinical;Clinical Trials;Collaborations;Community Outreach;Development;Devices;Disease;Education;Education and Outreach;Epigenetic Process;Faculty Recruitment;Flow Cytometry;Funding;Genetic;Goals;Grant;Health;Immunologic Monitoring;Incidence;Informatics;Infrastructure;Institution;International;Intervention;Intervention Studies;Investments;Kentucky;Legal patent;Malignant Neoplasms;Mediator;Mentors;Metabolic;Metabolism;Methods;Mission;NCI Center for Cancer Research;National Cancer Institute;Outcome;Oxidation-Reduction;Pathology;Patients;Peer Review;Phase;Population;Population Sciences;Positioning Attribute;Prevalence;Prevention;Program Development;Publications;Quality of life;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Rural;Science;Scientist;Series;Services;Shapes;Signal Transduction;Students;Therapeutic Clinical Trial;Therapeutic Trials;Training;Training Programs;Training and Education;Translating;Translational Research;Underserved Population;Universities;Validation;Vision;Youth;anti-cancer research;cancer care;cancer genomics;cancer prevention;cancer risk;cancer site;cancer survival;cellular oncology;clinical practice;clinical translation;community engagement;expectation;improved;in vivo;innovation;instrumentation;interdisciplinary collaboration;member;molecular oncology;mortality;next generation;novel therapeutics;patient oriented;personalized diagnostics;personalized therapeutic;precision medicine;programs;translational impact;translational oncology;translational pipeline;treatment response

public_health_relevance:
As the only NCI-designated Cancer Center in Kentucky the University of Kentucky Markey Cancer Center serves a statewide catchment area with a population of 4.4 million residents and extraordinary cancer prevalence. In its mission to reduce cancer incidence and mortality with a focus on Kentucky through research prevention treatment education and community engagement the center has made and will continue to make significant strides in advancing access to quality cancer care; implementing bold transformational research spanning basic translational and population science including clinical trials to address Kentuckys unique cancer rates; and introducing innovative population-level interventions to accelerate translational impact and significantly impact patients in the state and the nation.


application_id: 11146441
project_number: 5R01ES035133-03
project_title: Pre- and postnatal chemical mixture exposure adolescent sleep health and allostatic load
administering_ic: NIEHS
award_notice_date: 2025-08-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: ES
serial_number: 035133
program_official: GRAY, KIMBERLY A
project_start_date: 2023-09-12
project_end_date: 2028-06-30
study_section: Reproductive, Perinatal and Pediatric Health Study Section[RPPH]
contact_pi_person_id: 14131718
contact_pi: SEARS, CLARA G
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTA majority of U.S. adolescents are not getting sufficient sleep for optimal health. Sleep health is critical duringadolescence because of rapid neurodevelopment growth and body composition changes. Moreoverinadequate and poor-quality sleep can increase allostatic load or cumulative physiological wear and tear fromdisruptions across multiple regulatory systems that coordinate immune cardiovascular and metabolic function.Evidence indicates that developmental exposures to ubiquitous environmental toxicants may disruptneurobiological mechanisms that regulate sleep and allostasis. However whether these exposures aremodifiable risk factors for poor sleep during adolescence has not been rigorously examined. Our multidisciplinaryproject brings together experts in pediatric environmental health sleep and cardiometabolic health to identifywhether early life exposure to environmental toxicant mixtures disrupts adolescent sleep health and increasesallostatic load. This project focuses on mixtures of phthalates per-/polyfluoroalkyl substances (PFAS) andmetals. Most pregnant people infants and children are exposed to mixtures of these toxicants through diet andconsumer goods. The project leverages existing and new data from two well-characterized prospectivepregnancy and birth cohorts the Health Outcomes and Measures of the Environment (HOME) Study and theMaternal-Infant Research on Environmental Chemicals (MIREC) Study. Both cohorts previously enrolledpregnant women and followed children until ages 7-9 (MIREC n=300) or 10-12 (HOME n=256) years withadditional visits underway at ages 10-12 (MIREC) and 16-18 (HOME) years. Sleep characteristics will beexamined at two timepoints in both cohorts using actigraphy. We will quantify relations between environmentaltoxicant biomarkers during gestation early childhood school age and adolescence with sleep characteristics(Aim 1) and allostatic load (Aim 2) during adolescence. We will also examine whether exposure to environmentaltoxicant mixtures is associated with hypothalamus-pituitary-adrenal (HPA) activity catecholamines andsystemic inflammation biological intermediates of sleep-wake regulation and allostasis (Aim 3). Our analyseswill identify individual and joint effects of environmental toxicant mixtures and examine periods of heightenedsusceptibility during critical developmental periods. Identifying modifiable environmental factors that contributeto poor sleep health and allostatic load may inform novel interventions to reduce the risk of cardiovasculardisease the leading cause of morbidity and mortality in adulthood worldwide.

project_terms:
Adolescence;Adolescent;Adolescent Development;Adrenal Glands;Adult;Age;Biological;Biological Markers;Biometry;Birth;Body Composition;Cardiovascular system;Catecholamines;Characteristics;Chemicals;Child;Childhood;Cortisone;Data;Development;Diet;Disease;Enrollment;Environment;Environmental Exposure;Environmental Health;Environmental Risk Factor;Epidemiology;Exposure to;Foundations;Glycoproteins;Goals;Growth;Hair;Health;Homeostasis;Hydrocortisone;Hypertension;Hypothalamic structure;Immune;Individual;Infant;Inflammation;Intervention;Joints;Knowledge;Life;Link;Longitudinal Studies;Longitudinal cohort;Measures;Metabolic;Metals;Middle School Student;Morbidity - disease rate;Neurobiology;Neurosecretory Systems;Obesity;Outcome;Outcome Measure;Pathway interactions;Physiological;Pituitary Gland;Pituitary-Adrenal System;Poly-fluoroalkyl substances;Predisposition;Pregnancy;Pregnant Women;Process;Prospective cohort;Questionnaires;Research;Risk;Risk Factors;Risk Reduction;School-Age Population;Serum;Shapes;Sleep;Special Supplemental Nutrition Program for Women Infants and Children;System;Testing;Toxic Environmental Substances;Toxicant exposure;Visit;actigraphy;adequate sleep;allostasis;allostatic load;blood pressure elevation;cardiometabolism;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;cohort;consumer product;critical developmental period;design;early childhood;early life exposure;environmental chemical;high school;improved;improvement on sleep;indexing;infancy;modifiable risk;mortality;multidisciplinary;neurobiological mechanism;neurodevelopment;neurotoxic;novel;phthalates;pollutant;poor sleep;postnatal;prenatal;prospective;public health intervention;sleep health;sleep quality;sleep quantity;sleep regulation;systemic inflammatory response;toxic metal;toxicant;urinary

public_health_relevance:
PROJECT NARRATIVEExposure to environmental toxicants during early life development may negatively impact sleep health duringadolescence. This project will examine whether mixtures of phthalates per-/polyfluoroalkyl substances (PFAS)and metals during gestation infancy childhood and adolescent development are related to poorer sleep andhigher allostatic load cumulative wear and tear from physiological disruptions. Understanding whetherenvironmental toxicants that are commonly found in consumer products and residential environments impactsleep characteristics may lay the foundation for novel interventions to improve health.


application_id: 11146347
project_number: 5T32CA261786-05
project_title: Addressing cancer challenges through impactful training
project_terms: Address;Malignant Neoplasms;Training
administering_ic: NCI
award_notice_date: 2025-08-21
opportunity_number: PA-20-142
application_type: 5
activity_code: T32
ic: CA
serial_number: 261786
program_official: LIM, SUSAN E
project_start_date: 2021-08-01
project_end_date: 2026-07-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The Addressing Rural cancer Inequities through Scientific Excellence (ARISE) program aims to provide transdisciplinary and translational postdoctoral research training in rural cancer prevention control and survivorship. To reduce Appalachian residents highest cancer morbidity and mortality rates in the nation University of Kentuckys (UK) behavioral cancer training efforts must develop a new generation of collaborative and rigorous scientists. Led by two well-established cancer researchers with extensive track records of training ARISE will meet this critical need by providing multifaceted training opportunities to well-qualified postdoctoral scholars in applied behavioral science including intervention and dissemination and implementation science. Training will emphasize translating knowledge of risk factors into evidence-based behavioral interventions across the cancer spectrum (prevention to survivorship) for rural residents. ARISE trainees will select one of three thematic behavioral cancer tracks: environment risk behavior and health care delivery. We will recruit two trainees each year for a two- year fellowship. The training program based in the Center for Health Engagement and Transformation will operate in close collaboration with UKs National Cancer Institute-designated Markey Cancer Center; Center for Clinical and Translational Science; Center for Appalachian Research in Environmental Sciences; Office of Postdoctoral Affairs; Office of the Vice President for Research and departments across UKs 16 colleges. The 25 preceptors co-mentors and methodology mentors include well-funded investigators in transdisciplinary research with established collaborative relationships representing complementary areas of expertise including behavioral science; environmental carcinogenesis; clinical and translational research; and intervention and implementation science. Additional mentoring includes geospatial analysis mHealth and cluster randomized designs. Each trainee will have a mentoring committee with one primary mentor in her/his specified track and two secondary mentors with one from another track and a methodology mentor. Trainees will participate in a rigorous structured program that includes formal coursework training in the responsible conduct of research and workshops and seminars. Trainees will gain career development experiences and build a professorial network through scientific writing; presentations; grant preparation and review; and leadership opportunities. Special programming designed to improve expertise in rural cancer challenges includes research shadowing experience a personalized rural cancer patient experience and attendance at conferences. We will track trainee progress and mentor support through detailed annual evaluation.

public_health_relevance:
Addressing Rural cancer Inequities through Scientific Excellence (ARISE) is a postdoctoral training program at the University of Kentucky that will be a collaboration among the Center for Health Engagement and Transformation (CHET) the NCI-designated Markey Cancer Center (MCC) Center for Clinical and Translational Science (CCTS) UK Center for Appalachian Research in Environmental Sciences (UK-CARES) six colleges and 10 departments to provide interdisciplinary training in behavioral cancer research. The training program will have three tracks environment risk behavior and health care delivery and will provide didactic research experience and mentoring.


application_id: 11146053
project_number: 1R01AR084850-01A1
project_title: Regulation of Myonuclear Turnover Dynamics in Multinucleated Muscle Cells
administering_ic: NIAMS
award_notice_date: 2025-08-22
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AR
serial_number: 084850
suffix: A1
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2025-09-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZRG1 MSOS-L (05)]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: KIRBY, TYLER
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummarySkeletal muscle is comprised of post-mitotic multinucleated cells that are long-lived and must be maintainedfor the duration of an organisms lifespan. Effective tissue maintenance requires the turnover of damagedproteins and organelles including the nucleus. Recent findings clearly demonstrate that muscle stem cellscontinue to fuse into muscle fibers throughout adulthood yet the number of myonuclei remains constant acrossthe lifespan suggesting that there must be an opposing mechanism to degrade myonuclei. However nomechanism to selectively target and degrade a myonucleus has yet been identified leading to the longstandingdebate over whether entire myonuclei can be degraded and turned over. The project's overarching goal is todefine the rate of myonuclear turnover in adult skeletal muscles identify the mechanisms by which myonucleiare degraded and unravel the targeting complexes and cellular pathways involved in this process. The centralhypothesis is that accumulation of unrepairable nuclear damage leads to myonuclei undergoing turnover inadult muscle fibers through nucleophagy. This hypothesis stems from our preliminary data using a uniquemouse model that exhibits significant myonuclear and DNA damage due to a loss-of-function in lamin A and Cproteins. Using this model our preliminary data demonstrates that nuclear damage results in enhancedmyonuclear turnover with damaged myonuclei being enriched in autophagic markers but not apoptoticmarkers. The project comprises three specific aims: firstly determining the rate of myonuclear turnover acrossdifferent muscles and whether this rate changes with physical activity and aging; secondly exploring whethermyonuclear damage triggers turnover utilizing transgenic mouse models to induce myonuclear-specificdamage; and finally investigating the mechanism behind myonuclear degradation with a focus onnucleophagy. Findings from this project could fundamentally change how we think about myonuclear andgenomic maintenance during skeletal muscle aging with additional relevance for the long-term effectiveness ofgene therapy treatments for muscular diseases.

project_terms:
Adaptor Signaling Protein;Address;Adult;Age;Aging;Apoptotic;Autophagocytosis;Autophagosome;Biology;Cardiac Myocytes;Cell Aging;Cell Nucleus;Cell fusion;Cells;Cellular biology;Complement;Complex;DNA;DNA Damage;Data;Effectiveness;Event;Excision;Excision Repair;Exercise;Exhibits;Fluorescent in Situ Hybridization;Frequencies;Genetic;Genome Stability;Genomic DNA;Genomics;Giant Cells;Goals;Health;Homeostasis;Immunoprecipitation;Inhibition of Apoptosis;Knowledge;Lamin Type A;Longevity;Maintenance;Mitochondria;Modeling;Mouse Strains;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle satellite cell;Mutation;Myopathy;Neurons;Nuclear;Nuclear Envelope;Nuclear Lamina;Nuclear Proteins;Organelles;Organism;Pathway interactions;Physical activity;Population;Process;Proteins;Proteomics;RNA;Regulation;Reporter;Resolution;Rest;Signal Transduction;Skeletal Muscle;Testing;Therapeutic Intervention;Time;Tissues;Transgenic Mice;age-related disease;aging process;citrate carrier;env Gene Products;gene therapy;imaging approach;lamin C;life span;loss of function;mouse model;muscle aging;muscle progenitor cell;novel;pharmacologic;postmitotic;prevent;rate of change;receptor;response;sex;single nucleus RNA-sequencing;stem;stem cells

public_health_relevance:
NarrativeMaintaining healthy skeletal muscles is crucial for health and longevity. This project aims to address a criticalgap in our understanding of skeletal muscle biology by determining the extent and underlying mechanism ofmyonuclear turnover under resting conditions with age or in response to exercise. This project has importantimplications for the maintenance of muscle quality during the aging process and furthermore for the potentiallong-term efficacy of gene therapy strategies for treating muscle diseases.


application_id: 11145769
project_number: 5R01AA030308-03
project_title: Sex and Sex Hormone Factors Influencing Acute Alcohol Effects on Sleep Physiology
administering_ic: NIAAA
award_notice_date: 2025-08-25
opportunity_number: PA-20-184
application_type: 5
activity_code: R01
ic: AA
serial_number: 030308
program_official: KUMAR, SHAILESH
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS]
contact_pi_person_id: 12510124
contact_pi: WHITEHURST, LAUREN
other_pis: WEAFER, JESSICA J
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Rates of heavy drinking and Alcohol Use Disorder (AUD) are increasing in women at an alarming pace. Suchdrastic increases in drinking will have a significant negative impact on womens health. Unfortunately untilrecently heavy drinking has been considered a male-oriented problem and consequently research on alcohol-related harms in women has been minimal. One specific aspect of womens health that may be negativelyaffected by alcohol is sleep. Numerous studies in men show that although alcohol has an initial sedative effectit leads to frequent awakenings and impaired rapid eye movement sleep in the second half of the night.Preliminary evidence suggests that women experience similar impairment and that they may be even moresensitive to alcohol-disrupted sleep than men. Further in the general population women are at greater risk forinsomnia and sleep disturbances than men in part because womens sleep is sensitive to fluctuations inovarian hormones. Hormonal influences on sleep are especially pronounced in older women of latereproductive age. However the influence of sex and sex hormones on alcohol-disrupted sleep across thereproductive lifespan in women is unknown. Here we will determine the influence of sex menstrual cyclephase and sex hormones on alcohol-disrupted sleep in adults across the reproductive age range for women.Healthy women and men (age 21-45) will complete two pairs of experimental sessions in which they receive adose of alcohol (target BrAC = 100mg% intravenous) or placebo (saline) one hour prior to eight hours ofpolysomnographically-monitored sleep in the lab. Women will complete one alcohol-placebo session pairduring the mid-follicular phase of the menstrual cycle and one pair during the late luteal phase. Men willcomplete two session pairs at matched intervals. Participants will also complete two 5-day at-home monitoringperiods of naturalistic sleep and alcohol consumption patterns during the mid-follicular and late luteal phases.Sleep and alcohol use will be assessed with actigraphy daily sleep and wake diaries and alcohol wristsensors. We hypothesize that women will show greater disruption of sleep following alcohol than men and thatalcohol-disrupted sleep measured in lab with polysomnography and at-home with actigraphy will be morepronounced in the late luteal phase compared to the mid-follicular phase. We also expect that estradiol will benegatively associated with alcohol-disrupted sleep whereas progesterone will be positively associated withalcohol-disrupted sleep. This study will provide essential information regarding alcohol effects on sleep acrossthe reproductive age span in women and critically how these effects are moderated by sex menstrual cycleand fluctuations in sex hormones. Findings will directly inform future interventions aimed at reducing alcoholconsumption and the negative impacts of alcohol on sleep in women. Given the wide-ranging impact of sleepon other areas of function including cognition stress and well-being such interventions will have a substantialpositive impact on womens health.

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

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


application_id: 11145607
project_number: 5F31AI186545-02
administering_ic: NIAID
award_notice_date: 2025-08-05
opportunity_number: PA-23-272
application_type: 5
activity_code: F31
ic: AI
serial_number: 186545
program_official: GONDRE-LEWIS, TIMOTHY A
project_start_date: 2024-07-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZRG1-F05-D(21)L]
contact_pi_person_id: 78325660
contact_pi: KAISER, CATHERINE
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_title:
Comprehensive Characterization of LVV Integration and Impact on Host Cell Biology using Novel Genomic Technologies

project_abstract:
PROJECT SUMMARYLentiviral vectors (LVVs) are an effective gene therapy agent due to their ability to integrate into host DNAproviding stable expression of transgenes. LVVs have been under clinical development as a gene deliverysystem to treat diseases including blood cancers through the generation of chimeric antigen receptor (CAR) T-cells. The first two CAR T-cell therapies were approved for clinical use in the treatment of lymphoma or acutelymphoblastic leukemia in 2017 and since then four more CAR T-cell therapies have been approved by the Foodand Drug Administration (FDA) for clinical use. Despite the success of these agents on November 28 2023 itwas announced that all clinically approved CAR T-cell therapies were under FDA investigation due to theemergence of cellular transformation in patients receiving LVV-derived CAR T-cells leading to cancers andresulting in hospitalization or death. While much work has been done to define LVV integration profiles such asthe identification of preferential integration into intronic genomic elements it is still thought to be a mostly randomprocess. For example LVV integration has been seen in promoters transcription start sites exons anduntranslated regions resulting in differential gene expression and alternative splicing patterns when comparedto untransduced controls. Standard methods for characterizing integration profiles such as ligation-mediatedPCR (LM-PCR) remain constrained by short read lengths and only identify the integration sites but provide noinformation regarding the proviral integrity. Short-read sequencing is limiting in situations of integration into lowcomplexity or repeat-rich genomic areas that cannot be efficiently mapped with these data. Additionally LM-PCR and other common methods require priming from long-terminal repeat regions; however integratedlentiviral genomes contain large deletions including in some cases missing LTRs that would not be captured bycurrent methods and may result in incomplete transgene expression from that event. To address this unmetneed we developed a novel method single-molecule real-time capture (SMRTcap) that leverages long readsto resolve integrated lentiviral genomes. We hypothesize that current methods for resolving LVV integration areincomplete thereby limiting our ability to comprehensively characterize LVV integration sites proviral integrityand their impact on host cell biology. Using SMRTcap we will resolve LVV integrations in experimentally-generated primary CAR T-cells providing a complete view of integration sites clonal expansion and presenceof intact transgenes. Using single-cell (sc-) isoform sequencing (IsoSeq) and sc-RNA seq on these same CART-cells we will evaluate the influence of LVV integration on host gene expression splicing and isoform usage.These data will provide a comprehensive view of LVV integration into primary T cells and the impact of this eventon the host genome and host cell biology. These new insights are expected to contribute to vector safety profilingand provide critical understanding regarding LVV-related transformations in LVV-treated individuals.

project_terms:
Acute Lymphocytic Leukemia;Address;Alternative Splicing;Area;B lymphoid malignancy;Biological Assay;CAR T cell therapy;CBL gene;Cell Nucleus;Cells;Cellular biology;Cessation of life;Clinical;Clinical Trials;Clonal Expansion;Complementary DNA;Cytoplasm;DNA;Data;Dependence;Development;Disease;Disease remission;Elements;European;Event;Exons;Frequencies;Gene Expression;Gene Expression Regulation;Gene Therapy Agent;Gene set enrichment analysis;Generations;Genes;Genetic Transcription;Genome;Genomic Segment;Genomics;Hematopoietic Neoplasms;Hemoglobinopathies;Hospitalization;Human;Immune;Individual;Insertional Mutagenesis;Integrase;Intercistronic Region;Investigation;Length;Lentivirus;Lentivirus Vector;Ligation;Long Terminal Repeats;Lymphoma;Malignant Neoplasms;Maps;Mediating;Medicine;Methods;Molecular;Multiple Myeloma;Oncogenic;Outcome;Pathway interactions;Patients;Pattern;Process;Protein Isoforms;Provirus Integration;Proviruses;RNA;RNA Splicing;Reporting;Reproducibility;Resolution;Retroviridae;Reverse Transcription;Risk;Role;Safety;Sickle Cell Anemia;Spliced Genes;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Tissue-Specific Gene Expression;Transcription Initiation Site;Transcription Process;Transgenes;Translating;United States Food and Drug Administration;Untranslated Regions;Viral;Work;cell envelope;chimeric antigen receptor T cells;clinical development;gene delivery system;genotoxicity;insight;integration site;interest;knowledge integration;lentiviral integration;life span;metaplastic cell transformation;next generation sequencing;novel;promoter;single molecule;single-cell RNA sequencing;success;transgene expression;tumorigenesis;vector;viral RNA

public_health_relevance:
PROJECT NARRATIVELentiviral vectors (LVVs) are Food and Drug Administration (FDA) approved for clinical use as gene deliverysystems and therapeutics; however on November 28 2023 it was announced that all clinically approved LVV-transduced chimeric antigen receptor (CAR) T-cell therapies are under FDA investigation due to oncogenicdevelopment resulting in hospitalization or death. Current methods used for characterizing LVV integrationremain limited and cannot resolve events in highly repetitive genomic regions or provide information regardingtransgene intactness making it likely that integration events are not fully described. We aim to use a novel long-read enrichment method SMRTcap to comprehensively characterize LVV integration profiles and transgeneintegrity in experimental CAR T-cells while also evaluating the impact of these events on host gene regulationand splicing.


application_id: 11144998
project_number: 5K26DK138370-03
project_title: Initiate Research Opportunities and Networks for Early Career Investigators (IRON)
administering_ic: NIDDK
award_notice_date: 2025-08-18
opportunity_number: RFA-DK-22-012
application_type: 5
activity_code: K26
ic: DK
serial_number: 138370
program_official: LI, YAN
project_start_date: 2023-09-15
project_end_date: 2025-09-02
study_section: ZDK1-GRB-1(O3)
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This current proposal is in response to NIDDKs awareness and need for developing the next generation of biomedical researchers to achieve its mission. Hence early career investigators need the opportunity to gain research knowledge coupled with quality mentorship to assist with the proper application of those skills resulting in innovative and meaningful research. In addition to providing mentorship on research skills it is also important to understand the circumstances in which early career investigators have found themselves and work to develop needed soft (non-research) skills. In some cases mentees may need to unlearn learn and relearn certain behaviors and habits to be successful. Taken together my philosophy as a mentor is to provide experiences for early career investigators that will help them develop into well-rounded individuals who contribute to advancing science as well as be exemplary of reputable citizens in academe. To achieve this goal I am committed to the following specific aims: Aim 1: Continue to develop and hone mentoring skills that will equip me to meaningfully contribute to the career development and advancement of early-stage investigators. I will participate in mentor-focused trainings and workshops offered nationally as well as those offered regionally and locally by my institution. Aim 2: Use funded research to provide opportunities for mentees to gain hands-on experience in community-based research health inequities and research addressing social determinants of health that are aligned with NIDDKs mission as well as develop soft skills necessary to navigate a research career in academe. Funded research aligned with NIDDKs mission will be utilized to provide teachable moments in research design responsible conduct of research data management team science and dissemination of research findings. During these interactions I will work with mentees to identify and cultivate soft skills that need development for future success. Aim 3: Provide training and networking opportunities for mentees. I will utilize resources provided by this grant to identify training and workshops that will assist mentees with developing research and leadership skills attending scientific meetings and participating in networking events.

project_terms:
Address;Awareness;Behavior;Career Mobility;Coupled;Development;Educational workshop;Event;Funding;Future;Goals;Grant;Habits;Individual;Institution;Knowledge;Leadership;Learning;Mentors;Mentorship;Mission;National Institute of Diabetes and Digestive and Kidney Diseases;Philosophy;Research;Research Design;Research Personnel;Resources;Science;Training;Work;career;career development;community based research;data management;early experience;experience;health inequalities;innovation;meetings;next generation;response;responsible research conduct;skills;social health determinants;success

public_health_relevance:
Early career investigators need the opportunity to gain research knowledge coupled with quality mentorship to assist with the proper application of those skills resulting in innovative and meaningful research. In addition to providing mentorship on research skills it is also important to understand the circumstances in which early career investigators have found themselves and work to develop needed soft (non-research) skills. Taken together my philosophy as a mentor is to provide experiences for early career investigators that will help them develop into well-rounded individuals who contribute to advancing science as well as be exemplary of reputable citizens in academe


application_id: 11144523
project_number: 5R35ES032876-05
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2025-09-16
opportunity_number: RFA-ES-20-009
application_type: 5
activity_code: R35
ic: ES
serial_number: 032876
program_official: CARLIN, DANIELLE J
project_start_date: 2021-08-01
project_end_date: 2029-06-30
study_section: ZES1-LWJ-D(R3)
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTLung cancer is the leading cause of cancer death with little improvement in survivability over many decades.Understanding and support for lung cancer have suffered from the stigma that the disease is merely aconsequence of tobacco use when in fact other agents are a major factor in the disease. Many people with lungcancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However whilelung cancer kills more people than colon breast and prostate cancer combined it receives less federal fundingthan each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All establishedlung carcinogens cause CIN yet the mechanisms for how they do have received little attention. Metal exposureis a worldwide health concern. Metals cause lung cancer and carcinogenic metals are a component in tobacco.Metals are poor mutagens but potently induce CIN yet how metals cause lung cancer and CIN is poorlyunderstood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induceCIN in lung cancer. We use hexavalent chromium [Cr(VI)] a human lung carcinogen of major public healthconcern as our primary metal of interest although we will compare Cr(VI) outcomes with other metal lungcarcinogens. We will study how Cr(VI) induces structural and numerical CIN considering human lung fibroblastepithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types tomore complex three-dimensional mixed cell culture studies. We enhance and deepen our understanding ofthese mechanisms with a One Environmental Health approach which leverages the ability of wildlife to resistCr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover we maximize theimpact of these findings by translating our outcomes into animals and into a powerful and unique collection ofhuman subjects and populations ranging from workers with primarily Cr(VI) exposure to workers with a mixedmetal exposure including Cr. This combined approach of humans animals and cell lines with One EnvironmentalHealth tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particularwe will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable atthe cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus ourproposed R35 program will revolutionize our understanding of Cr(VI) CIN metal carcinogenesis and lungcancer while also providing important insights for other cancers that involve CIN. Outcomes will include majorscientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic;2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells thathave transformed and 4) how to prevent neoplastic change from occurring leading to improved risk assessmenttreatments and health outcomes for people exposed to metals.

project_terms:
3-Dimensional;Animals;Attention;Cancer Etiology;Carcinogens;Cell Line;Cells;Cessation of life;Chromosomal Instability;Collection;Colon Carcinoma;Complex;Disease;Environmental Health;Epithelium;Event;Fibroblasts;Funding;Health;Heritability;Human;Individual;Lung;Malignant Breast Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Metal Carcinogenesis;Metal exposure;Metals;Minority;Mutagens;Neoplastic Cell Transformation;Outcome;Persons;Population;Public Health;Risk Assessment;Tobacco;Tobacco use;Translating;United States;carcinogenicity;cell type;chromium hexavalent ion;human subject;improved;induced pluripotent stem cell;insight;interest;mixed cell culture;neoplastic;novel;novel strategies;prevent;programs;social stigma;stem cell model;tobacco user;tool

public_health_relevance:
PROJECT NARRATIVELung cancer is the number one cause of cancer death in the United States and metals are a major cause of thedisease. Our study focuses on how hexavalent chromium a metal with widespread exposure known to causelung cancer causes chromosome instability a hallmark event in lung cancer. Our findings will transform ourunderstanding of how metals cause chromosome instability and lung cancer which may spur new potentialtreatment targets new approaches to reduce and prevent metal-induced lung cancer and new insights to betterdetermine and manage safer exposure levels for this major public health concern.


application_id: 11144270
project_number: 5R01NS133250-03
project_title: Bisphenol-Induced Blood-Brain Barrier Dysfunction in Alzheimers Disease
administering_ic: NINDS
award_notice_date: 2025-07-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 133250
program_official: YIN, XILING
project_start_date: 2023-09-15
project_end_date: 2028-07-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
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:
Identifying environmental risk factors for Alzheimers Disease (AD) is critical to mitigate cognitive decline inhumans. We provide first evidence showing that endocrine disrupting bisphenols (BP) are clinically relevantenvironmental risk factors for AD. Human exposure to BPA and the bisphenol analogs BPF and BPS is inevitabledue to their ubiquitous presence in the environment. Our data show that BPA triggers blood-brain barrierdysfunction and cognitive impairment both hallmarks of AD indicating that environmental BPs are a critical yetunderrecognized AD risk factor. Key characteristics of BP-induced barrier dysfunction include: 1) loss of theamyloid-beta (Ab) clearance transporter P-glycoprotein (P-gp) and 2) development of barrier leakage. Both thesefactors contribute to a pathological cascade that leads to cognitive decline in AD. While there is evidence thatBP exposure results in a dysfunctional barrier the mechanism underlying this phenomenon is unknown and keymechanistic data linking BPs and AD are not available which hinders our understanding of environmental riskfactors for AD. In this application we address this critical unmet need and propose to define the relevance ofBPs as risk factors for AD. Our objective in this proposal is to define signaling steps through which BPs inducebarrier dysfunction and contribute to cognitive decline in AD. Based on preliminary data our central hypothesisis that BPs induce barrier dysfunction increase Ab levels and enhance cognitive decline in an AD model. Ourrationale for this research is that identifying the mechanism through which BPs induce barrier dysfunction andexacerbate cognitive impairment will provide proof-of-concept that endocrine disruptors are an environmentalrisk factor for AD. The hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanismresponsible for BP-induced barrier dysfunction. 2) Determine BP levels barrier dysfunction and cognition in ADpatients compared to CNI. 3) Develop a strategy to repair BP-induced barrier dysfunction and slow cognitivedecline in vivo. In Aim 1 we will identify signaling steps that lead to BP-induced P-gp loss and barrier leakage inisolated mouse brain capillaries and we will verify these findings in capillaries from KO mice and in isolatedhuman brain capillaries. In Aim 2 we will determine BP levels and the degree of barrier dysfunction BP levels inhuman tissue samples from cognitive normal individuals preclinical AD MCI and AD patients. In Aim 3 we willblock BP signaling to mitigate barrier dysfunction and evaluate the benefit of this strategy on slowing cognitivedecline in vivo in a mouse AD model. The proposed research is innovative because it represents a substantivedeparture from the status quo by shifting to a mechanism-driven approach focused on the impact endocrinedisruptors have on barrier function and cognition in AD. The proposed research is significant because it isexpected to create a paradigm shift in our understanding of the importance of environmental risk factors for AD.

project_terms:
ABCB1 gene;Abeta clearance;Address;Aging;Air;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Beverages;Blood brain barrier dysfunction;Blood capillaries;Brain;Characteristics;Cognition;Cognitive;Cognitive deficits;Data;Development;Dust;Endocrine Disruptors;Endocrine disruption;Environment;Environmental Impact;Environmental Risk Factor;Estrogen Receptor 2;Exposure to;Extravasation;FDA approved;Food;Fulvestrant;Functional disorder;Health;Human;Impaired cognition;Impairment;Individual;Knockout Mice;Knowledge;Link;Medical Device;Mission;Monkeys;Mus;National Institute of Environmental Health Sciences;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Outcome;Oxidative Stress;PIK3CG gene;Paper;Pathologic;Pharmaceutical Preparations;Plastics;Public Health;Research;Risk Factors;Rodent;Sampling;Signal Transduction;Soil;Testing;Time;Tissue Sample;Work;analog;burden of illness;cerebral capillary;clinically relevant;cognitive enhancement;drinking water;exposed human population;human tissue;in vivo;in vivo Model;innovation;neuron development;pre-clinical;repaired

public_health_relevance:
The proposed research is relevant to public health because it is expected to identify bisphenols as environmentalrisk factors for blood-brain barrier dysfunction and provide a mechanistic link between bisphenols barrierdysfunction and cognition in Alzheimers disease. Thus the proposed research is relevant to the missions ofthe NINDS the NIA and the NIEHS that pertain to developing fundamental knowledge of environmental impactson human health that will help promote healthier lives and reduce the burden of diseases and conditions relatedto aging.


application_id: 11144269
project_number: 5R01NS129668-03
project_title: Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans
administering_ic: NINDS
award_notice_date: 2025-07-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 129668
program_official: LEENDERS, MIRIAM
project_start_date: 2023-08-01
project_end_date: 2028-07-31
study_section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR]
contact_pi_person_id: 9428270
contact_pi: CHERRA, SALVATORE JAMES
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummarySynaptic development is a highly conserved process that underlies the functional connectivity of the nervoussystem. Deficits in synaptic development are associated with multiple neurological disorders like autismspectrum disorders intellectual disabilities epilepsy and schizophrenia. Therefore restoration of healthysynapse development in cases of neurodevelopmental disorders represents one goal for developing bettertreatments. However the lack of molecular targets to achieve this goal presents a significant barrier to thedevelopment of new therapies. Identifying the signaling pathways that promote or restore synapse developmentwill reveal new mechanisms for modulating neuronal circuit development and function. The overall goal for theproposed research is to uncover how a series of small GTPases coordinate synapse development at theCaenorhabditis elegans neuromuscular junction. The central hypothesis is that PXF-1 a Rap guanine nucleotideexchange factor promotes synapse development through the sequential activation of Rap Ras and RacGTPases to sustain perisynaptic actin filaments during neuromuscular development. To identify the molecularmechanisms that govern the putative GTPase signaling cascade we will use genetics and cell biology to identifythe guanine nucleotide exchange factors and GTPase activating proteins that modulate each GTPase in thepathway. We will use fluorescent biosensors and genetic engineering to elucidate the molecular mechanismsthrough which Rap Ras and Rac signaling pathways interact with one another. The proposed research isinnovative because it uses the powerful model system of Caenorhabditis elegans to study how GTPase networksfunction as molecular switches to control synapse development and motor circuit function. The development anduse of new molecular tools to observe and modulate signal transduction in vivo will provide additional innovationsfor cellular and molecular neuroscience. The studies proposed in this application are significant because theywill reveal how small G protein signaling networks promote synapse development and how modulation of theseGTPase signaling modules can mitigate neuronal circuit dysfunctions.

project_terms:
Actins;Affect;Alzheimer's Disease;Animals;Binding;Biochemistry;Biological Assay;Biological Models;Biophysics;Biosensor;Brain;Caenorhabditis elegans;Cellular biology;Complex;Data;Development;Dominant-Negative Mutation;Electron Microscopy;Electrons;Ensure;Epilepsy;F-Actin;Fluorescence Microscopy;Foundations;Functional disorder;Future;GTPase-Activating Proteins;Genetic;Genetic Engineering;Goals;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate Phosphohydrolases;Impairment;In Vitro;Intellectual functioning disability;Knowledge;Light;Maintenance;Measures;Microfilaments;Microscopic;Mission;Modeling;Molecular;Molecular Target;Monomeric GTP-Binding Proteins;Motor;Motor Neurons;Mutation;Nervous System;Nervous System Disorder;Nervous System Physiology;Neurodegenerative Disorders;Neurodevelopmental Disorder;Neuromuscular Junction;Neurons;Neurophysiology - biologic function;Neurosciences;Organism;Pathway interactions;Pervasive Development Disorder;Polymers;Presynaptic Terminals;Process;Proteins;Public Health;Regulation;Research;Schizophrenia;Series;Signal Pathway;Signal Transduction;Signaling Protein;Synapses;Synaptic Vesicles;United States National Institutes of Health;autism spectrum disorder;cholinergic;cholinergic neuron;cholinergic synapse;disability;improved;in vitro Assay;in vivo;innovation;insight;light microscopy;motor neuron development;mutant;nervous system development;neural circuit;neuromuscular;neuronal circuitry;new therapeutic target;novel therapeutics;polymerization;presynaptic;prevent;protein degradation;protein protein interaction;ras GTPase-Activating Proteins;restoration;synaptic function;therapeutic development;tool

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because it focuses on identifying new therapeutic targets forneurological disorders such as epilepsy autism spectrum or other pervasive developmental disorders.Determining how small G protein networks coordinate nervous system development and function will providesignificant advances in the understanding of brain function and nervous system disorders at a fundamental level.Therefore the proposed research is relevant to NIHs mission to seek fundamental knowledge about livingsystems and to reduce illness and disability.


application_id: 11143913
project_number: 5R01AA030485-04
administering_ic: NIAAA
award_notice_date: 2025-08-18
opportunity_number: RFA-AA-21-016
application_type: 5
activity_code: R01
ic: AA
serial_number: 030485
program_official: PERRUCCIO, ELIZABETH M
project_start_date: 2022-09-10
project_end_date: 2027-07-31
study_section: ZAA1-DD(17)V
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: HARRIS, LESLEY BETH;KERR, JELANI
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-01
project_title:
Alcohol Misuse Gut Microbial Dysbiosis and PrEP Care Continuum: Application and Efficacy of SBIRT Intervention

project_abstract:
Pre-exposure prophylaxis (PrEP) a medication regimen to reduce HIV transmission risk among HIV negativeindividuals has utility in helping to reach national HIV prevention goals. However clinical side effectsparticularly those impacting gastrointestinal (GI) (nausea vomiting loss of appetite) hepatic and renal injuryoutcomes may inhibit PrEP persistence. Importantly alcohol use which is frequent in PrEP users may interactwith PrEP and exacerbate PrEP-associated adverse GI effects and consequently affect PrEP persistence.Recent data implicates that these side effects are likely associated with changes in the gut microbiome(dysbiosis). Despite the important ramifications that PrEP alcohol and their combined use may have on thegut dysbiosis and subsequent PrEP continuance there is little research to elucidate this interaction and fewattempts to address it. Moreover there is little research exploring decision-making processes regarding alcoholand PrEP utilization and adherence among PrEP users. To address these gaps in research this study willemploy the following aims. Aim 1: Qualitatively explore mechanisms by which alcohol use impactsmovement through the PrEP continuum and understand how an early intervention and treatmentapproach impacts alcohol use and PrEP adherence. Aim 2: Investigate the effectiveness of the SBIRTintervention in preventing hazardous alcohol use and its impact on gut dysbiosis in PrEP users. Withinthis longitudinal cohort study we will identify alcohol impacted participants with patterns of useranging from episodic to long-term (engaging in risky or hazardous use). Aim 3: To determinealterations in the gut microbiome (dysbiosis) intestinal homeostasis systemic inflammation andmarkers of liver disease associated with hazardous alcohol use among PrEP users. Recruiting from localPrEP clinics we will determine alterations in the gut microbiome intestinal homeostasis systemic inflammationand markers of liver disease associated with alcohol and PrEP use. We will also execute a randomized controltrial among PrEP users demonstrating heightened alcohol use to test the effectiveness of the Screening BriefIntervention & Referral to Treatment (SBIRT) intervention to reduce alcohol use and examine subsequentimpact on the gut microbiome compared to individuals receiving treatment as usual and PrEP users notdemonstrating elevated alcohol use. Finally we will employ qualitative methods (in-depth interviews) andanalysis to understand decision-making factors influencing PrEP adherence and alcohol use over time. Prioritypopulations including those engaging in alcohol use need to increase engagement in the PrEP CareContinuum to optimize HIV prevention. Clinical research has yet to focus on interactions between PrEPalcohol use and GI adverse events. This study may have important implications for mitigating a salientchallenge to PrEP adherence and persistence (side-effects) and elucidating from clinical and publichealth standpoints factors promoting maintenance in the PrEP care continuum.

project_terms:
AIDS prevention;Address;Adherence;Adverse event;Affect;Alcohol abuse;Alcohol consumption;Alcohols;Ambulatory Care Facilities;Behavioral;Biological;Caring;Clinic;Clinical;Clinical Research;Continuity of Patient Care;Data;Data Collection;Decision Making;Early Intervention;Early treatment;Effectiveness;Event;Exhibits;Feedback;Goals;HIV;HIV Seronegativity;Health;Health Care;Individual;Injury to Kidney;Internal Medicine;Intervention;Interview;Intestinal permeability;Kidney Diseases;Liver diseases;Longitudinal Studies;Longitudinal cohort study;Maintenance;Movement;Nausea;Outcome;Participant;Pathogenicity;Pattern;Persons;Pharmaceutical Preparations;Population;Process;Public Health;Qualitative Methods;Randomized;Randomized Controlled Trials;Reaction;Regimen;Research;Research Personnel;Risk;Structure;Subgroup;Testing;Time;Treatment Effectiveness;Triage;Universities;Vomiting;alcohol measurement;alcohol misuse;alcohol risk reduction;appetite loss;attenuation;dysbiosis;effectiveness testing;efficacy evaluation;enteric dysbiosis;experience;gastrointestinal;gut dysbiosis;gut microbiome;gut-liver axis;improved;intestinal homeostasis;liver function;liver injury;microbial;microbial community;pre-exposure prophylaxis;prevent;recruit;reduced alcohol use;screening;screening brief intervention referral and treatment;side effect;systemic inflammatory response;transmission process;treatment as usual;treatment program;uptake

public_health_relevance:
This longitudinal study systematically examines the dynamic changes in the gut microbiome (dysbiosis) in thecontext of regular use of PrEP with or without hazardous alcohol drinking. The study also pursues arandomized control trial (RCT) to determine the efficacy of SBIRT (Screening Brief Intervention & Referral toTreatment) in reducing the risk of alcohol drinking and associated pathogenic changes in the gut liver axis


application_id: 11143861
project_number: 5U2FFD007449-05
administering_ic: FDA
award_notice_date: 2025-06-24
opportunity_number: PAR-21-174
application_type: 5
activity_code: U2F
ic: FD
serial_number: 007449
program_official: VARGO, ADRIANNA
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: ZFD1-ORA-G(02)1
contact_pi_person_id: 80167502
contact_pi: HAMILTON, DORIS
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 094630642
primary_uei: Q8K6DER1H1X4
duns_number: 094630642
uei: Q8K6DER1H1X4
fips: US
organization_id: 4536701
organization_name: KENTUCKY STATE DEPARTMENT OF AGRICULTURE
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406018311
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_title:
Path C The FDA's Cooperative Agreement Program for States and Territories to Implement a National Produce Safety Program (U2F) Clinical Trials Not Allowed

project_abstract:
KDA Produce Safety Program Project Summary/AbstractIn 2022 the KDA Produce Safety Program assumed fully state authority for ProduceSafety in Kentucky via the passage of a State Produce Safety Statute/Regulation.Under the 2021-2026 Period of Performance KDA intends to shift its efforts frombuilding a state program to that of full implementation of FDAs national Produce SafetyProgram. During the next 5-year Period of Performance KDA aims to utilize this robustregulatory foundation along with fully executed foundational program SOPs to fullyexecute a robust Farm Inventory Education/OutreachInspection/Compliance/Enforcement and Produce-Related Event Response foundationtowards the specific aim of assisting federal/state partners and Kentucky producegrowers in achieving Standards for the Growing Harvesting Packing and Holding ofProduce for Human Consumption (21 CFR Part 112).The overall health relatedness of this project is that of consumer and public healthprotection by implementing specific goals/objectives in the Project Plan aimed atminimizing the risk of serious adverse health consequences or death from consumptionof contaminated produce through the application of science-based minimum standardsfor the safe growing harvesting packing and holding of produce raw agriculturalcommodities grown for human consumption. This cooperative agreement is for fullprogram execution directed towards grower education technical assistancedevelopment of a verified inventory of covered farms and conducting prioritizedinspections of farms covered by the Produce Safety Rule. KDA and its sub-awardeeswill continue to conduct education outreach and identification of covered farms. KDAslong-term objectives specific aims and key focus during 2021-2026 Produce SafetyCAP Grant Period of Performance seek to ensure that robust Administrative FarmInventory Regulatory Program Foundation Education/Outreach andInspection/Compliance/Enforcement systems are in place and fully executed in order toadvance Federal/State efforts for a nationally integrated food safety system (IFSS)enhance produce safety in the Commonwealth and abroad and achieve high rates ofcompliance with FDAs Produce Safety Rule and the state statute/regulation.

public_health_relevance:
KDA Produce Safety Program Project NarrativeThe relevance of this project to public health is to minimize the risk of serious adversehealth consequences or death from consumption of contaminated produce through theapplication of science-based minimum standards for the safe growing harvestingpacking and holding of produce raw agricultural commodities grown for humanconsumption as contained in 21 CFR Part 112. This project will allow KDA to continueto build a robust verified farm inventory which will be shared with our federal partners.Through both the application of a robust Education/Outreach andInspection/Compliance/Enforcement program as promulgated in Kentuckys ProduceSafety Statute (KRS 260.765 to 260.772.) and Produce Safety AdministrativeRegulation (302 KAR 60:010) the KDA Produce Safety Program will ensure that bothcovered and exempt growers of covered produce understand and where applicableapply the regulatory mandates and produce safety best practices to reduce produce-related illnesses and ensure a safe wholesome food supply for the Commonwealth andabroad.


application_id: 11142487
project_number: 4R01AI148241-05
project_title: Iron independent role for yersiniabactin in Yersinia pestis
administering_ic: NIAID
award_notice_date: 2025-06-02
opportunity_number: PA-20-185
application_type: 4
activity_code: R01
ic: AI
serial_number: 148241
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2021-06-04
project_end_date: 2027-05-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY Transitional metals (e.g. Fe Zn Mn) are required by bacteria in order to grow. As such mammals have avariety of mechanisms to sequester these metals during infection effectively limiting their availability for use bybacteria (referred to as nutritional immunity). Yersinia pestis which causes the human disease plague neededto evolve high-affinity metal acquisition mechanisms to overcome nutritional immunity and colonize its hosts.Because these mechanisms are key to Y. pestis virulence they represent potential therapeutic targets for thetreatment or prevention of plague. Therefore our long term goals are to identify the mechanisms used by Y.pestis to evade host nutritional immunity and define their roles in virulence. Recently we have made the excitingdiscovery that yersiniabactin (Ybt) a siderophore essential for Y. pestis iron (Fe) acquisition is also able to bindto zinc (Zn) and contributes to Zn acquisition in vitro. Furthermore using a hemochromatosis mouse model thatis defective in Fe-mediated nutritional immunity we demonstrated for the first time that Ybt contributes tovirulence in an Fe-independent manner. Using a Y. pestis mutant defective in Zn acquisition was also showedthat the host protein calprotectin which is a key component to Zn-mediated nutritional immunity is a barrier toY. pestis infection and Ybt contributes to overcoming this barrier in both pneumonic and bubonic plague.Together these data are our premise for the conceptually innovative hypothesis that Ybt not only contributes tovirulence through Fe acquisition but also contributes to Zn acquisition which aids in overcoming calprotectinmediated nutritional immunity. In this proposal we will build on these exciting discoveries. In Aim 1 we will definethe mechanisms that govern metal selectivity of Ybt and the re-acquisition of Ybt-Zn by the bacterium. In Aim 2we will define the Ybt secretion mechanisms used by Y. pestis and determine the therapeutic potential ofinhibiting these secretion systems during plague. Finally in Aim 3 we will define the role of host calprotectinduring plague and the contribution of Ybt to the ability of Y. pestis in overcoming calprotectin mediated Znsequestration. Importantly Ybt is a conserved virulence factor in many Gram-negative bacteria. Therefore thedata generated from these studies has the potential to provide us with a broader understanding of the role of Ybtin the virulence of multiple pathogens. Ultimately these data will provide a foundation for the rational design ofnew therapeutic approaches targeting these mechanisms to combat Y. pestis infection.

project_terms:
3-Dimensional;Affinity;Attenuated;Bacteria;Binding;Bubonic Plague;Cells;Characteristics;Chemicals;Crystallography;Data;Defect;Development;Drug Targeting;Foundations;Goals;Gram-Negative Bacteria;Hemochromatosis;Human;Immune response;In Vitro;Infection;Iron;Kinetics;Lead;Leukocyte L1 Antigen Complex;Leukocytes;Mammals;Mediating;Membrane;Metals;Modeling;Molecular;Mus;Mutagenesis;Nutritional Immunity;Plague;Pneumonic Plague;Predisposition;Prevention;Proteins;Pump;Research Personnel;Role;Siderophores;Solid;Specificity;System;Testing;Therapeutic;Time;Virulence;Virulence Factors;Work;Yersinia pestis;Zinc;combat;efflux pump;fitness;human disease;improved;inhibitor;innovation;mouse model;mutant;neutrophil;novel;novel therapeutic intervention;novel therapeutics;pathogen;pathogenic bacteria;permease;rational design;receptor;response;therapeutic candidate;therapeutic target;transposon sequencing;yersiniabactin

public_health_relevance:
PROJECT NARRATIVEHumans have developed mechanisms to restrict bacterial access to metals during infection and thus pathogensin turn have evolved high-affinity metal acquisition systems to overcome this restriction. This project will identifythe mechanisms used by Yersinia pestis to acquire zinc in order to cause the human disease plague. As metalacquisition is essential for virulence defining these mechanisms will reveal novel targets for the development ofnew anti-plague therapeutics.


application_id: 11142470
project_number: 5R01AA030774-02
project_title: Selective Glucocorticoid Receptor Antagonism in Alcohol Use Disorder: A Human Neuroscience Study
administering_ic: NIAAA
award_notice_date: 2025-08-13
opportunity_number: PA-20-184
application_type: 5
activity_code: R01
ic: AA
serial_number: 030774
program_official: SENEVIRATNE, CHAMINDI
project_start_date: 2024-08-01
project_end_date: 2028-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
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/SUMMARY Perturbations of the hypothalamic-pituitary-adrenal (HPA) axis characterize alcohol use disorder (AUD).The HPA axis is the primary stress-response system and cortisol is the major adrenal glucocorticoid hormonein most mammals. A negative feedback system involving glucocorticoid receptors (GRs) regulates HPA axisactivity and cortisol secretion. Preclinical studies have shown glucocorticoid receptor (GR) antagonists reducealcohol (ALC) reward withdrawal and stress-induced relapse in preclinical studies. Despite this robustliterature these areas are understudied in humans perhaps because the only clinically available GRantagonist mifepristone is not selective. The proposed rigorous crossover study will translate provocative preclinical findings implicating GRs inAUD to humans using a selective GR antagonist PT150. Participants (N=34 17 females 17 males) willcomplete an experimental session after at least 5 days of maintenance on each PT150 dose (0 450 900mg/day) to determine responses to experimentally induced stress. Participants will complete a separateexperimental session to determine if PT150 attenuates the pharmacodynamic effects of ALC (0.5 g/kg). We willrecord behavioral (i.e. ALC demand craving mood and subjective effects) neuroendocrinological (i.e.cortisol) and physiological (i.e. heart rate blood pressure breath ALC level) responses before stress or ALCand periodically afterwards for 120 mins. Finally we will determine whether PT150 reduces ALC use (i.e.number of drinks and heavy drinking days/week) craving and stress in the natural ecology. We predict: 1)stress induction will increase cortisol ALC demand and negative mood and PT150 will attenuate theseresponses 2) ALC will increase ALC demand and produce prototypical subjective effects and PT150 willattenuate these effects and 3) PT150 will decrease drinking craving and stress in the natural ecology.Exploratory aims will determine if: 1) responses/changes differ in females and males; 2) baseline cortisol orstress levels will predict behavioral or neuroendocrinological responses to stress and attenuation by PT150;and 3) behavioral and neuroendocrine responses and attenuation by PT150 during the stress-inductionsession predict changes in the naturalistic ecology. This project will expand the scope of clinical neuroscience research on AUD by focusing on GRantagonism in humans. Rigorous preclinical research supports this proposal. The proposed research couldprovide the impetus for subsequent clinical research to develop PT150 as an adjunct therapy for AUD.Because HPA dysregulation occurs in stimulant opioid and tobacco use disorders this project could also spurinterest in elucidating the role of GR antagonism in other substance use disorders. The proposed work willproduce an immediate and sustained impact.

project_terms:
Adrenal Glands;Affinity;Alcohol consumption;Alcohol withdrawal syndrome;Alcohols;Area;Attenuated;Auditory;Behavior assessment;Behavioral;Bilateral;Biological Availability;Blood;Blood Pressure;Businesses;Clinical;Clinical Pharmacology;Clinical Research;Cognitive;Consumption;Corticosterone;Cross-Over Studies;Development;Dose;Ecology;Environment;Feedback;Female;Glucocorticoid Receptor;Glucocorticoids;Goals;Heart Rate;Heavy Drinking;Hormones;Human;Hydrocortisone;Hypothalamic structure;Kentucky;Literature;Maintenance;Mammals;Memory;Mifepristone;Moods;Neuroendocrinology;Neurosciences;Neurosciences Research;Neurosecretory Systems;Oncology;Oral;Participant;Patients;Performance;Pharmacodynamics;Pharmacology Study;Pharmacotherapy;Physiological;Pituitary Gland;Placebos;Preclinical data;Progesterone Receptors;Public Health;Questionnaires;Relapse;Reporting;Research;Research Personnel;Research Support;Rights;Role;Self Administration;Severities;Stress;Substance Use Disorder;Surveys;System;Testing;Therapeutic;Tobacco Use Disorder;Translating;Universities;Withdrawal;Work;alcohol demand;alcohol effect;alcohol measurement;alcohol reward;alcohol seeking behavior;alcohol use disorder;antagonist;attenuation;behavior prediction;biological adaptation to stress;comparison control;conditioned place preference;craving;drinking;electronic data;foot;human subject;hypothalamic-pituitary-adrenal axis;improved;innovation;interest;male;negative mood;opioid use disorder;pre-clinical;pre-clinical research;preclinical study;prolonged abstinence;reduced alcohol use;response;social;stimulant use disorder;stressor;tool

public_health_relevance:
PROJECT NARRATIVE The research proposed in this application consists of a rigorous crossover study to determine whetherglucocorticoid receptor antagonism attenuates behavioral and neuroendocrinological responses toexperimentally induced stress in non-treatment-seeking patients with alcohol use disorder (AUD) thepharmacodynamic effects of alcohol (ALC) and drinking craving and stress in the natural environment. Theproposed study is innovative and important because it might spur the development of PT150 as an adjuncttherapy for alcohol use disorder.


application_id: 11142190
project_number: 1R21AI187757-01A1
project_title: Protective roles of CD180 and NOD1 in the protective immunity against cerebral Toxoplasma infection
administering_ic: NIAID
award_notice_date: 2025-07-15
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 187757
suffix: A1
program_official: PESCE, JOHN T
project_start_date: 2025-07-15
project_end_date: 2027-06-30
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The molecules that recognize pathogen-associated molecular patterns (PAMPs) are an important first-linedefense system to recognize an invasion and proliferation of pathogens and promptly activate the protectiveimmunity. Toxoplasma gondii an intracellular protozoan parasite establishes chronic infection in the brain andreactivation of this chronic infection can cause sever encephalitis. For preventing this disease the immunesystem needs to rapidly detect proliferation of tachyzoites (the acute stage form) in the brain during the earlystage of reactivation of the infection for effectively activating the protective immunity. Thus the defense systemthat recognizes the PAMPs-recognizing molecules expressed in the brain should play crucial roles in readilydetecting tachyzoite growth and activating the protective immunity during the early stage of reactivation of theinfection. We previously identified that IFN-g is required for the protective immunity to prevent reactivation ofcerebral T. gondii infection. Our studies also identified that microglia tissue-resident macrophages in the brainproduce IFN-g in response to cerebral tachyzoite growth and that production of IFN-g by brain-resident cells iscritical for promptly activating cerebral innate immunity and facilitating migration to T cells into the brain toprevent reactivation of the infection. Notably our recent study revealed that cerebral mRNA levels for twoPAMPs-recognizing molecules CD180 and nucleotide oligomerization domain 1 (NOD1) markedly increase inassociation with IFN-g production by brain-resident cells during reactivation of T. gondii infection. CD180 isexpressed on microglia and classified as one of sensomes of microglia for detecting endogenous ligands andmicrobes in both humans and mice. Therefore it would be possible that CD180 recognizes tachyzoite-derivedmolecules and activates IFN-g production by microglia. Macrophages also express CD180 and they also playimportant roles in preventing cerebral tachyzoite growth. CD180 has also been shown to upregulate TNF-aexpression in macrophages in a bacterial infection. TNF-a in addition to IFN-g plays important roles ininhibiting cerebral tachyzoite growth. Thus it is possible that CD180 activates IFN-g and TNF-a production bymicroglia and macrophages against tachyzoite growth and promptly activate both innate and T cell-mediatedprotective immunity to prevent reactivation of T. gondii infection. NOD1 recognizes peptidoglycan moietiesfrom Gram-negative bacteria and single stranded RNA from various viruses. A recent study identified thatNOD1 is required for restricting replication of Trypanosoma cruzi an intracellular parasite in IFN-g-activatedmacrophages. In addition mice deficient in both NOD1 and NOD2 have decreased IFN-g levels in their plasmaduring cerebral malaria. NOD1 also enhances cerebral TNF-a production in intracerebral haemorrhage. Thusthe proposed studies focus to determine whether CD180 (Aim 1) and NOD1 (Aim 2) expressed in microgliaand macrophages play important roles in activating their production of IFN-g and TNFa and promptly activatingboth innate and T cell-mediated protective immunity to prevent reactivation of T. gondii infection.

project_terms:
Acute;Antigens;Bacterial Infections;Blood;Blood - brain barrier anatomy;Brain;Cells;Cerebral Malaria;Cerebral hemisphere hemorrhage;Cerebrum;Classification;Cytoplasm;Disease;Dose;Effector Cell;Encephalitis;Gram-Negative Bacteria;Growth;Hematopoietic;Host Defense;Human;ITGAM gene;Immune;Immune system;Immunity;Immunocompromised Host;In Vitro;Individual;Infection;Interferon Type II;Invaded;Knock-out;Knockout Mice;Life;Ligands;Lung;Macrophage;Mediating;Messenger RNA;Microbe;Microglia;Modeling;Molecular;Mouse Strains;Mus;Mycobacterium tuberculosis;Natural Immunity;Neoplasms;Nucleotides;Organ Transplantation;Parasites;Pattern;Pattern Recognition;Peptidoglycan;Plasma;Play;Prevention;Production;Proliferating;RNA;Resistance;Role;Surface;System;T-Lymphocyte;TNF gene;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Trypanosoma cruzi;Upregulation;Virus;cell type;chronic infection;conditional knockout;improved;microbial;migration;mortality;mouse model;pathogen;prevent;rapid detection;response;toxoplasmic encephalitis;viral RNA

public_health_relevance:
The molecules that recognize pathogen-associated molecular patterns (PAMPs) are animportant first-line defense system to promptly recognize an invasion and proliferation ofpathogens and activate the protective immunity to prevent the pathogen growth. Whereasreactivation of infection with Toxoplasma gondii in the brain can cause sever encephalitis theroles of the PAMPs-recognizing molecules in the brain in the host defense against reactivationof the infection remain unknown. Since our recent study revealed marked increases in cerebralexpression of two PAMPs-recognizing molecules CD180 and NOD1 in the protective immunityduring reactivation of the infection the proposed studies focus to elucidate the roles of CD180and NOD1 in the protective immunity to prevent reactivation of cerebral infection with T. gondii.


application_id: 11141802
project_number: 5R44CA288032-02
project_title: A PROGNOSTIC ASSAY FOR METASTATIC CLEAR CELL RENAL CELL CARCINOMA
administering_ic: NCI
award_notice_date: 2025-09-09
opportunity_number: PA-23-230
application_type: 5
activity_code: R44
ic: CA
serial_number: 288032
program_official: LOU, XING-JIAN
project_start_date: 2024-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1-CDPT-V(13)B]
contact_pi_person_id: 1915551
contact_pi: COUGHLIN, RICHARD THOMAS
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 080083976
primary_uei: FR2EBJKP5G63
duns_number: 080083976
uei: FR2EBJKP5G63
fips: US
organization_id: 10040856
organization_name: LAGRANGE SCIENTIFIC, LLC
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT An estimated 79000 Americans were diagnosed with renal carcinoma in 2022 and approximately 13920died primarily as a result of metastasis. First line treatment involves localized surgical removal of the primarytumor as systemic therapies are generally reserved for metastatic dissemination. While ccRCC surveillanceprotocols have improved over recent years aggressive management with immunomodulators andchemotherapeutic agents is generally withheld until after significant recurrence or metastasis is identified;although this is generally too late to effectively manage or deter advanced cancerous spread which is reflectedby a post-metastasis 5-year survival rate of just 14%. The goal of this Phase II SBIR is to further address theabsence of quantifiable targeted metabolite biomarkers in ccRCC tissues that accurately and specificallypredict early disease progression to metastasis. Ultimately we seek to identify those patients that expressaggressive subtype(s) of renal cancer that would benefit from earlier initiation of systemic therapy. Likewiseevaluation of this newly identified 12-marker panel can determine those patients who will have metastaticdisease with 100% specificity and may confidently choose a more conservative management approach. There is a clear unmet clinical need to stratify aggressive cancer subpopulations within certainmalignancies like ccRCC yet there are currently no prognostic or diagnostic tests on the market that predictmetastasis. In pilot studies LAGRANGE SCIENTIFIC was able to overcome major problems that encumberedprevious metabolic studies such as primary tumor tissue heterogeneity and day-to-day as well as lab-to-labMS variability. Additionally further refinement of our pre-analytical and post-acquisition normalizationtechniques in addition to metabolite quantification methods have demonstrated stronger accuracy and higherrobustness. Indeed we have identified in our feasibility studies a panel of metabolite markers that are 100%specific and 83% sensitive  with 100% PPV and 94% NPV  in identifying ccRCC patients that progress tometastasis at the time of primary ccRCC tumor resection (1.7 - 4.6 years sooner than standard of care). Inorder to help validate our prototype we will utilize the ccRCC biorepositories from the Eastern Virginia MedicalSchool PROBE cohort Ontario Institute for Cancer Research Tumor Bank University of Florida University ofVirginia and UT Health San Antonio; which account for over 894 renal tumors with associated patient data andfollow-up. We will begin prospective tissue collection at the University of Florida Jacksonville and continuecollection at UT Health San Antonio which are accompanied by updated databases that further allow us toidentify patients who underwent a primary ccRCC tumor and metastasized (Cases) vs patients who did notprogress to metastasis (Controls). Paired Normal adjacent tissue will be obtained when feasible. For thisPhase II R&D we will expand upon our extremely successful results from our pilot proof-of-concept studiesand further develop our prototype and commercialization strategies.

project_terms:
Address;Alberta province;Algorithms;American;Biological Assay;Biological Markers;CLIA certified;Cancerous;Case/Control Studies;Characteristics;Chemicals;Clear cell renal cell carcinoma;Clinical;Collection;Cooperative Human Tissue Network;Core Biopsy;Data;Data Analyses;Databases;Diagnosis;Diagnostic;Diagnostic tests;Disease;Disease Progression;Early identification;Early treatment;Evaluation;Excision;Feasibility Studies;Florida;Goals;Health;Heterogeneity;Histopathology;Immunomodulators;Individual;Kidney Neoplasms;Label;Laboratories;Lead;Legal patent;Malignant Neoplasms;Marketing;Methanol;Methods;Morbidity - disease rate;Nature;Neoplasm Metastasis;Ontario;Operative Surgical Procedures;Pathologist;Pathology;Patients;Performance;Phase;Physicians;Pilot Projects;Primary Neoplasm;Prognostic Marker;Protocols documentation;Receiver Operating Characteristics;Recurrence;Renal Carcinoma;Risk;Running;Sampling;Services;Shipping;Small Business Innovation Research Grant;Source;Specificity;Specimen;Surgical Oncologist;Survival Rate;Systemic Therapy;Techniques;Technology;Testing;Texas;Therapeutic Intervention;Time;Tissue Banks;Tissue Sample;Tissues;Training;Translating;Tumor Bank;Tumor Tissue;Tumor stage;United States National Institutes of Health;Universities;Update;Virginia;algorithm development;analytical method;anti-cancer research;biobank;biomarker panel;case control;chemotherapeutic agent;clinical diagnosis;cohort;commercialization;detection limit;diagnostic biomarker;diagnostic development;experience;follow-up;high risk;improved;innovative technologies;liquid chromatography mass spectrometry;medical schools;metabolic abnormality assessment;metabolomics;mortality;multidisciplinary;multiple reaction monitoring;phase 2 study;predictive marker;predictive panel;prognostic;prognostic assays;programs;prospective;prototype;quality assurance;research and development;sample collection;standard of care;testing services;tumor;tumor heterogeneity;validation studies

public_health_relevance:
PROJECT NARRATIVE The aggressive and unpredictable nature of metastatic clear cell renal cell carcinoma (ccRCC) is reflectedby high rates of morbidity and mortality. While drastic improvements to post-surgical surveillance protocolshave been made over recent years early identification of progression from primary tumor to a disseminatedmetastatic disease state remains a difficult challenge for physicians and frequently results in detrimental delaysof therapeutic intervention. LAGRANGE SCIENTIFIC is developing an innovative technology that accurately andspecifically identifies which patients at the time of primary tumor resection will experience a disseminatedccRCC metastasis and with Phase II support will mature this highly accurate prognostic test for laterprogression to metastasis into a regulatory-approved laboratory testing service.


application_id: 11141695
project_number: 5R42MH135825-03
administering_ic: NIMH
award_notice_date: 2025-06-25
opportunity_number: PA-22-178
application_type: 5
activity_code: R42
ic: MH
serial_number: 135825
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2024-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-ISB-Z(10)B]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078515036
primary_uei: HSZNRZ4JS954
duns_number: 078515036
uei: HSZNRZ4JS954
fips: US
organization_id: 10032228
organization_name: BIOPTICSTECHNOLOGY, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405131245
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-01
project_title:
Time-resolved laser speckle contrast imaging of resting-state functional connectivity in neonatal brain

project_abstract:
ABSTRACTContinuous monitoring of neonatal brain development is crucial for effective management of brain injury andassociated complications thus reducing healthcare burden and costs. One rapidly developing method for earlycharacterization of abnormal brain development is to map resting-state functional connectivity (rs-FC) acrossdistinct regions of the brain. However currently available neuroimaging technologies are either expensive anddifficult to use continuously (fMRI and PET) or lack the combination of temporal-spatial resolution and large field-of-view (FOV) to image distributed rs-FC (EEG and near-infrared spectroscopy and tomography). In collaborationwith University of Kentucky inventors Bioptics Technology is developing validating and commercializing arevolutionary time-resolved laser speckle contrast imaging (TR-LSCI) technology that enables noncontact fasthigh-resolution imaging of cerebral blood flow (CBF) over a large FOV. TR-LSCI illuminates picosecond-pulsedwidefield coherent near-infrared light onto the brain and synchronizes a newly developed picosecond-gatedhigh-resolution single-photon avalanche diode (SPAD) camera for 2D mapping of cerebral blood flow (CBF) atdifferent depths into the head. By applying the time-gated strategy TR-LSCI differentiates short and long photonpaths through the layered head tissues at different depths thus eliminating the need for time-consuming complex3D reconstruction in near-infrared diffuse optical tomography technologies. In preliminary studies continuousmapping of CBF at different depths has been demonstrated by a lab-made benchtop TR-LSCI prototype in flow-simulating phantoms and in vivo rodents. In this Fast Track STTR proposal through two phases we will developoptimize validate and commercialize a user-friendly portable TR-LSCI device for fast high-solution andmultiscale imaging of CBF and rs-FC in neonatal rodents (Phase 1) and neonatal piglets (Phase 2). SpecificallyPhase 1 will optimize and assess the benchtop TR-LSCI prototype for imaging CBF and extracting rs-FC (derivedfrom time-course CBF images) in neonatal rodents with perinatal hypoxic-ischemic encephalopathy (HIE).Neonatal rats are used in this Phase 1 feasibility test to de-risk the TR-LSCI before its full-scale development inneonatal piglets during Phase 2. HIE is selected to study as it affects 2-9 babies per 1000 term births and isassociated with severe neurodevelopmental problems and mortality. Phase 2 will develop optimize and assessa user-friendly portable TR-LSCI device for continuous imaging of CBF and rs-FC in neonatal piglets with HIE.Neonatal piglets are selected to study as their head size and post-HIE pathology are analogous to humanneonates. TR-LSCI results will be correlated with MRI results and clinical outcomes to identify biomarkers forassessing neonatal brain injury after HIE. While this proposal tests it on HIE models of neonatal rats and pigletsas the first step for preclinical commercialization the TR-LSCI device is broadly applicable to investigate manyneurovascular diseases beyond HIE occurring in human neonates thereby providing a significant opportunityfor future clinical development and commercialization.

project_terms:
3-Dimensional;Affect;Algorithms;Animal Model;Biological Markers;Brain;Brain Injuries;Brain imaging;Brain region;Calibration;Cerebrovascular Circulation;Clinical;Collaborations;Complex;Consumption;Development;Diffuse;Diffusion;Disease;Early Diagnosis;Electroencephalography;Functional Magnetic Resonance Imaging;Future;Head;Health;Human;Image;Imaging Device;Imaging technology;Infant;Investigation;Kentucky;Laboratories;Laser Speckle Imaging;Light;Magnetic Resonance Imaging;Maps;Methods;Modality;Modeling;Near-Infrared Spectroscopy;Neonatal;Neonatal Brain Injury;Neonatal Intensive Care Units;Neurodevelopmental Problem;Neurosciences Research;Noise;Operating System;Outcome;Pathology;Perinatal anoxic ischemic brain injury;Phase;Photons;Physiologic pulse;Positron-Emission Tomography;Property;Rattus;Resolution;Rest;Risk;Rodent;Scalp structure;Signal Transduction;Small Business Technology Transfer Research;Statistical Models;System;Technology;Term Birth;Testing;Time;Tissues;Universities;Variant;biomarker identification;blood imaging;brain abnormalities;care costs;cerebral hemodynamics;clinical application;clinical development;commercialization;continuous monitoring;cost;cranium;denoising;design;diffuse optical tomography;experimental study;feasibility testing;health care burden;high resolution imaging;imager;improved;in vivo;lens;mortality;neonatal brain;neonatal brain development;neonatal hypoxic-ischemic brain injury;neonate;neuroimaging;neurovascular;operation;porcine model;portability;pre-clinical;prevent;prototype;reconstruction;spatiotemporal;tomography;user-friendly

public_health_relevance:
PROJECT NARRATIVEContinuous monitoring of neonatal brain development is crucial for effective management of brain injury andassociated complications thus reducing healthcare burden and costs. Bioptics Technology is developingvalidating and commercializing a revolutionary time-resolved laser speckle contrast imaging (TR-LSCI)technology that enables noncontact fast high-resolution imaging of cerebral blood flow and resting-statefunctional connectivity across distinct regions of the brain for noninvasive and continuous assessment ofneonatal brain development to prevent brain injury. While the proposal tests this imaging technology in perinatalhypoxic-ischemic encephalopathy models of neonatal rats and piglets as the first step for preclinicalcommercialization the TR-LSCI device is broadly applicable to investigate many neurovascular diseases beyondHIE occurring in human neonates thereby providing a significant opportunity for future clinical development andcommercialization.


application_id: 11141215
project_number: 5R35GM155281-02
project_title: Cellular and Molecular Determinants of Post-Burn Myopathy
administering_ic: NIGMS
award_notice_date: 2025-05-20
opportunity_number: PAR-23-145
application_type: 5
activity_code: R35
ic: GM
serial_number: 155281
program_official: CHAO, CHIEN-CHUNG
project_start_date: 2024-08-01
project_end_date: 2029-05-31
study_section: Maximizing Investigators' Research Award - D Study Section[MRAD]
contact_pi_person_id: 12654514
contact_pi: OWEN, ALLISON M.
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSevere burn trauma triggers profound muscle atrophy and weakness which persists for years post- injury. Todate research efforts have predominantly explored hypermetabolic and catabolic signaling within muscle cellsresulting from burn injuries with limited attention to other contributing factors.. The intricate processes ofmuscle regeneration and remodeling involve multiple cell types within the muscle niche including fibroblastsand immune cells. We propose that burn injuries disrupt crucial cell-to-cell signaling pathways resulting inmuscle dysfunction that cannot be solely attributed to hypermetabolism. We are uniquely positioned to pursueour long-term goal of unveiling cellular and molecular drivers of burn-induced myopathy with the aim ofidentifying innovative therapeutic targets that preserve muscle size and function. Over the next five years wewill pursue four interconnected yet distinct projects. Project 1 will identify cellular determinants of musclefibrosis after severe burn injury. Recent findings indicate significant collagen deposition post-murine burninjury indicative of unresolved fibrosis which may increase tissue stiffness and reduce strength. We willemploy a comprehensive multi-omic (transcriptomic and proteomic) approach to unveil cellular and moleculardeterminants of burn-induced fibrosis. Identified pathological mediators will be studied through transgenic andpharmacological interventions. Various techniques will assess collagen dynamics including architectureorientation and cross-linking to comprehend ECM remodeling potential post-burn injury. Project 2 willdetermine the impact of burn injury on immune cell function and its consequence on muscle wastingand weakness. We will assess immune cell abundance and phenotype in muscle in the days to monthsfollowing burn injury. Additionally we will investigate how burn injury epigenetically metabolically andfunctionally reprograms immune cells. Upon identification of cellular perpetuators of muscle dysfunction afterburn we may pursue cell depletion strategies to directly examine their role. Project 3 will elucidate effect ofimmunomodulation on muscle physiology after burn injury. We will explore whether modifyingmacrophage phenotype using Toll-like receptor (TLR) agonists can promote healthy ECM turnover andimproves muscle mechanics and strength. Project 4 will fill the knowledge gap regarding the role of muscleMyD88 in burn-induced cachexia and muscle regeneration. MyD88 a TLR adaptor molecule expressed inmuscle has been implicated in cancer cachexia yet it is also required for myofiber regeneration. We willemploy a skeletal muscle MyD88 knockout transgenic animal to determine whether MyD88 exerts a pro-restorative or pro-wasting effect following burn injury. These projects collectively support our overarching aim:to enhance our understanding of burn-induced cellular and molecular dysfunction which will identify noveltherapeutic targets for improving muscle function in patients after severe burn injury.

project_terms:
Agonist;Architecture;Atrophic;Attention;Burn Trauma;Burn injury;Cachexia;Cancer Cachexia;Cell Physiology;Cells;Collagen;Deposition;Epigenetic Process;Extracellular Matrix;Fibroblasts;Fibrosis;Functional disorder;Goals;Hospitals;Immune;Immunologics;Impairment;Injury;Knock-out;Knowledge;Macrophage;Mechanics;Mediator;Metabolic;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Cells;Muscle Weakness;Muscle function;Muscular Atrophy;Myopathy;Natural regeneration;Pathologic;Patients;Pharmacotherapy;Phenotype;Positioning Attribute;Process;Proteomics;Quality of life;Recovery of Function;Research;Role;Signal Pathway;Signal Transduction;Skeletal Muscle;Survivors;Techniques;Tissues;Toll-like receptors;Transgenic Animals;Transgenic Organisms;cell type;crosslink;immunoregulation;improved;innovation;mortality;multiple omics;muscle physiology;muscle regeneration;new therapeutic target;preservation;programs;severe burns;therapeutic target;transcriptomics;wasting

public_health_relevance:
PROJECT NARRATIVESevere burn injury triggers profound muscle wasting and weakness which continues long after hospitaldischarge and results in functional limitations that impair quality of life and contribute to increased morbidityand mortality among burn survivors. The information gained in this program will advance our currentunderstanding of the mechanisms by which burn injury triggers skeletal muscle dysfunction with a uniquefocus on fibrogenic and immunologic mechanisms. Elucidating non-canonical cellular and molecularmechanisms of burn-induced muscle dysfunction will unveil therapies to mitigate atrophy and weakness afterburn injury thus improving physical functional recovery in survivors.


application_id: 11140402
project_number: 5UL1TR001998-09
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2025-08-08
opportunity_number: PAR-18-940
application_type: 5
activity_code: UL1
ic: TR
serial_number: 001998
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2027-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: HARTMANN, KATHERINE E
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) has created an integrated home for clinical and translational research which promotes scientific progress and discoveries at every phase of the translational continuum. The CCTS has partnered with communities in Central Appalachia to address multiple generations of recalcitrant health challenges related in part to the economic distress of rural communities. The CCTS has fundamentally transformed UK and Central Appalachia through the development of strong academic-community research networks and collaborations within the CTSA consortium. Appalachia faces stunning health liabilities further magnified by the opioid and substance abuse epidemic which has greatly impacted eastern Kentucky and West Virginia. The strong UK research portfolio puts the UK CCTS in an optimal position to lead local regional and national research efforts focused on rural health challenges. The aligned missions of UK UK HealthCare and the CCTS focus on achieving health for all in Kentucky and require engaging in highly innovative collaborative and dynamic translational research to address rural health needs. The CCTS will continue to educate the translational workforce of the future engage rural communities in translational and bi-directional team science and work with the national network to advance transdisciplinary research and clinical trials through the following Specific Aims: 1) develop innovate and transform our research environment to promote impactful science and discovery within our integrated health care system to meet the unique health needs of Central Appalachian residents; 2) lead institutional innovation in the delivery of impactful clinical and translational research that covers the lifespan fully engages the community and embraces team science; 3) catalyze an efficient university-wide clinical trials organization which adds value to the CTSA consortium by engaging participants from rural Central Appalachia; and 4) foster and enhance a workforce characterized by representation across all translational science disciplines and populations. The UK CTSA hub is uniquely positioned in the National CTSA Consortium to foster novel technologies team science clinical trial start-up and cutting-edge translational research across the lifespan with a focus on rural communities. We have a particular focus on the Central Appalachian community a rural area that reflects many of the most pressing health concerns of the nation. This focus will ultimately elevate the health and quality of life of rural communities throughout the United States

project_terms:
Acceleration;Address;Appalachian Region;Cardiovascular system;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communities;Development;Diabetes Mellitus;Discipline;Distress;Economics;Environment;Epidemic;Face;Fostering;Future;Generations;Health;Health Care;Health Priorities;Health Services Accessibility;Home;Institution;Integrated Health Care Systems;Kentucky;Lead;Malignant Neoplasms;Mission;Modeling;Neurosciences;Obesity;Persons;Phase;Population;Positioning Attribute;Quality of life;Research;Research Personnel;Resources;Rural;Rural Community;Rural Health;Rural Population;Science;Scientific Inquiry;Special Population;Structure;Substance abuse problem;Translational Research;United States;Universities;West Virginia;Work;attractin protein;clinical center;community academic partnership;community collaboration;community engaged research;community engagement;community research;innovation;life span;multidisciplinary;new technology;opioid abuse;opioid use;patient engagement;programs;rural area;substance use;workforce needs

public_health_relevance:
The UK CTSA program hub is uniquely positioned in the National CTSA Consortium to foster novel technologies team science clinical trial start-up and cutting-edge translational research across the lifespan. Our UK CTSA hub has a significant presence on the national stage. Our focus on the Central Appalachian community a rural region with many of the highest priority health concerns of the nation (i.e. cardiovascular neuroscience cancer obesity/diabetes) including as an epicenter for the opioid and substance use epidemic distinguishes our mission and activities. The programs in this proposal will ultimately elevate the health and quality of life for people of this region and provide a national model for rural populations facing challenges in access to care.


application_id: 11139793
project_number: 3R35HL155649-04S1
project_title: Determinants of Aorta Heterogeneity
administering_ic: NHLBI
award_notice_date: 2024-07-26
opportunity_number: RFA-HL-20-011
application_type: 3
activity_code: R35
ic: HL
serial_number: 155649
suffix: S1
program_official: CHARETTE, MARC F
project_start_date: 2021-06-01
project_end_date: 2028-05-31
study_section: ZHL1-CSR-I(O2)
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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
project_abstract:
AbstractAortopathies including aneurysms dissection and rupture represent a key challenge in HLBSresearch. In the past twenty years of our continuously funded research on aortopathies wehave contributed to many mechanistic insights into the aortopathy research including a newconcept: There are regional characteristics of the aorta in regard to diverse embryonic originsand functions of cells. The overall hypothesis of this R35 program is that heterogeneity ofcellular origins imparts functional variances along the length of the aorta including diversity ofextracellular matrix stability which in turn contributes to regional specificity of aortopathies.Regional specificity of aortopathies is present in many mouse models that we have validatedand characterized. Our initial single cell transcriptomic and proteomic data have also implicatednew potential contributors to heterogeneity of the normal aortic biology and aortopathies. Threemajor themes are proposed in this program: (1) What are the structural and molecularmechanisms that contribute to biological and pathophysiological heterogeneity along the lengthof the aorta? (2) Are cellular and extracellular heterogeneity a basis for regional specificity ofaortopathies? (3) How do signaling pathways extracellular matrix and crosstalk betweenresident aortic cells coordinate to promote the heterogeneity of aortopathies? We have robusttools including a spectrum of reagents multiple classic and new mouse modelsultrasonography MRI intravital microscopy proteomics and single cell RNA sequencingtechniques. In addition to aortopathy research the PI has more than 30-year expertise in thefields of lipoprotein metabolism inflammation and atherosclerosis research. Aortopathies arenot a sole aortic disease but is associated with a wide range of diseases or syndromes thatmay affect skin lung kidney brain bone and other organs. The proposed research programwill benefit from the flexibility to pursue potential contributions of other tissues and organs toaortopathies and vice versa the influences of aortopathies on other tissues and organs. ThisR35 mechanism will also benefit the PIs strength in basic research enhance his interaction withthe translational research in the clinical arena and train the next generation of scientists.

project_terms:
Affect;Aneurysm;Aorta;Aortic Diseases;Atherosclerosis;Basic Science;Biological;Biology;Brain;Cell Physiology;Cells;Characteristics;Clinical;Data;Disease;Dissection;Embryo;Extracellular Matrix;Funding;Heterogeneity;Inflammation;Kidney;Length;Life;Lipoproteins;Lung;Magnetic Resonance Imaging;Medical;Metabolism;Molecular;Operative Surgical Procedures;Organ;Pathogenesis;Patient observation;Pharmaceutical Preparations;Proteomics;Reagent;Research;Rupture;Scientist;Signal Pathway;Skin;Specificity;Syndrome;Techniques;Therapeutic;Tissues;Training;Translational Research;Ultrasonography;bone;extracellular;flexibility;insight;intravital microscopy;mouse model;next generation;novel;programs;single-cell RNA sequencing;tool;transcriptomics

public_health_relevance:
Project NarrativeAortopathy including aneurysms dissection and rupture are life-threatening diseases that haveno validated medications. The only therapeutic option is watchful waiting prior to major surgicalintervention. This project will provide novel mechanistic insight into these diseases that willenable more focused efforts in understanding the disease pathogenesis and developing medicaltreatment.


application_id: 11139623
project_number: 5K23AG075262-04
administering_ic: NIA
award_notice_date: 2025-09-08
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: AG
serial_number: 075262
program_official: RIDDLE, MELISSA
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Career Development for Clinicians/Health Professionals Study Section [AGCD-3]
contact_pi_person_id: 16198324
contact_pi: RHODUS, ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_title:
Improving Person-Environment Fit of Community-Residing Older Adults with Dementia Through Assessment and Individualized Intervention

project_abstract:
Project SummaryAging with Alzheimer's disease and related dementias (ADRD) is compounded by onset of behavioral andpsychiatric symptoms (BPSD) seen in over 80% of those with the condition. BPSD often precipitate caregiverburden institutionalized care and increased rates of mortality. Despite the critical need there currently are fewnon-pharmacological interventions to manage BPSD and those that exist have weak evidence. Research: Theproject titled Improving Person-Environment Fit of Community-Residing Older Adults with Dementia ThroughAssessment and Individualized Intervention identifies person-environment relationships as a mechanism ofaction to guide assessment of and intervention for functional behavior within the home context for persons withADRD. By improving the relationship between persons with ADRD and their home environment (person-environment fit) it is hypothesized that people with ADRD will have improved BPSD and activity engagementwithin their home. We will employ the NIH Stage Model of Behavioral Intervention Development to defineassessment of person-environment fit (Stage 0; Aim 1) and pilot the feasibility of a telehealth intervention tomaximize person-environment fit within the homes of community-residing adults with ADRD within ruralcommunities (Aim 2). Findings of this research will inform discovery of best practices for a non-pharmacologicalenvironmental approach to BPSD for persons with ADRD living in their home. Candidate: Dr. Elizabeth Rhodusis an early-career investigator who is transitioning from a NIH T32-funded postdoctoral fellowship to a full-timetenure-track faculty position at the University of Kentucky (UK) College of Medicine. Three training goals willenhance her trajectory toward becoming an independent successfully funded investigator: 1) Develop a strongknowledge base on integrated physiological and behavioral assessment of person-environment interactions oncommunity-dwelling people living with ADRD 2) Build expertise in development and implementation ofbehavioral interventions among older adults with ADRD and 3) Expand understanding of research strategies forinclusion of underrepresented populations in aging studies. Mentors/Environment: The current careerdevelopment plan includes substantial mentorship didactic training and experiential learning at the UK Centerfor Health Equity Transformation with Director Dr. Nancy Schoenberg (primary mentor) UK Sanders-BrownCenter on Aging with Associate Director Dr. Donna Wilcock (co-mentor) Dr. Anton Porsteinsson (mentor) aprominent clinical researcher and psychiatrist for treatment of BPSD and a renowned interdisciplinary advisorycommittee. Dr. Rhodus will receive support from her institution through internal grants faculty educationnetworking and scholarship. Dr. Rhodus has full support from UK (see institutional letter of support) to advanceher career development and research activities. Thus the overall objective of this K23 application is to propelthe career development of Dr. Rhodus to an independent scientist in ADRD research using the findings of thisproject to inform a future extramural R01 targeting non-pharmacological interventions for BPSD management.

project_terms:
Active Learning;Address;Adoption;Adult;Advisory Committees;Aggressive behavior;Aging;Agitation;Alzheimer's Disease;Alzheimer's disease related dementia;Analysis of Covariance;Anxiety Disorders;Behavior;Behavior Therapy;Behavior assessment;Behavioral;Behavioral Mechanisms;Behavioral Model;Behavioral Symptoms;Career Mobility;Caregiver Burden;Caregivers;Caring;Client satisfaction;Clinic;Clinical;Clinical Treatment;Clinical Trials Design;Clinical assessments;Communities;Country;Cues;Data;Death Rate;Dementia;Development;Development Plans;Diagnosis;Environment;Extramural Activities;Faculty;Fellowship;Fostering;Foundations;Funding;Future;Goals;Grant;Health Services Accessibility;Health equity research;Home;Home environment;Individual;Institution;Institutionalization;Intervention;Interview;Kentucky;Letters;Measurement;Measures;Medicine;Mental Depression;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Morbidity - disease rate;Neurology;Neurosciences;Nonpharmacologic Therapy;Pamphlets;Performance;Persons;Physiological;Population;Positioning Attribute;Postdoctoral Fellow;Protocols documentation;Proxy;Psychiatrist;Psychophysiology;Quality of life;Randomized Controlled Trials;Reporting;Research;Research Activity;Research Personnel;Residencies;Rural;Rural Appalachia;Rural Community;Safety;Scholarship;Science;Scientist;Single-Blind Study;Sleep Disorders;Stimulus;Surveys;Teacher Professional Development;Testing;Training;Underrepresented Populations;United States National Institutes of Health;Universities;Work;aging in place;arm;behavior change;behavioral response;career;career development;caregiver education;caregiver quality of life;college;community based research;dementia care;dimension reduction;empowerment;environmental intervention;evidence base;experience;feasibility trial;follow-up;health disparity;health equity;improved;in-home care;innovation;knowledge base;mortality;novel strategies;older adult;patient home care;programs;psychiatric symptom;research and development;response;rural area;satisfaction;skills;social;standard of care;supportive environment;telehealth;tenure track;therapy development;tool

public_health_relevance:
Project NarrativeThe short-term goal of this K23 award is the development of the PI as an independent investigator skilled in theassessment and behavioral intervention most especially focused on underrepresented and vulnerable agingpopulations in rural regions who are disproportionately impacted by dementia. The proposed research will usea non-pharmacological environmental approach to develop assessments and tailored interventions that can bedelivered via telehealth to improve behaviors and activity engagement for people with dementia in their home.The long-term goal is to empower older adults with dementia to age in place within their home with minimalbehavior disruption and maximum activity participation.


application_id: 11139567
project_number: 5R21AI183992-02
project_title: Description of HIV social behavior using a phylogenetic model of structured co-evolution
administering_ic: NIAID
award_notice_date: 2025-05-07
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 183992
program_official: GEZMU, MISRAK
project_start_date: 2024-07-16
project_end_date: 2026-05-31
study_section: HIV Molecular Virology, Cell Biology, and Drug Development Study Section[HVCD]
contact_pi_person_id: 12290862
contact_pi: MAGALIS, BRITTANY
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYChronic viral and bacterial infections are characterized by pathogens that are difficult to control by the hostimmune system and therapeutic interventions. Evasion of anti-infection mechanisms for a number of thesepathogens can be attributed to the formation of structured populations comprised of highly organized pathogensubgroups with specialized cooperative functions. Pathogen communities such as biofilms can arise as a resultof replication initiating with just one infectious particle. Effective persistence in the face of natural and syntheticdefenses however requires maintenance in the form of compensatory mutations that correct for deleteriousmutations favoring individual fitness over that of the population. These co-evolutionary events can be observedover time via genomic sequencing of individual subgroups and importantly can be used to investigate unknownbiological pathways or mechanisms. HIV shares many characteristics with bacterial biofilms and other socialviruses including chronic infection antiretroviral resistance and population structure among and within infectedhost organs. Given these characteristics it was not surprising to uncover initial evidence of across-tissue co-evolution in the SIV-infected macaque model. In the absence of a cure for HIV infection there is a critical needto explore alternative behaviors that can explain HIV persistence and lead to novel therapeutic strategies. Theoverarching objective of this proposal is to improve our understanding of the complex population dynamicsthat characterize chronic HIV infection through 1) development of a novel statistical phylogenetic tool (GOSIP)and framework capable of reliably identifying cooperative behavior through compensatory evolution and 2)application of this tool/framework to full-genome sequence data available from an existing cohort of extensivelysampled SIV-infected macaques. The central hypothesis is that the implementation of a statistical graphicalmodeling approach can accurately capture co-evolving sites in interacting subpopulations including those of theSIV intra-host population. The innovation of this project lies in its treatment of cooperative behavior as thedriving factor of the HIV population survival in the face of immune and therapeutic defenses which can bestatistically inferred via a novel phylogenetic platform.

project_terms:
Address;Adopted;Altruism;Anatomy;Anti-retroviral resistance;Anti-viral Therapy;Antibiotic Therapy;Area;Automobile Driving;B-Lymphocyte Epitopes;Bacteria;Bacterial Infections;Behavior;Biological;Characteristics;Chronic;Communities;Complex;Cooperative Behavior;Data;Development;Drug resistance;Epitopes;Event;Evolution;Exhibits;Frequencies;Genes;Genome;Genomics;Goals;HIV;HIV Infections;Health;Hepatitis C virus;Human;Immune;Immune Evasion;Immune response;Immune system;Immunotherapeutic agent;Immunotherapy;Individual;Infection;Length;Life;Macaca;Maintenance;Measurable;Microbial Biofilms;Modeling;Mutation;Nature;Organ;Organism;Pathway interactions;Pattern;Phylogenetic Analysis;Phylogeny;Play;Population;Population Dynamics;Prevention;Prokaryotic Cells;Proteins;RNA;Research;Resistance;Role;SIV;Sampling;Shapes;Site;Social Behavior;Social Interaction;Specific qualifier value;Structure;Subgroup;Systemic infection;Testing;Therapeutic;Time;Tissue Sample;Tissues;Variant;Vertebrates;Viral;Virus;Virus Diseases;biofilm species;chronic infection;cohort;conditional mutant;design;experience;fitness;genomic data;immunogenic;improved;in vivo;innovation;lens;mutation correction;neutralizing antibody;novel;novel therapeutic intervention;overpopulation;particle;pathogen;prevent;simulation;social;stem;tool;treatment strategy;whole genome

public_health_relevance:
PROJECT NARRATIVEThe proposed research involves the development of a novel statistical phylogenetic tool for identification ofpathogen social interactions and its potential application for treatment of HIV as a cooperative biosystem withinthe human host. Simulated compensatory mutations in a structured population as well as publicly availablelongitudinal genomic data from the SIV-infected macaque model will be used to validate the tool and test thecentral hypothesis surrounding HIV social behavior. The goal of this study is to improve our understanding of theinteractions at the pathogen population level involved in immune evasion and drug resistance that plagueshuman health.


application_id: 11139388
project_number: 5R01DK137790-02
administering_ic: NIDDK
award_notice_date: 2025-07-22
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: DK
serial_number: 137790
program_official: UNALP-ARIDA, AYNUR
project_start_date: 2024-07-15
project_end_date: 2028-04-30
study_section: Digestive and Nutrient Physiology and Diseases Study Section [DNPD]
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: O'GRADY, GREG
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_title:
Definitive Evaluation of Gastric Dysrhythmia as a Disease Mechanism by a Novel Body Surface Gastric Mapping Technique

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

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

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


application_id: 11139096
project_number: 1R21AI185450-01A1
project_title: Adjuvanted Intranasal influenza vaccine to generate lung resident-memory T cells
administering_ic: NIAID
award_notice_date: 2025-08-15
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 185450
suffix: A1
program_official: ARNOLD, MICHELLE MARIE
project_start_date: 2025-08-15
project_end_date: 2027-07-31
study_section: Vaccines Against Infectious Diseases Study Section[VID]
contact_pi_person_id: 14403429
contact_pi: GANDHAPUDI, SIVA KUMAR
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:
ABSTRACTInfluenza vaccine capable of providing broadly cross-reactive and heterosubtypic Immunity (HSI) is astrategic solution to overcome the uncertainties associated with annual influenza immunizations. Lungresident memory CD8 T cells are important players in heterosubtypic immunity and protection after influenzainfections. Current vaccine technologies used in influenza vaccines are not very effective in generating lungresident T cell memory with the exception of live attenuated influenza vaccines (LAIV). We have recentlydemonstrated an enantiomer specific 12-dioleoyl-3-trimethylammonium-propane (R-DOTAP) as immunestimulatory cationic lipid (CL) which can adjuvant intramuscularly administered recombinant proteins togenerate robust cellular and antibody mediated response. In preliminary studies we observed this CL canalso induce potent immune responses when administered intranasally. In this proposal we will characterizeT cell-mediated immune responses to R-DOTAP adjuvanted influenza vaccines delivered as an intranasalformulation with emphasis on its ability to generate tissue-resident memory CD8 T cells and provideprotective and cross-reactive CD8 T cell immunity to an infection challenge. In the first specific aim we willevaluate lung-resident memory T cell induction by intranasal R-DOAP adjuvanted recombinant proteinvaccine. In the second specific aim we will evaluate the vaccines efficacy to protect mice from aheterosubtypic Influenza A challenge. A thorough characterization of R-DOTAPs ability to induce lungresident T cells will be useful for the adjuvant development field and contribute to the development of effectivenext-generation vaccines.

project_terms:
Adjuvant;Adoptive Transfer;Agonist;Ammonium;Antibodies;Antibody-mediated protection;Antigens;Attenuated;Biological Assay;Biotechnology;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Clinical Trials;Collaborations;Development;Drug Modulation;Epitopes;FluMist;Formulation;Goals;Human;Human papillomavirus 16;Immune;Immune response;Immunity;Immunization;Immunophenotyping;Infection;Inflammation;Influenza;Influenza A virus;Influenza vaccination;Intramuscular;Intranasal Administration;Lipids;Lung;Mediating;Memory;Modeling;Mucous Membrane;Mus;Peptide Vaccines;Peripheral;Propane;Proteins;Public Health;Recombinant Proteins;Recombinants;Recommendation;Research;Role;Route;Safety;Subunit Vaccines;System;T cell response;T memory cell;T-Cell Activation;T-Lymphocyte;Technology;Testing;Tissues;Uncertainty;Vaccinated;Vaccine Adjuvant;Vaccines;Viral;Virus;cell mediated immune response;cross immunity;cross reactivity;efficacy evaluation;enantiomer;influenza infection;influenza virus vaccine;influenzavirus;innovation;live attenuated influenza vaccine;manufacture;nanoparticle;novel vaccines;phase 3 testing;response;tissue resident memory T cell;trafficking;universal influenza vaccine;vaccine delivery;vaccine efficacy;vaccine evaluation;vaccine safety

public_health_relevance:
Project NarrativeThis project will we will develop and test an intranasal influenza vaccine using R-DOTAP nanoparticles andrecombinant influenza proteins. We will assess the vaccine ability to generate vaccine specific T cell immunityin the lungs which is essential for protection. Information obtained through this research will directly benefitpublic health through the development of a safe and effective vaccine against influenza.


application_id: 11138735
project_number: 5R01HL174922-02
project_title: Dual targeting chemokine receptors prevents chemotherapy-induced cardiotoxicity
administering_ic: NHLBI
award_notice_date: 2025-06-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 174922
program_official: POIZAT, CORALIE ISABELLE
project_start_date: 2024-08-01
project_end_date: 2028-05-31
study_section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA]
contact_pi_person_id: 12101586
contact_pi: TAN, YI
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Doxorubicin (DOX) is an effective chemotherapeutic drug to treat cancer. However DOX-induced cardiotoxicity(DICT) has limited its use. Dexrazoxane is the only current FDA-approved agent for preventing DICT but itscardioprotective effect is incomplete and the side effects also limit its use. Thus the search for newcardioprotective agents for DICT continues. SDF-1 and its receptor CXCR4 play essential roles in cardiovasculardevelopment and diseases. Constitutive loss either one of them results in perinatal lethality partially due tocardiac septum defects. Myocardial supplement of SDF-1 attracts stem cells that express CXCR4 to the site ofinjury to promote cardiac regeneration and angiogenesis. However their roles in cardiovascular system remaincontroversial. For instance heterozygous deletion of CXCR4 in mice reduced infarct size and CXCR4overexpression increased infarct size and reduced cardiac function along with excessive cardiac inammatorycell infiltration. CXCR7 is a lately identified second receptor for SDF-1. CXCR7 binds SDF-1 with an affinity aboutten times higher than CXCR4 and it can either positively or negatively affect SDF-1/CXCR4 axis-mediatedfunctions. This raises a concern as to how to distinguish the roles of SDF-1/CXCR7 from SDF-1/CXCR4 incardiac protection. We showed that SDF-1 prevents cardiac lipotoxicity through CXCR7 but not CXCR4. A single-cell RNA-seq analysis revealed the most abundant expression of CXCR7 in cardiomyocytes and cardiomyocyte-specific CXCR7 deletion showed more prominent cardiac dysfunction after myocardial infraction suggesting anessential cardiac protection. Given the protective effects of CXCR7 in cardiomyocytes and the harmful effects ofCXCR4-mediated cardiac excessive inflammation we tested the protective effects of a dual targeting compoundwith specific antagonistic activity against CXCR4 and potent agonistic activity on CXCR7 against DICT. Wefound this compound treatment significantly prevented DOX-induced cardiac dysfunction cell deathinflammation and fibrosis along with upregulation of signals involving in cardiac energy reserve metabolicprocess and downregulation of signals involving in mast cell infiltration and activation but without affecting thesuppressive effects of DOX on tumor growth. We thus hypothesize that dual targeting compound preventsDICT by activating cardiac CXCR7 to reprogram cardiomyocyte metabolism and prevent cardiacdysfunction and by antagonizing CXCR4 to inhibit cardiac mast cell infiltration and activation but withoutaffecting the suppressive effects of DOX on tumor growth. This hypothesis will be tested through specificaims: 1) Optimizing the protective effects against DICT in tumor-free and tumor-bearing mice; 2) Determiningwhether it prevents DICT through activating CXCR7/AMPK and prevents cardiac cell death and dysfunction; 3)Determining whether it prevents DICT through inhibiting CXCR4-mediated cardiac mast cell infiltration andactivation. Successful completion of this project will reveal new insight into the underlying mechanisms behindand provide fundamental evidence for it as a novel approach for preventing DICT in future clinical studies.

project_terms:
Affect;Affinity;Agonist;Binding;CXCR;CXCR4 Receptors;CXCR4 gene;Cancer Survivor;Cardiac;Cardiac Myocytes;Cardiometabolic Disease;Cardiotonic Agents;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular system;Cell Death;Cells;Clinical Research;Development;Dexrazoxane;Disease;Dose;Down-Regulation;Doxorubicin;Etiology;FDA approved;Fibrosis;Functional disorder;Future;Genetic Transcription;Glucans;Glycogen;Health;Heart;Heart Septal Defects;Heart failure;Heterozygote;Immune;Immune response;Immunocompetent;Infarction;Infiltration;Inflammation;Inflammatory;Injury;Knockout Mice;Lymphoma;Malignant Neoplasms;Mediating;Metabolism;Mitochondria;Mus;Myocardial;Myocardial Infarction;Myocardial dysfunction;Myocarditis;Myocardium;Pathologic;Pathway interactions;Performance;Perinatal mortality demographics;Play;Prevention approach;Refractory;Role;Series;Signal Transduction;Site;Stromal Cell-Derived Factor 1;Testing;Upregulation;adenoviral mediated;antagonist;cardiac angiogenesis;cardiac regeneration;cardioprotection;cell mediated immune response;chemokine receptor;chemotherapeutic agent;chemotherapy;clinical application;clinically relevant;heart defect;heart function;heart metabolism;improved;innovation;insight;mast cell;mouse model;myocardial injury;neovascularization;novel strategies;overexpression;postnatal;prevent;programs;protective effect;sensor;side effect;single-cell RNA sequencing;stem cells;treatment strategy;tumor;tumor growth;tumorigenesis

public_health_relevance:
The objective of this study is to validate an innovative concept that the unique dual TC14012 protects againstdoxorubicin-induced cardiotoxicity (DICT) by activating cardiac CXCR7 to reprogram cardiomyocytemetabolism and prevent cardiac dysfunction and by antagonizing CXCR4 to inhibit cardiac mast cell infiltrationand activation in multiple mouse models. We will first optimize the doses of TC14012 for protecting againstDICT in two tumor-free and tumor-bearing mouse models and then we will determine its direct effects andmechanisms on energy reserve metabolism and mitochondrial function in cardiomyocytes and on cardiac mastcell infiltration and degranulation. This project will reveal new insight into the underlying mechanisms behindand provide fundamental evidence for TC14012 as a novel approach for the prevention of DICT in futureclinical studies.


application_id: 11138433
project_number: 5P50MD019476-02
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2025-02-18
opportunity_number: RFA-MD-23-011
application_type: 5
activity_code: P50
ic: MD
serial_number: 019476
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: ZMD1-MLS
subproject_number: 5091
contact_pi_person_id: 10552456
contact_pi: WILLIAMS, LOVORIA B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Modified Project Summary/Abstract Section ABSTRACT The Community Engagement andDissemination Core of University of Kentucky (UK) ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities) provides a critical and integral component of UK ASCENDs objective to achieve healthier lives by promoting community-engaged research (CER) success among early-stage investigators (ESIs) through the ASCEND Scholars Program (ASP) a novel and comprehensive CER Training Program followed by a rigorous CER Pilot Program; and bi-directional engagement with community stakeholders through a Community Advisory Board (CAB). Fostering such research success through community engagement is critical everywhere and particularly in Kentucky recently ranked as #50 in national health standing with the nations highest cancer mortality and among the highest rates of other diseases. The mission of the CEDC is to ensure that these ESIs ASCEND Scholars form and sustain productive research collaborations and engage in impactful dissemination activities with community stakeholders. The CEDC is led by experienced NIH-funded community-engaged health researchers and supported by strong and enduring community and institutional partnerships. The CEDC has the following aims: (1) Cultivate bidirectional interactions between ESIs and community stakeholders to stimulate research collaborations and participatory planning processes and (2) Disseminate research findings to a broad range of audiences to ensure translation of research results into sustainable community-level and system-level changes that improve health. These aims will be achieved by leveraging existing and developing new institution-wide resources coordinating interactions with a CAB to facilitate sustainable relationships with community stakeholders and collaborating with the other UK ASCEND Cores. The CEDC will achieve bi-directional interaction between ESIs and community stakeholders by managing a central Resource Catalog that supports CER infrastructure developing a Research Dissemination Toolkit and Individualized CER Plans and hosting an annual community-researcher Summit. The dissemination and translation aim will be achieved by the provision and exchange of evidence-based health information and ESI research findings through UKs Community Health Worker Program and the creation of a Sustainability Planning Guide. The CEDC constitutes a critical resource interwoven throughout UK ASCEND. Such bi-directional collaboration enhances the likelihood of achieving UK ASCENDs outcomes ESI CER career development community engagement and ESI research success. The CEDC will promote the integration and authentic engagement of community perspectives into ESIs CER training and pilot projects critical to improving health.

project_terms:
Address;Appalachian Region;Black race;Catalogs;Collaborations;Communities;Community Health Aides;Consultations;Development;Disease;Disparity;Doctor of Philosophy;Economically Deprived Population;Ensure;Equity;Faculty;Feedback;Fostering;Funding;Goals;Grant;Health;Hispanic;Individual;Institution;Kentucky;Leadership;Malignant Neoplasms;Mission;Modeling;National Institute on Minority Health and Health Disparities;Outcome;Pilot Projects;Play;Population Heterogeneity;Process;Productivity;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Rural;Scholars Program;System;Training;Training Programs;Translational Research;Translations;Trust;United States National Institutes of Health;Universities;Work;Writing;career development;community advisory board;community engaged research;community engagement;community organizations;community partners;community partnership;design;disparity elimination;evidence base;experience;health disparity;health equity;health equity promotion;improved;interest;member;minority health;minority health disparity;mortality;novel;outcome disparities;programs;research data dissemination;skill acquisition;socioeconomic disadvantage;success;symposium;tool;training project


application_id: 11138426
project_number: 5P50MD019476-02
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2025-02-18
opportunity_number: RFA-MD-23-011
application_type: 5
activity_code: P50
ic: MD
serial_number: 019476
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: ZMD1-MLS
subproject_number: 5090
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Modified Project Summary/Abstract Section  ABSTRACT The Investigator Development Core (IDC) of UK ASCEND proudly proposes the ASCEND Scholar Program (ASP) comprised of two transformative and linked opportunities to achieve healthier lives by promoting community-engaged research (CER) success among early-stage investigators (ESIs). The ASP strategy was influenced by two national evidence-based programs UK institutional data and a career development model implemented in three UK ESI cohorts. Sixteen ESIs over four cohorts will be selected to become ASCEND Scholars and engage in a three-component CER Training Program followed by an opportunity to deploy their skills through the CER Pilot Program. The CER Training Program includes multilevel mentorship scientific and social networking and professional enrichment followed by the CER Pilot Program. UK ASCENDs CER Pilot Program will provide the preliminary studies necessary for highly competitive NIH grant applications. To ensure a pathway for continued research excellence we also will offer CER Pilot Projects to eight postdoctoral fellows in the first and fifth years of the award. Throughout the ASP and in conjunction with the Community Engagement and Dissemination Core ESIs will authentically interact with community stakeholders to successfully undertake impactful research. The IDC has the following aims: (1) Embed research-focused ESIs into the three-component CER training program and (2) Implement a rigorous CER pilot project program that leads to collaborative and sustainable interactions with community stakeholders and the successful dissemination of scholarly products including publications presentations and grant submissions leading to research success. The IDC benefits from strong leadership provided by a senior-career level NIH-funded translational researcher. Our experienced and complementaryleadership teamwillwork to promote excellence in community-engaged healthresearch throughmentorship networking and professional enrichment followed by a CER pilot project that will serve as preliminary studies for publications presentations and subsequent NIH grant submissions. Our long-term objective is to increase the critical mass of early-stage investigators exceptionally capable of undertaking CER that improves health.

project_terms:
Address;Affect;Appalachian Region;Applications Grants;Area;Award;Black race;Cardiovascular Diseases;Communities;Data;Development;Diabetes Mellitus;Disease;Economically Deprived Population;Educational workshop;Ensure;Evidence based program;Extramural Activities;Faculty;Fostering;Funding;Goals;Grant;Health;Health equity research;Hispanic;Institution;Kentucky;Leadership;Link;Malignant Neoplasms;Medicine;Mentors;Mentorship;Minority Groups;Modeling;Nervous System Disorder;Neurologic;Obesity;Outcome;Pathway interactions;Pilot Projects;Postdoctoral Fellow;Publications;Research;Research Personnel;Research Priority;Research Training;Rural;Scholars Program;Social Network;Substance Use Disorder;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;Work;Writing;career;career development;cohort;college;community advisory board;community engaged research;community engagement;community partnership;design;disparity elimination;diversity and inclusion;experience;health disparity;health equity;health equity promotion;improved;member;minority health;minority health disparity;model development;peer;programs;skill acquisition;skills;skills training;social;socioeconomic disadvantage;success;translational scientist


application_id: 11138422
project_number: 5P50MD019476-02
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2025-02-18
opportunity_number: RFA-MD-23-011
application_type: 5
activity_code: P50
ic: MD
serial_number: 019476
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: ZMD1-MLS
subproject_number: 5089
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Modified Project Summary/Abstract Section ABSTRACT The Administrative Core of University of Kentucky (UK) ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities) provides strategic leadership for program oversight management and evaluation of the proposed activities. The Core also provides governance cross-core collaboration and communication fiscal management and institutional coordination to achieve our objective of achieving healthier lives by promoting community-engaged research (CER) success among early stage investigators (ESIs) through the ASCEND Scholars Program (ASP) which consists of two linked opportunities: (1) the CER Training Program and (2) the CER Pilot Program with bi-directional engagement of community stakeholders through a Community Advisory Board (CAB). Motivated by the health challenges experience by populations living in Kentucky - a state ranked among the worst in overall health- the UK ASCEND Administrative Core will provide scientific and strategic direction and oversight. This Core is led by two Co-Directors who are also multiple principal investigators who have successfully collaborated on grant applications and leadership initiatives. Housed in the Center for Health Engagement and Transformation (CHET) and in collaboration with the UK Center for Clinical and Translational Research (CCTS) and other institutional strengths we will embed ESIs within the rich research environments of institutionally designated Research Priority Areas cancer neurological disorders substance use disorders cardiovascular disease and diabetes/obesity. The Administrative Core aims to: (1) Provide scientific leadership and governance fiscal and regulatory management effective communication strategies and cross-sector collaboration for all programmatic activities consistent with NIH protocols and optimal community partnerships and (2) Continuously examine UK ASCEND's performance and progress through the systematic deployment of formative and summative evaluation approaches using optimal measures evaluation science standards and community engagement principles. Our three primary outcomes include: ESI CER career development community engagement and ESI research success. The Administrative Core will serve as the nexus for all UK ASCEND communication meetings fiscal management regulatory activities interactions with the NIH and evaluation activities ever mindful of our key objective-- to promote health by attaining success in community-engaged health research.

project_terms:
Acceleration;Address;Affect;Appalachian Region;Applications Grants;Area;Black race;Cardiovascular Diseases;Clinical Research;Collaborations;Communication;Communities;Dedications;Development;Diabetes Mellitus;Disease;Economically Deprived Population;Ensure;Environment;Equity;Evaluation;Fostering;Foundations;Goals;Health;Health Promotion;Health equity research;Hispanic;Home;Infrastructure;Institution;Investments;Kentucky;Lead;Leadership;Link;Malignant Neoplasms;Measures;Nervous System Disorder;Obesity;Outcome;Performance;Population;Principal Investigator;Productivity;Protocols documentation;Research;Research Personnel;Research Priority;Research Training;Scholars Program;Science;Substance Use Disorder;Teacher Professional Development;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;cancer health disparity;career development;clinical center;community advisory board;community based participatory research;community engaged research;community engagement;community partnership;data sharing;disparity elimination;diversity and inclusion;experience;health disparity;health equity;health equity promotion;health inequalities;improved;innovation;meetings;mindfulness;novel;primary outcome;programs;rural underserved;skills;socioeconomic disadvantage;success


application_id: 11138421
project_number: 5P50MD019476-02
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2025-02-18
opportunity_number: RFA-MD-23-011
application_type: 5
activity_code: P50
ic: MD
serial_number: 019476
program_official: STINSON, NATHANIEL
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: ZMD1-MLS(J1)
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: CONWELL, DARWIN LEWIS;WILLIAMS, LOVORIA B
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:
ABSTRACTThe University of Kentucky (UK) will establish Achieving Success in Community-Engaged research to elimiNate Disparities (UK ASCEND) driven by one overarching objectiveto advance health by promoting community-engaged research (CER) success among ESIs. We propose the comprehensive ASCEND Scholars Program (ASP) a CER Training Program followed by a robust CER Pilot Program infused with bi-directional engagement with community stakeholders. The proposed Center of Excellence in Investigator Development and Community Engagement is led by multiple principal investigators with complementary expertise and experience scaffolded by a well-resourced and committed university structure and leadership and centered within longstanding community partnerships. Housed in UKs preeminent community-engaged health research and training center the Center for Health Engagement and Transformation (CHET) UK ASCEND proposes the following aims: (1): Coordinate bold and effective scientific leadership and governance fiscal and regulatory management communication and dissemination strategies and evaluation to assess key outcomes on CER training and success (Administrative Core). (2): Cultivate community-engaged health research success among early stage investigators (ESIs) by immersing them into a productive research career advancement program the ASCEND Scholars Program consisting of a three-component CER Training Program followed by an opportunity to deploy those skills through a CER Pilot Program within an environment of strong community partnerships and institutional strengths (Investigator Development Core); (3): Catalyze and sustain long-standing bidirectional community stakeholder-ESI research partnerships and translate findings into community and system-level innovations that promote health (Community Engagement and Dissemination Core). We will focus on three outcomes: ESI CER career development community engagement and ESI research success. UK ASCEND takes a comprehensive orientation to addressing health challenges by fostering authentic exchanges among community stakeholders researchers providers and policymakers. UK ASCEND has the motivation vision and capacity to conduct the most impactful health promotion research by providing comprehensive rigorous and inclusive CER training essential for impactful scientific discovery.

project_terms:
Address;Career Mobility;Communication;Communities;Development;Environment;Evaluation;Fostering;Health;Health Promotion;Institution;Kentucky;Leadership;Mission;Motivation;Outcome;Policy Maker;Principal Investigator;Productivity;Provider;Research;Research Personnel;Research Training;Resources;Scholars Program;Structure;System;Training;Training Programs;Translating;Universities;Vision;career development;community engaged research;community engagement;community partnership;design;disparity elimination;dissemination strategy;experience;innovation;programs;public health relevance;scaffold;skill acquisition;skills;success

public_health_relevance:
Public Health RelevanceThe University of Kentucky (UK) proudly proposes UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities). UK ASCEND will cultivate community-engaged research (CER) success among early-stage investigators (ESIs) by implementing and evaluating the innovative ASCEND Scholars Program (ASP). Housed in the Center for Health Engagement and Transformation and leveraging UKs rich and collaborative community partnerships and institutional strengths the ASPs strategically designed comprehensive CER Training Program leads directly into a CER Pilot Program that will provide the skills development bi-directional engagement with community stakeholders and preliminary studies needed to foster research independence and promote health for all.


application_id: 11137622
project_number: 5R00AA029467-05
administering_ic: NIAAA
award_notice_date: 2025-08-12
opportunity_number: PAR-19-343
application_type: 5
activity_code: R00
ic: AA
serial_number: 029467
program_official: CUI, CHANGHAI
project_start_date: 2021-08-06
project_end_date: 2027-05-31
study_section: NSS
contact_pi_person_id: 11656822
contact_pi: JARAMILLO, ANEL ARIANA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-06-01
project_title:
Neuropeptide-dependent parabrachial control of the BNST during alcohol abstinence-induced negative affect

project_abstract:
PROJECT SUMMARY/ABSTRACT Abstinence from alcohol use induces a negative affective state that can lead to maladaptive responsesto stress and relapse. Preclinical studies have begun to identify neurocircuits and peptide targets that regulatenegative affect during abstinence. As the field has begun to develop a deeper understanding of the circuitriesparticipating in addiction and negative affect the next step is to understand how communication within thesecircuits is modulated particularly at the neuropeptide and microcircuit level. The bed nucleus of the striaterminalis (BNST) is a fundamental component of abstinence-relevant neurocircuitry as it modulates stress andalcohol-related behavior in a neuropeptide-dependent manner. To investigate peptide-specific BNST circuitrymodulating negative-affect during abstinence we will focus on afferents from the parabrachial nucleus (PBN)a brainstem region that functions as a danger signal. PBN projections to the BNST release calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) peptides thatmodulate pain and fear circuits respectively. Our studies implicate heterogenous and sexually dimorphiccontrol within the PBNBNST circuit as PBN projections induce heterogeneous ex vivo activity in BNST cellsand female-specific anxiety-like behavior with BNSTPBN activation. Furthermore our preliminary studiessuggest a role for the PBN in alcohol-withdrawal as inactivation is anxiolytic following alcohol exposure. Thisproposal will significantly build on this foundational evidence by investigating how CGRP and PACAPcontribute to PBNBNST circuit induced abstinence-induced behavior in vivo and ex vivo activity.Accordingly the mentored K99 phase will build on my in vivo fiber photometry recordings and provide trainingin ex vivo recordings to determine the role of CGRP on BNSTPBN activity abstinence-induced behavior(AIM1) and the contribution of PACAP on the CGRP-neuromodulation (AIM2). The independent R00 phasewill investigate the role of PACAP on BNSTPBN at the microcircuit level and alcohol-related states with thegoal to further delineate the intricacies of peptide crosstalk (AIM3). The proposed studies and related careerdevelopment training plan in this MOSAIC Pathway to Independence Award collectively provide the idealmechanism to transition the applicant to a career as an independent addiction neuroscientist. The results willsignificantly advance our understanding of neurocircuit mechanisms at the peptide and microcircuit level inprotracted abstinence while informing the use of peptidergic pharmacotherapies in alcohol use disorders.

project_terms:
Abstinence;Affect;Alcohol consumption;Alcohol withdrawal syndrome;Alcohols;Animal Model;Anti-Anxiety Agents;Anxiety;Award;Behavior;Behavioral;Biological Availability;Brain Stem;Calcitonin Gene-Related Peptide;Cell Nucleus;Cells;Chronic;Clinical Trials;Communication;Complex;Corticotropin-Releasing Hormone;Data;Development;Electrophysiology (science);Ethanol;Female;Fiber;Fright;Goals;Individual;Learning;Maintenance;Measures;Mental Depression;Mentors;Mus;Neural Pathways;Neurons;Neuropeptides;Pain;Pathway interactions;Peptides;Peripheral Nervous System;Pharmacology;Pharmacotherapy;Phase;Photometry;Population;Pre-Clinical Model;Regulation;Relapse;Reporter;Research;Resolution;Role;Sex Differences;Signal Transduction;Site;Specificity;Stress;Structure of terminal stria nuclei of preoptic region;Synapses;System;Testing;Training;Transgenic Animals;Transgenic Organisms;addiction;affective disturbance;alcohol abstinence;alcohol behavior;alcohol exposure;alcohol use disorder;anxiety-like behavior;career;career development;cell type;chronic alcohol ingestion;comorbidity;diagnostic tool;experience;hypothalamic-pituitary-adrenal axis;in vivo;insight;interest;negative affect;neural circuit;neurophysiology;neuroregulation;novel;parabrachial nucleus;peptide hormone;pituitary adenylate cyclase activating polypeptide;polypeptide;preclinical study;response;sex;sexual dimorphism;skills;sobriety;therapeutic target;vapor

public_health_relevance:
PROJECT NARRATIVEAlcohol use disorder is often comorbid with anxiety depression and stress thereby making it harder tomaintain sobriety. To alleviate negative affective disturbances in abstinence this project will provide insight onnovel peptide targets within neural pathways that will lead to better diagnostic tools and treatment options.


application_id: 11137597
project_number: 5R01NS088555-09
project_title: B Cells Directly Alter Adaptive Plasticity to Support Functional Recovery After Stroke
administering_ic: NINDS
award_notice_date: 2025-07-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 088555
program_official: BOSETTI, FRANCESCA
project_start_date: 2015-02-01
project_end_date: 2026-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The central hypothesis of this R01 renewal focuses on a subset of B cells that provide neurotrophic support to counter cognitive impairment and improve motor function after ischemic stroke a key risk factor for the development of vascular contributions to cognitive impairment and dementia (VCID). These neurotrophic B cells secrete brain-derived neurotrophic factor (BDNF) and may be critical to countering the development of VCID. Unfortunately the patient population most at risk for stroke and VCID aged individuals have impaired B cell development and secretion of growth factors that could limit protection from post-stroke depression and dementia. Sex is also a factor as elderly women with post-stroke dementia have the lowest levels of circulating BDNF though no prior studies have directly linked a loss of neurotrophic immune cell populations and the development of VCID. Based on our pilot data we will test: if a subset of post-stroke B cells (i.e. B cellsBDNF+) upregulate BDNF after encountering glutamate; if B cellsBDNF+ limit the development of VCID and support motor recovery; and if B cell-derived BDNF is impaired in aged females. We will use 4 mos. (young) and 16 mos. (aged) female and male mice to test if B cellsBDNF+ support neuronal function plasticity motor and multi-domain cognitive recovery post-stroke. Aim 1 will test if after stroke (1A) glutamate binds to B cells to increase BDNF production and drive recovery-linked intracellular Ca2+ signaling that is sex- and age-dependent. We will (1B) use B cellsNtrk2tm1Ddg/J in vitro totest if the BDNF receptor TrkB is required for BDNF production and in vitro neuroprotection. Aim 2 will test if B cellsBDNF+ support remote plasticity as well as cognitive and motor recovery in a primary motor cortex (M1) photothrombosis stroke model. Inducible depletion of (2A) all B cells or (2B) specific B cell-derived BDNF in young and aged female hCD20TamCre/ BDNFfl/fl mice and littermate controls will occur either acute (day 0) or delayed (beginning day 7 post-stroke). Primary outcomes will include 1) preservation of Pavlovian stimulus-reinforcer learning on an automated touchscreen task 2) improved forelimb precision reaching and 3) peri-infarct and contralesional M1 plasticity. Aim 3 will test if B cell-derived BDNF augments long-term cognitive and motor recovery. Aged C57BL/6J female mice will receive tMCAo or sham surgery and adoptive transfer of B cells that (3A) overexpress BDNF or (3B) lack BDNF the latter derived from hCD20TamCre/BDNFfl/fl donor mice beginning day 7 post-stroke. Primary outcomes will include 1) ameliorated hippocampal-specific cognitive deficits tested via touchscreen pattern separation 2) improved precision skilled reaching and 3) regional ipsi- and contralesional diapedesis of B cells as determined via whole brain serial two-photon tomography that correlates to within-animal magnitude of brain circuit-specific cognitive function and motor recovery. These studies will confirm an age-dependent loss of a novel subset of B cells B cellsBDNF+ in females that develop VCID. They will also confirm that therapeutically targeting B cells can counter post-stroke dementia and motor deficits a potential treatment supporting plasticity-based recovery after any CNS injury or disease.

project_terms:
Acute;Adult;Affect;Age;Anatomy;Animals;Anxiety;Area;Automobile Driving;Award;B-Cell Acute Lymphoblastic Leukemia;B-Cell Development;B-Lymphocyte Subsets;B-Lymphocytes;Binding;Brain;Brain region;Brain-Derived Neurotrophic Factor;Cell Survival;Cell secretion;Cell surface;Cells;Central Nervous System Diseases;Cognitive deficits;Data;Dementia;Development;Elderly woman;FDA approved;Female;Forelimb;Genetic Polymorphism;Genetic Transcription;Glutamates;Growth Factor;Health;Hippocampus;Immune;Immune system;Impaired cognition;Impairment;In Vitro;Individual;Infarction;Infiltration;Interleukin-10;Ischemia;Ischemic Stroke;Learning;Leukocytes;Link;Mediating;Memory;Middle Cerebral Artery Occlusion;Modeling;Motor;Motor Activity;Motor Cortex;Mus;N-Methyl-D-Aspartate Receptors;Neuronal Plasticity;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Pattern;Population;Production;Publishing;Recovery;Recovery Support;Recovery of Function;Research;Risk Factors;Role;Signal Transduction;Stimulus;Stroke;Support System;Synaptic Transmission;Tamoxifen;Techniques;Testing;Therapeutic;Upregulation;adoptive B cell transfer;age related;aged;aging population;automated assessment;central nervous system injury;cognitive function;cognitive recovery;dentate gyrus;disability;excitotoxicity;extracellular;functional plasticity;improved;in vitro testing;learning strategy;long-term recovery;male;migration;motor deficit;motor function improvement;motor recovery;neuroinflammation;neuronal survival;neuroprotection;neurotrophic factor;novel;overexpression;patient population;post stroke;post stroke dementia;post stroke depression;preservation;primary outcome;reinforcer;response;rituximab;sex;sham surgery;skills;stroke model;stroke recovery;stroke risk;synaptogenesis;therapeutic target;tomography;touchscreen;two-photon;vascular cognitive impairment and dementia

public_health_relevance:
PROJECT NARRATIVEStroke the leading cause of long-term adult disability has no FDA-approved therapeutic treatments to boostlong-term recovery in part because we do not understand long-term mechanisms that influence recovery. Thisresearch proposes to identify mechanisms of neurotrophin support by B cells an immune cell subset thatmoves into uninjured areas of the post-stroke brain to support recovery. These studies will be critical inunderstanding how the immune system supports neuronal plasticity to improve long-term motor and cognitiverecovery after stroke with critical consideration of age and sex in the response of B cells to stroke.


application_id: 11136875
project_number: 5K25AI177810-03
project_title: Understand the mechanism of SARS-CoV-2 entry by single-molecule approaches
administering_ic: NIAID
award_notice_date: 2025-07-16
opportunity_number: PA-20-199
application_type: 5
activity_code: K25
ic: AI
serial_number: 177810
program_official: PLIMACK, MARY KATHERINE BRADFORD
project_start_date: 2024-07-11
project_end_date: 2029-07-31
study_section: Microbiology and Infectious Diseases Advisory Committee[MID]
contact_pi_person_id: 15362631
contact_pi: SHRESTHA, PRAKASH
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its transmission across theworld was the cause of the COVID-19 pandemic. The CoV entry is mainly initiated by the binding of furincleavage activated spike (S) protein with ACE2 receptor protein on the surface of host cell. Next S2cleavage by transmembrane protease serine 2 (TMPRSS2) on the cell surface induce the conformationalchange of S2 subunit to activate the membrane fusion and entry of virus genetic material. Therefore Sprotein has been the major target to design the vaccines and therapeutics. While a handful ofinvestigations have been reported about the structure of S protein:ACE2 complex critical questions aboutthe detachment of S1/S2 subunits structural changes in S2 and their dynamics to activate the membranefusion remain. These answers will help to improve the current understanding of the mechanism of virusentry and should be highly significant for the development of effective preventions and therapeutics. I propose to combine novel DNA nanoswitch calipers (DNC) single-molecule fluorescence integratedoptical tweezers and high-throughput magnetic tweezers to study the dynamics of the molecular eventsassociated with the membrane fusion process of viral entry and analyze the heterogeneity of neutralizingantibodies (nAbs). Using DNC that I developed we showed the measurement of multiple distances within atarget biomolecule at angstrom level precision. Next we showed the high-throughput measurements inmagnetic tweezers to analyze the heterogeneous mixture of peptides. Therefore DNCs are useful to studymulticomponent protein-protein interactions and simultaneously monitor the structural changes associated withthe process. By executing these projects I will have the following three important answers. First I will measurebinding dynamics of full-length S protein and monomer/dimer ACE2 receptor proteins to understand the entireenergy landscape governing the interaction of these proteins. Second I will measure the detachment kineticsof S1/S2 subunits induced by TMPRSS2 and determine the change in conformation of S2. These reactionsare critical to understand the membrane fusion process. Third I will utilize the similar approach to measure thebinding dynamics of nAbs with S protein. By high-throughput measurements in magnetic tweezers I willanalyze the efficacy and heterogeneity of nAbs to understand the immune response of the patients andvaccinated individuals and also validate DNC assay with a cell-based pseudovirus neutralization assay. Hence the proposed work will provide detailed insight into understanding the mechanism of SARS-CoV-2 entry and rapid analysis of immune response of the patients. My quantitative approaches and advancedsingle-molecule approaches will bring insights into the field of virology and immunology. This study will alsogive me firsthand experience in biochemistry molecular biology virology and immunology enabling me tobetter apply my quantitative and physical training to more topics in biological research in the future.

project_terms:
2019-nCoV;ACE2;Adopted;Animals;Antibodies;Binding;Binding Sites;Biochemistry;Biological Assay;COVID-19 pandemic;Cell membrane;Cell surface;Cells;Complex;Coronavirus;Correlative Study;DNA;Data;Development;Dissociation;Epitopes;Event;Fluorescence;Future;Genetic Materials;Glycoproteins;Heterogeneity;Human;Immune Evasion;Immune response;Immunology;In Vitro;Infection;Investigation;Kinetics;Label;Length;Magnetism;Maps;Measurement;Measures;Mechanics;Mediating;Membrane;Membrane Fusion;Methods;Molecular Biology;Molecular Conformation;Monitor;Mutation;Patients;Peptides;Physiological;Predisposition;Prevention;Process;Proteins;Reaction;Receptor Cell;Reporting;Resolution;SARS-CoV-2 infection;SARS-CoV-2 spike protein;SARS-CoV-2 variant;Serine Protease;Structure;Surface;Therapeutic;Thermodynamics;Time;Training;Vaccinated;Vaccine Design;Vaccinee;Variant;Viral;Virus;Virus Diseases;Visualization;Work;biological research;design;dimer;experience;fluorescence imaging;improved;insight;molecular dynamics;monomer;nanoswitch;neutralizing antibody;neutralizing monoclonal antibodies;novel;optic tweezer;optical traps;patient response;polyclonal antibody;protein complex;protein protein interaction;receptor;receptor binding;single molecule;tool;transmission process;variants of concern;virology;virus genetics;virus infection mechanism

public_health_relevance:
Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) the causative agent of the Covid-19pandemic infects the host cell by binding its spike protein with the angiotensin-converting enzyme 2 (ACE2) onthe host receptor cells. Structurally spike protein has two subunits S1 and S2 and is a trimer while the ACE2protein is a homodimer; however critical questions about the dynamics of the molecular interactions to activatethe membrane fusion remain. This project will determine the dynamics of each molecular interactionassociated with the SARS-CoV-2 entry thus helping to design more effective countermeasures.


application_id: 11136787
project_number: 3K01HL149984-04S1
project_title: Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2024-07-13
opportunity_number: RFA-HL-19-026
application_type: 3
activity_code: K01
ic: HL
serial_number: 149984
suffix: S1
program_official: HUANG, LI-SHIN
project_start_date: 2021-07-15
project_end_date: 2025-06-30
study_section: ZHL1-CSR-Z(O1)
contact_pi_person_id: 14305741
contact_pi: SHEPPARD, MARY BURCHETT
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 SummaryThe applicant for this NIH Diversity K01 (RFA-HL-19-026) application is Dr. Mary Sheppard an AssistantProfessor at the University of Kentucky College of Medicine. Dr. Sheppards area of research interest isMarfan syndrome and she has established an Aortic Clinic in the Department of Surgery. Her long term careergoal is to develop new therapeutics for thoracic aortic aneurysm. This decision was influenced by her personalchallenges with this diagnosis. Desiring more treatment options Dr. Sheppard has decided to embark onadditional training in basic science research. Her short term goals which form the basis for the research planare: (1) to develop preclinical research skills that will enable her to identify new therapeutic targets to treatvascular diseases; (2) to establish herself as an expert in aneurysm research; and (3) to submit an R01funding application upon this projects completion. Dr. Sheppard has assembled an impressive mentoring teamcomposed of Drs. Daugherty Cassis Graf and Milewicz. Her primary mentor Dr. Daugherty has extensiveexpertise in animal models of aneurysm formation and he has been a successfully funded NIH investigator forseveral decades. Co-mentor Dr. Lisa Cassis is an expert in the renin-angiotensin system and sexualdimorphism of aortic aneurysms. Co-mentor Dr. Greg Graf is an expert in cholesterol metabolism and statinpharmacology. Dr. Dianna Milewicz an expert in medical genetics has a career in translational studiesfocused on genetic predisposition to vascular diseases. All mentors are senior scientists with a track record ofsuccessfully mentoring new faculty to independent NIH funding. This mentor team will assist Dr. Sheppard inlearning laboratory techniques which include advanced microscopy subcellular fractionationimmunohistochemistry and fluorescence activated cell sorting. The proposed research will examine themechanisms by which statins attenuate thoracic aortic aneurysm growth in a mouse model of Marfansyndrome. The impact of Ras farnesylation on aneurysm growth Raf/ERK expression matrixmetalloproteinase activity elastin fragmentation and leukocyte accumulation will be evaluated in Aim 1. Theimpact of statin combined with -adrenoceptor antagonist or angiotensin receptor blocker in thoracic aorticaneurysm will be investigated in Aim 2. The findings of these studies will form the preliminary data for an R01research application which will transition Dr. Sheppard from trainee status to independent physician-scientist.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Adrenergic Receptor;Aneurysm;Angiotensin Receptor;Animal Model;Aorta;Aortic Aneurysm;Aortic Diseases;Aortic Rupture;Area;Atenolol;Attenuated;Basic Science;Biological Assay;Blood Vessels;Cause of Death;Cell Fractionation;Cell membrane;Cellular Membrane;Cholesterol;Cholesterol Homeostasis;Clinic;Clinical Research;Confocal Microscopy;Cultured Cells;Data;Diagnosis;Disease;Dissection;Elasticity;Elastin;Etiology;FBN1;Faculty;Farnesyl Transferase Inhibitor;Fluorescence-Activated Cell Sorting;Funding;Future;Gel;Gelatinase A;Genetic Diseases;Genetic Predisposition to Disease;Goals;Growth;Human;Hypertension;Immunohistochemistry;Incubated;Infusion procedures;Kentucky;Laboratories;Laboratory Study;Lead;Learning;Leukocytes;Life;Losartan;Marfan Syndrome;Matrix Metalloproteinases;Measurement;Measures;Medical Genetics;Medicine;Mentors;Microscopy;Mus;Operative Surgical Procedures;Oxidoreductase;Patients;Persons;Pharmaceutical Preparations;Pharmacology;Physicians;Plasma;Pravastatin;Production;Proteins;Publications;RAS inhibition;Regimen;Renin-Angiotensin System;Research;Research Personnel;Research Project Grants;Retrospective Studies;Risk;Scientist;Senior Scientist;Signal Transduction;Signaling Molecule;Smooth Muscle Myocytes;Techniques;Testing;Therapeutic Uses;Thoracic Aortic Aneurysm;Thoracic aorta;Tissues;Training;Transforming Growth Factor beta;United States National Institutes of Health;Universities;Vascular Diseases;Vascular Smooth Muscle;Work;antagonist;ascending aorta;career;clinically relevant;college;experimental study;farnesyl pyrophosphate;farnesylation;in vivo;insight;interest;mouse model;new therapeutic target;novel therapeutics;pharmacologic;pre-clinical research;prevent;professor;repaired;sexual dimorphism;skills;standard of care;translational study;ultra high resolution;ultrasound

public_health_relevance:
Project NarrativeMarfan syndrome is a genetic condition that causes thoracic aortic aneurysm a life-threatening dilation of thelargest blood vessel in the body. This research project will examine how statin medicines prevent thoracicaortic aneurysm growth and whether they add benefit to the medicines currently used to treat thoracic aorticaneurysm in Marfan syndrome.


application_id: 11136560
project_number: 5KL2TR001996-09
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2025-07-28
opportunity_number: PAR-18-940
application_type: 5
activity_code: KL2
ic: TR
serial_number: 001996
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2027-06-30
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: BUSH, MATTHEW LEE
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:
The University of Kentucky Center for Clinical and Translational Science (CCTS) proposes to sustain and enhancethecurrent KL2 program currently in its ninth year of National Institutes of Health (NIH) support. By providing two to three years of release time (75% effort) and research funding support for mentored career development the program is designed to accelerate the academic growth for the next generation of leaders in clinical and translational research (CTR). The program has four programmatic objectives: 1) to provide a curriculum that meets core training needs of CTR scholars 2) to support a mentored program of research training that expedites development of research careers 3) to support personalized training programs that expedite CTR career development and 4) to provide continuous assessment and quality improvement of both individual scholar career development and overall KL2 program. The program has garnered strong institutional support; across the nine years the initial two NIH-supported training slots have been expanded to seven slots (four NIH-supported three institutionally supported). The program supports career development of scholars with research interests that cross the lifespan (prenatal through elderly) and the full spectrum of clinical and translational science including translational clinical community/policy studies and clinical and translational research (CTR) methods/processes (e.g. biomedical informatics) focusing on a broad array of health topics. Scholars and mentors represent a wide range of disciplines and colleges including Medicine Nursing Dentistry Pharmacy Health Sciences Public Health Education Engineering and Arts and Sciences. All program graduates (n=18) remain actively engaged in CTR have made important contributions to science through published research and have successfully competed for extramural funding with 14 as principal investigators. We are requesting renewed NIH support of four KL2 scholar training slots. The training of a minimum of three additional institutionally sponsored early-career scholars will continue to be fully integrated with these NIH-supported scholars to sustain a cohort of at least seven scholars. The foundation of the proposed program will continue to be practical research experiences within multidisciplinary teams guided by experienced mentors with a Faculty Oversight Committee monitoring the successful career development of these future CTR leaders. Educational technology promotes vigorous yet efficient competency training programs. Further our enhanced team science training programs will focus specifically on developing leadership skills. Institutionally sponsored pipeline programs targeting undergraduates medical students residents fellows and clinical instructorswill support the availability of a strong pool of candidates for the KL2 program. In sum the KL2 program is accelerating the career development of future leaders of the biomedical research workforce who are well prepared to address todays complex research challenges and spearhead future advances in human health.

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


application_id: 11136459
project_number: 5K23AR079583-04
project_title: Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness
administering_ic: NIAMS
award_notice_date: 2025-08-12
opportunity_number: PA-20-205
application_type: 5
activity_code: K23
ic: AR
serial_number: 079583
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2022-08-08
project_end_date: 2027-07-31
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 14923231
contact_pi: MAYER, KIRBY P
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Survival of critical illness such as sepsis and acute respiratory failure is accompanied by seriousphysical complications with many patients acquiring long-term impairments. Mechanisms and factors thatimpede the recovery of muscle size and function after hospitalization are not understood. It is unclear ifrecovery after critical illness leads to a subsequent deficiency in the ability to make new proteins (proteinsynthesis) or if a catabolic/inflammatory environment persists preventing muscle regrowth which involvesmuscle stem cell (satellite cell) fusion to myofibers. We will address gaps in knowledge by studying skeletalmuscle proteostasis cellular environment and RNA and mitochondrial biogenesis after critical illness withclosely aligned physical function outcomes. Understanding the cellular environment in the period after hospitalrelease and how it impacts muscle protein turnover will direct efforts to effective therapies to acceleratemuscle regrowth. The overall goal of this application is to identify cellular properties of muscle that maycontribute to long-term physical disability in survivors of critical illness. Overall I hypothesize that aberrantcellular processes in muscle are underlying prolonged functional impairments in patients after critical illness. InAim 1 we will determine the longitudinal trajectory of muscle and physical function recovery and establishmuscle morphological and cellular characteristics in patients after critical illness. We hypothesize that patientswith higher severity of illness in the ICU and with longer duration of mechanical ventilation will have the mostpersistent muscle weakness and deficits in muscle power in recovery. In Aim 2 we will identify cellularmechanisms that contribute to muscle dysfunction after critical illness. We hypothesize that patients withpersistent muscle weakness and fatigue have impaired mitochondrial function compared to controls. Moreoverwe hypothesize that survivors of critical illness have elevated myofibrillar protein synthesis and ribosomebiogenesis in early recovery but muscle regrowth does not occur due to elevated proteolysis. The overarchinggoal of this proposal focuses on elucidating the factors that lead to muscle mass dysregulation in recovery andinform why some patients develop persistent disability and others gradually improve. The proposed mentoringteam provides the knowledge and training to develop into an independent clinical investigator integrating basicand applied science. The proposed training plan in Aim 1 emphasizes clinical trial methodologies and complexlongitudinal analyses. For aim 2 the training focuses on skeletal muscle experiments; specifically knowledgeto assess muscle proteostasis mitochondrial content and function and muscle morphology. I will learn thetechnical skills to examine skeletal muscle including stable isotope labeling immunohistochemistry westernblot analysis and microscopy will be gained. Moreover the proposed research and training plan provides thenecessary training and mentorship to translate findings in this proposal into the development of targetedrehabilitation and pharmacological interventions in future R01 studies.

project_terms:
Acceleration;Acute respiratory failure;Address;Adult;Applied Research;Basic Science;Biogenesis;Biopsy;COVID-19;Cell Physiology;Cells;Characteristics;Chronic disability;Clinical;Clinical Investigator;Clinical Sciences;Clinical Trials;Complex;Critical Illness;Data;Deuterium Oxide;Development;Environment;Functional disorder;Functional impairment;Future;Gait speed;Goals;Grant;Growth;Health;Hospitalization;Hospitals;Human;Immunohistochemistry;Impairment;Inflammatory;Intensive Care Units;Intervention;Knowledge;Knowledge acquisition;Label;Learning;Long-term physical disability;Lower Extremity;Macrophage;Measures;Mechanical ventilation;Mentors;Mentorship;Methodology;Microscopy;Mitochondria;Mitochondrial Proteins;Morphology;Muscle;Muscle Fatigue;Muscle Proteins;Muscle Weakness;Muscle function;Muscle satellite cell;Outcome;Patient-Focused Outcomes;Patients;Pattern;Performance;Pharmacotherapy;Phase;Phenotype;Physical Function;Physical Rehabilitation;Property;Protein Biosynthesis;Proteins;Proteolysis;Quality of life;RNA;Recovery;Recovery of Function;Regression Analysis;Rehabilitation therapy;Research;Respiration;Ribosomes;Sepsis;Severity of illness;Skeletal Muscle;Stable Isotope Labeling;Statistical Data Interpretation;Survivors;Technical Expertise;Testing;Time;Training;Translating;Walking;Western Blotting;cell type;comparison control;disabled;effective therapy;experimental study;functional outcomes;improved;inflammatory milieu;longitudinal analysis;muscle form;muscle progenitor cell;muscle strength;novel;patient subsets;physical impairment;physically handicapped;prevent;protein degradation;proteostasis;rehabilitation research;rehabilitation strategy;skeletal muscle wasting;skills;stem

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


application_id: 11136444
project_number: 5R01HL168633-03
project_title: The serotonergic system in periaortic fat regulates regional aortopathy development
administering_ic: NHLBI
award_notice_date: 2025-08-15
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 168633
program_official: VARAGIC, JASMINA
project_start_date: 2023-08-01
project_end_date: 2027-07-31
study_section: Atherosclerosis and Vascular Inflammation Study Section[AVI]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Aortopathies are dangerous vascular diseases with no known therapy that can occur in different aortic regionsdepending on genetic and environmental factors. Periaortic fat surrounding different regions of the aorta iscomposed of different adipocyte and neuronal elements and has been reported to be associated with humanaortopathies. Preliminary data demonstrate levels of serotonin (5HT) in periaortic fat differ according to aorticregion and similarly there is differential expression of the 5HT3 receptor (Htr3) along the aortic length.Infusion of angiotensin II (AngII) a well-known stimulus of regional aortopathies was associated withregulation of 5HT levels in thoracic brown periaortic but not white abdominal periaortic fat and AngII promotedneuronal release of 5HT from thoracic aortic sections with adherent periaortic fat. Moreover J774macrophages responded to 5HT to promote inflammation and altered basal mitochondrial respiration throughan Htr3-mediated mechanism. Notably administration of an Htr3 antagonist to AngII-infused mice abolishedregional aortopathies. We hypothesize that periaortic fat-derived 5HT acts at Htr3 on resident or recruitedmacrophages within periaortic fat to promote aortic adventitial inflammation and stimulate mitochondrialreactive oxygen species production contributing to AngII-induced aortopathies. An ability of periaortic fat-derived 5HT and macrophage Htr3 to influence the aortic adventitia is likely due to the absence of an anatomicbarrier. Moreover we hypothesize that regional differences in periaortic fat-derived production of 5HT itsregulation by AngII and its ability to stimulate macrophage Htr3 contribute to regional differences in AngII-induced aortopathies. Aim 1 will define the impact of regional differences in the synthesis of 5HT and itsregulation by AngII in periaortic fat on the regional development and progression of AngII-inducedaortopathies. Aim 2 will define mechanisms of macrophage Htr3 on regional development of AngII-inducedaortopathies and investigate mechanisms of 5HT/Htr3 to promote macrophage inflammation and mitochondrialdysfunction. Results from these studies will identify a novel role for periaortic fat through a 5HT/Htr3mechanism on regional aortopathy development and may identify new therapeutic targets optimized tospecific regional aortopathies.

project_terms:
Abdomen;Adipocytes;Anatomy;Aneurysm;Angiotensin II;Aorta;Aortitis;Area;Brown Fat;Calcium;Catabolism;Cations;Cd68;Chest;Complement;Dangerousness;Data;Deamination;Development;Diffuse;Disease;Elements;Environmental Risk Factor;Enzymes;Exposure to;Fatty acid glycerol esters;Functional disorder;Genetic;Human;Hydrogen Peroxide;In Vitro;Inflammasome;Inflammation;Infusion procedures;Ion Channel Gating;Left;Length;Ligands;Link;Lipopolysaccharides;Macrophage;Mediating;Mitochondria;Modeling;Monoamine Oxidase;Mus;Mutant Strains Mice;Myelogenous;Necrosis Induction;Neurons;Neurotransmitters;Peripheral;Production;Protein Isoforms;Reactive Oxygen Species;Regulation;Reporting;Respiration;Risk;Role;Rupture;Serotonergic System;Serotonin;Sex Chromosomes;Side;Source;Stimulus;Thermogenesis;Thoracic aorta;Tropisetron;Tryptophan;Tryptophan 5-monooxygenase;Tunica Adventitia;Vascular Diseases;abdominal aorta;abdominal fat;antagonist;aortic arch;differential expression;in vivo;male;mitochondrial dysfunction;nerve supply;neural;new therapeutic target;novel;receptor;recruit;regional difference;sex;therapeutic target;uptake

public_health_relevance:
We will define mechanisms for regional formation of aneurysms in the aorta a deadly disease with notherapies. We will focus on a neurotransmitter produced by fat surrounding the aorta. This novel target mayprovide a therapeutic target for aneurysmal disease.


application_id: 11135395
project_number: 5K01AG073698-04
administering_ic: NIA
award_notice_date: 2025-08-12
opportunity_number: PA-20-190
application_type: 5
activity_code: K01
ic: AG
serial_number: 073698
program_official: JOSEPH, LYNDON
project_start_date: 2022-08-01
project_end_date: 2027-06-30
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 12504171
contact_pi: SAMAAN, MICHAEL A
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_title:
Quantifying the Mechanism and Impact of Hip Extensor Muscle Dysfunction During Aerobic Exercise in Hip Osteoarthritis

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

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

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


application_id: 11135367
project_number: 5R01HL172813-02
project_title: Circadian Regulation of Cardiac Electrophysiology
administering_ic: NHLBI
award_notice_date: 2025-04-02
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 172813
program_official: SHI, YANG
project_start_date: 2024-07-09
project_end_date: 2028-04-30
study_section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA]
contact_pi_person_id: 7001509
contact_pi: DELISLE, BRIAN P
other_pis: SCHRODER STUMPF, ELIZABETH A
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract.Circadian clocks play a fundamental role in aligning physiological and behavioral processes to predictablechanges in the daily environment. For decades circadian signaling has been implicated in the development ofcardiac arrhythmias and sudden cardiac death (SCD) in individuals with cardiovascular disease. Howevernumerous critical knowledge gaps persist regarding the connection between circadian clocks circadianrhythms and SCD. This research proposal addresses these knowledge gaps by investigating the molecularmechanisms underlying the circadian regulation of ion channel transcripts and proteins that impact arrhythmiasusceptibility.Aim 1 will elucidate the molecular mechanisms responsible for the circadian regulation of cardiac ion channelgenes essential for cardiac excitability. Through comprehensive promoter analyses utilizing real-timebioluminescence assays (LumiCycle) we will identify the conserved cis-regulatory element(s) essential forcircadian activity. The identified cis-regulatory element(s) will be validated using ChromatinImmunoprecipitation and electrophoretic mobility shift assays.Aim 2 focuses on determining how circadian alignment and misalignment affect the transcription andtranslation of genes essential for normal cardiac electrophysiology. We will explore the impact of time-restrictedfeeding on the transcriptional and translational regulation of myocardial genes important for cardiac excitabilityby employing mRNA-seq and Ribo-seq technology.Aim 3 will determine the physiological implications of circadian alignment and misalignment on cardiacelectrophysiology autonomic regulation and arrhythmia susceptibility. We will assess the impact ofmanipulating feeding-fasting cycles on cardiac electrophysiology and arrhythmia susceptibility utilizing anarrhythmogenic mouse model with impaired cardiac conduction and ventricular refractoriness (Scn5a+/-). Wewill also investigate how feeding-fasting cycles modulate the autonomic nervous system's regulation of cardiacelectrophysiology using an inducible cardiomyocyte-specific Rrad knockout mouse model (iCSRrad).This interdisciplinary project lies at the interface between chronobiology and cardiac electrophysiology and itwill generate new knowledge to provide valuable insight into how circadian clocks and alignment impact therisk for cardiac arrhythmias. In addition the results of this project are expected to identify novelchronotherapeutic strategies that can readily be adopted to mitigate arrhythmogenic risk in vulnerablepopulations.

project_terms:
ARNTL gene;Address;Adopted;Affect;Arrhythmia;Autonomic nervous system;Behavior;Behavioral;Biochemical;Biological Assay;Bioluminescence;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac Myocytes;Cardiovascular Diseases;Chronobiology;Circadian Rhythms;Complement;Cues;Darkness;Data;Development;Electrophoretic Mobility Shift Assay;Electrophysiology (science);Environment;Fasting;Feeding behaviors;Gene Expression;Gene Expression Profiling;Gene Expression Regulation;Genes;Genetic Transcription;Genomics;Heart;Impairment;Individual;Ion Channel;Ion Channel Protein;Knock-out;Knockout Mice;Knowledge;Laboratories;Light;Mediating;Messenger RNA;Molecular;Mus;Myocardial;Periodicity;Persons;Pharmaceutical Preparations;Physiological;Physiology;Play;Predisposition;Process;Proteins;Refractory;Regulation;Regulator Genes;Regulatory Element;Research;Research Proposals;Risk;Role;Signal Transduction;Technology;Telemetry;Time;Time-restricted feeding;Tissues;Transcript;Transcriptional Regulation;Translational Regulation;Translations;Ventricular;Vulnerable Populations;chromatin immunoprecipitation;circadian;circadian pacemaker;circadian regulation;environmental change;feeding;in vivo;insight;mRNA sequencing;mouse model;multiple datasets;novel;promoter;ribosome profiling;sudden cardiac death;suprachiasmatic nucleus;tool;transcription factor;translatome

public_health_relevance:
Project NarrativeThe overall objective of the proposed research is to elucidate molecular mechanisms regulating the circadianexpression of ion channel transcripts and proteins that impact arrhythmia susceptibility. To do this we will applycontemporary genomic biochemical and molecular tools to interrogate the circadian regulation of myocardialion channel transcription and translation in cardiomyocytes. We will complement these studies by usingelectrophysiology approaches that allow us to determine whether feeding behavior can be manipulated as achronotherapeutic strategy to ameliorate the risk for cardiac arrhythmias.


application_id: 11135345
project_number: 5P20GM155899-02
project_title: Community Engagement and Outreach (CEO) Core
administering_ic: NIGMS
award_notice_date: 2025-07-29
opportunity_number: PAR-23-257
application_type: 5
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: ZGM1-RCB-3
subproject_number: 9136
contact_pi_person_id: 79485266
contact_pi: DUNN, KELLI MATHESON BULLARD
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Community Engagement and Outreach Core (CEO) plays a pivotal role in achieving the Louisville Clinical and Translational Research Centers (LCTRC) mission to build clinical and translational (C&T) research capacity that addresses the severe health problems among Kentucky residents. With the IDEA award the CEO will leverage existing and build new community-to-bedside alliances to strengthen our workforce resources and infrastructure to address the burden of chronic disease among KY residents. We will target residents of urban Louisville and 18 rural counties within the Owensboro area since these locations suffer disproportionately from chronic diseases. The CEO will foster safe respectful and multi-directional communication so community members researchers and other stakeholders can share health concerns knowledge and research ideas/findings using Community Knowledge Exchange Sessions. We will use a newly revamped health literacy framework to empower our target audience to use attained health knowledge to make informed decisions about their health and willingness to participate in C&T research. We will support both community and academic researchers so they can collaborate on clinical and translational research using community based participatory (CBPR) principles. CBPR seeks to actively engage the community in all phases of the research process while addressing community-identified health concerns. Researchers will take advantage of LCTRC resources guidance and input from key stakeholders especially community members community partners and faculty mentors. In collaboration with LCTRC cores the CEO will offer investigators and research staff training in C&T CPBR and cultural respect. This will provide researchers with essential strategies to overcome the barriers (e.g. distrust lack of health literacy) to recruit and retain study participants in C&T research. In collaboration with a community-engaged advisory board and LCTRC cores the CEO will help make all health education materials communications and resources accessible to all populations. This multi-pronged approach will build trust needed to recruit and retain our audience into community-led and investigator-initiated C&T research. In addition empowerment of researchers and the population will inspire them to make voluntary changes to reduce the burden of disease at the individual- community- and professional-levels.

project_terms:
Address;Area;Award;Awareness;Cardiometabolic Disease;Cardiovascular system;Center for Translational Science Activities;Chronic Disease;Clinic;Clinical;Clinical Investigator;Clinical Research;Collaborations;Communication;Communities;Community Health;Community Outreach;Data;Educational Materials;Ensure;Fostering;Goals;Health;Health Care;Health behavior;Health education;Household;Improve Access;Individual;Infrastructure;Intervention;Investments;Kentucky;Knowledge;Location;Malignant Neoplasms;Medical;Metabolic;Mission;Modality;Obesity;Outcome;Participant;Personal Satisfaction;Phase;Physicians;Play;Population;Poverty;Prevention;Process;Research;Research Methodology;Research Personnel;Research Project Grants;Resources;Role;Rural;Rural Population;Smoking;Training;Translating;Translational Research;Trust;Universities;Urban Population;Vision;base;burden of chronic illness;burden of illness;citizen science;combat;community academic partnership;community based participatory research;community building;community engagement;community involvement;community partners;distrust;education research;empowerment;experience;faculty mentor;health knowledge;health literacy;healthcare partner;improved;innovation;member;population health;prevent;programs;pulmonary;recruit;research study;rural area;rural counties;socioeconomics;willingness

public_health_relevance:
Impact: The CEO Core in concert with stakeholders will invest in both community-led and community-participatory C&T research to prevent manage and treat chronic diseases using multi-directional inputs.


application_id: 11135338
project_number: 5P20GM155899-02
project_title: Health Resources (HR) Core
administering_ic: NIGMS
award_notice_date: 2025-07-29
opportunity_number: PAR-23-257
application_type: 5
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: ZGM1-RCB-3
subproject_number: 9135
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overarching goal of the University of Louisville (UofL) CTR-D application is to develop promote and support clinical and translational research at UofL and our affiliated partners. A critical component of this effort is the Health Resources core (HRC) which will manage all research supported by the CTR-D. It will support two types of projects with the goal of developing a Clinical and Translational (C&T) workforce and strengthening investigator-initiated C&T research. The HRC is responsible for establishing appropriate mechanisms to administer these projects including soliciting applications arranging for their review and selecting meritorious applications for funding with priority given to investigations of diseases that affect CTR-D populations or involve collaborations of basic clinical and translational researchers. Our objective is to provide new clinical and translational investigators with the necessary resources to increase their competitiveness to secure extramural funding and to create the next generation innovations to improve the quality of life of Kentuckians and beyond. We will achieve our goal through the following Specific Aims: Specific Aim 1Solicit review and select new Pilot Projects to allow investigators to test ideas with the potential to develop independent applications such as NIH career development (K-series) or small developmental research project awards (e.g. R21). Specific Aim 2Solicit review and select new Developmental Projects for 2 years of support for independent investigators with the requisite background and scientific expertise. Specific Aim 3Pair project leads of HR Core projects that involve clinical trials with experienced clinician scientists who serve as mentors and make necessary core resources available to investigators.  Specific Aim 4Monitor HR Core projects to ensure study participant safety and that all federal state local and organizational regulatory requirements are met. We will also monitor projects for abstract paper grant application and external funding productivity. IMPACT: The research supported in this core will result in a critical increase in clinical and translational research at UofL and it partners and will develop our next generation of clinical and translational scientists.

project_terms:
Affect;Applications Grants;Award;Center for Translational Science Activities;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Unit;Collaborations;Communities;Community Outreach;Development;Disease;Ensure;Ethics;Extramural Activities;Funding;Future;Goals;Grant;Grant Review Process;Health Resources;Institution;Investigation;Link;Mentors;Monitor;Paper;Persons;Pilot Projects;Population;Productivity;Recommendation;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Scientist;Secure;Series;Testing;Training;Translational Research;United States National Institutes of Health;Universities;Work;career development;community engaged research;community engagement;data management center;design;experience;innovation;investigator training;next generation;participant safety;programs;quality of life improvement;translational scientist;virtual

public_health_relevance:
The research supported in this core will result in a critical increase in clinical and translational research at UofL and its partners and will develop our next generation of clinical and translational scientists.


application_id: 11135333
project_number: 5P20GM155899-02
project_title: Research Design Compliance and Data Management (RDCD)
administering_ic: NIGMS
award_notice_date: 2025-07-29
opportunity_number: PAR-23-257
application_type: 5
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: ZGM1-RCB-3
subproject_number: 9134
contact_pi_person_id: 9599235
contact_pi: KONG, MAIYING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Research Design Compliance and Data Management (RDCD) Core envisions itself as an unwaveringbeacon dedicated to supporting LCTRC investigators with timely and robust statistical assistance onexperimental design and data analysis access to Electronic Health Records (EHR) databases to conduct C&Tresearch facilitation of clinical trials and creation of research databases and guidance and resources on riskmanagement federal regulatory and reporting compliance on human subjects research.The UofL RDCD Core is under the leadership of Dr. Maiying Kong who is a professor in the UofL Departmentof Bioinformatics and Biostatistics (DBB) holds the Wendell Cherry Chair in Clinical Trial Research and is theDirector of Biostatistics Core at the UofL Brown Cancer Center (BCC). She has formed a talented team thatincludes four faculty members from the DBB the UofL Health (ULH) Chief Medical Information Officer (Dr. SunitaKasliwal) and her staff and the Chief Director of the UofL Clinical Trial Unit (Rachel Sheppard) and her staff.The RDCD Core aims to foster close collaboration between these accomplished DBB members and the C&Tresearchers. While ULH possesses valuable access to two extensive EHR databases Epic Cosmos and theCerner Learning Health Network (LHN) availability of these databases to UofL C&T researchers has beenrestricted. The RDCD Core is taking proactive steps to establish a partnership with ULH to make these EHRdatabases accessible to UofL C&T researchers. In conclusion the RDCD Core will harness a wealth of expertiseand resources to bring its vision to fruition through the following Specific Aims:Specific Aim 1: Provide state-of-the-art statistical support in design analysis and dissemination offindings across a spectrum of basic science translational clinical and population health studies.Specific Aim 2: Facilitate and provide guidance on the use of EHR and other large clinical datasets toensure compliance with NIH and institutional data management policies to safeguard protected healthinformation.Specific Aim 3: Provide guidance resources and training to enhance the competency of LCTRCresearchers in conducting human subjects research.Impact: RDCD Core is an essential piece of a successful UofL CTR-D program. The successful execution of thiscore will establish a centralized resource and coordination hub to provide LCTRC investigators with essentialsupport in research design data analysis compliance and data management. Furthermore through ourpartnership with ULH we will make both national Epic Cosmos and the Cerner LHN EHR databases and localEDW databases accessible which will enable LCTRC investigators to conduct C&T research with heightenedefficiency precision and put a direct focus on improving patient care.

project_terms:
Area;Basic Science;Bioinformatics;Biometry;Biostatistics Core;Cancer Center;Center for Translational Science Activities;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Unit;Collaborations;Community Outreach;Competence;Consultations;Data Analyses;Data Set;Databases;Dedications;Development;Educational workshop;Electronic Health Record;Ensure;Experimental Designs;Faculty;Fostering;Funding;Grant;Health;Health Resources;Health protection;Human Subject Research;Individual;Institution;Journals;Leadership;Learning;Medical;Mentorship;Methodology;Patient Care;Policies;Population Study;Publications;Records;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Risk Management;Talents;Training;Training Activity;Translational Research;United States National Institutes of Health;Universities;Vision;Work;clinical database;community engagement;data management;data management center;data warehouse;design;electronic data;improved;interdisciplinary collaboration;member;population health;professor;programs;translational scientist


application_id: 11135332
project_number: 5P20GM155899-02
project_title: Professional Development (PD) Core
administering_ic: NIGMS
award_notice_date: 2025-07-29
opportunity_number: PAR-23-257
application_type: 5
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: ZGM1-RCB-3
subproject_number: 9133
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Louisville Clinical and Translational Research Center (LCTRC) Professional Development (PD) Core shallpromote a diversity of training experiences to build a knowledgeable and thriving collaborative cross-disciplinarycommunity of Clinical and Translational Researchers at the University of Louisville (UofL). The PD Core aims toaddress a lack of critical mass of investigators proficient in the core competencies required to create and translateour innovations successfully. Through coordination with the Health Research (HR) Community Engagement andOutreach (CEO) and Research Design Compliance and Data Management(RDCD) Cores and with oversight from the Administrative Core (AC) the PD Core will build an innovativeeducational program and mentoring program with the following aims:Specific Aim 1: Develop a core of well-trained and supported early-stage clinician-investigators capableof securing grant funding to sustain UofL's commitment to research and translation to practice.Specific Aim 2: Build interdisciplinary teams and networks of investigators to promote innovation in C&TResearch.Specific Aim 3: Nurture our pipeline of clinician scientists by developing C&T research skills andcompetencies in our clinical professional students.Specific Aim 4: Train clinical research coordinators and research nurses in best practices and policiesand mentoring practices to better support UofLs clinical research enterprise. We will train and retain aclinical research coordinator workforce to support anticipated increases in C&T research provide 24/7 coveragefor acute care studies and support community-engaged research in the LTCRC. Regular interactions with theCEO Core shall promote and facilitate engagement in research by diverse members of the local community.Impact. Success will lead to a sustained base of well-trained clinician-scientists and mentors representing thediverse backgrounds of our target communities in South/West Louisville and Owensboro as they conductinvestigator-initiated C&T research in interdisciplinary teams in our LTCRC and improved healthcare outcomesfor the communities within Kentucky and beyond.

project_terms:
Address;Award;Center for Translational Science Activities;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Competence;Credentialing;Degree program;Dental Students;Development;Discipline;Doctor of Philosophy;Education;Educational workshop;Engineering;Faculty;Funding;Future;Grant;Growth;Health;Investigation;K-Series Research Career Programs;Kentucky;Medical Students;Mentors;Mentorship;Nursing Research;Outcome;Physicians;Policies;Productivity;Research;Research Design;Research Personnel;Research Project Grants;Scholars Program;Science;Scientist;Secure;Students;Time;Training;Training Programs;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;acute care;base;care outcomes;career development;community building;community engaged research;community engagement;data management center;design;experience;improved;innovation;member;professional students;programs;skill acquisition;skills;success;translational scientist;web site


application_id: 11135327
project_number: 5P20GM155899-02
project_title: Administrative Core (AC)
administering_ic: NIGMS
award_notice_date: 2025-07-29
opportunity_number: PAR-23-257
application_type: 5
activity_code: P20
ic: GM
serial_number: 155899
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: ZGM1-RCB-3
subproject_number: 9132
contact_pi_person_id: 2105319
contact_pi: KLEIN, JON
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The goal of this Administrative Core (AC) is to create the Louisville Clinical and Translational Research Center(LCTRC) that provides a programmatic approach to C&T research that expands and fully integrates efforts andconnects them directly with existing IDeA COBREs and the INBRE programs at UofL. The AC will lead andmanage the cores supporting a single point of access for C&T research for UofL students faculty andcommunity members.The AC will provide governance needs assessment evaluation and ensure the cores work togethercohesively and in a coordinated manner through the following Specific Aims:Specific Aim 1: Create a formal management and governance structure.Specific Aim 2: Administer resources to increase clinical trial capacity and capabilities.Specific Aim 3: Increase LCTRC and UofL IDeA COBREs and INBRE interaction and synergy.Specific Aim 4: Create and optimize a Tracking and Evaluation program.Impact. Achieving these aims will create a flexible and accountable management structure for increased C&Tresearch; enlarge the C&T research infrastructure and add novel capabilities that will allow us to perform moreC&T investigations in the urban and rural populations. The LCTRC will serve as a single point of contact forC&T research infrastructure training funding and community engagement which will ultimately lead to noveltherapeutics decreased health disparities and improved public health.

project_terms:
Accidents;Accountability;Achievement;Address;Admission activity;Award;Budgets;Cancer Center;Cardiac;Caring;Center for Translational Science Activities;Centers of Research Excellence;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Clinical Research;Clinical Trials;Clinical Trials Unit;Collaborations;Communication;Communities;Diabetes Mellitus;Educational Curriculum;Ensure;Environmental Health;Evaluation;Faculty;Feedback;Funding;Goals;Health;Health Care;Hospitals;Human Resources;Incidence;Individual;Infrastructure;Kentucky;Kidney Diseases;Lead;Malignant Neoplasms;Measures;Medical center;Mentorship;Metabolic Diseases;Methods;Monitor;Needs Assessment;Nervous System Disorder;Nervous System Trauma;Patients;Performance;Policies;Program Evaluation;Public Health;Reduce health disparities;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Rural;Rural Health;Rural Population;Strategic Planning;Structure;Students;Technology;Time;Training;Translational Research;Transplantation;Universities;Urban Population;Work;cardiovascular health;chronic liver disease;citizen science;clinical center;clinical investigation;community engagement;conflict resolution;flexibility;health care availability;improved;innovation;member;metropolitan;novel;novel therapeutics;programs;rural area;synergism;translational research program;urban area;wearable sensor technology


application_id: 11135325
project_number: 5P20GM155899-02
project_title: Louisville Clinical And Translational Research Center (LCTRC)
administering_ic: NIGMS
award_notice_date: 2025-07-29
opportunity_number: PAR-23-257
application_type: 5
activity_code: P20
ic: GM
serial_number: 155899
program_official: RICHARDS, CRYSTAL LYNETTE
project_start_date: 2024-07-10
project_end_date: 2029-06-30
study_section: ZGM1-RCB-3(CD)
contact_pi_person_id: 2105319
contact_pi: KLEIN, JON
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The vision of the Louisville Clinical and Translational Research Center (LCTRC) is to build an impactful Clinical and Translational (C&T) research program at the University of Louisville (UofL) to improve the health of Kentucky (KY) communities. Kentucky is by any measure a poor and largely rural state with a single large metropolitan center that suffers disproportionately from many chronic diseases. For example KY is ranked first in the U.S. in cancer and COPD incidence. To address these problems the UofL in its research strategic planning process created Programs of Distinction in cardiovascular disease neuroscience cancer and metabolic disease. Thus UofL has been very deliberate about developing research programs to meet the states most pressing health problems. However UofL has approached C&T research of these health problems through underfunded and admittedly uncoordinated efforts in clinical trials infrastructure research design research funding and mentorship. Also until 2019 UofL C&T research was performed almost exclusively at two facilities. In 2019 UofL created UofL Healthcare (ULH) that has 11 hospitals a cancer center and multiple outpatient centers. ULH with its larger footprint and patient volume has challenged the capacity of our C&T infrastructure but also created a major opportunity to increase the amount and quality of our C&T research. The long-term goal of the LCTRC is to build the needed workforce and expertise at UofL and our affiliated healthcare systems to conduct impactful and community engaged C&T research. We will achieve this goal through these five Specific Aims:Specific Aim 1: Expand and fully integrate clinical and translational research at UofL ULH and other healthcare partners. (Administrative and Community Engagement and Outreach Cores).Specific Aim 2: Create and implement professional development for early-career clinician investigators students and C&T research staff (Professional Development Core).Specific Aim 3: Develop Pilot and Developmental projects to support community scientists trainees early-career and established C&T investigators (Health Research Core).Specific Aim 4: Establish a centralized resource that provides LCTRC investigators with essential support in research design data analysis compliance and data management (Research Design Compliance and Data Management Core).Specific Aim 5: Invest in both community-led and community-participatory C&T research to improve public health using multi-directional inputs sensitive to the needs of all stakeholders. (Synergistic among all Cores). Successful implementation of the LCTRC will create a single point of access program for C&T research that allows us to perform studies in urban and rural populations that ultimately improve public health.

project_terms:
Address;Admission activity;Award;Biomedical Research;Biometry;Cancer Center;Cardiac;Cardiovascular Diseases;Caring;Center for Translational Science Activities;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Clinical Informatics;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Community Participation;Community Physician;Data Analyses;Databases;Development;Diabetes Mellitus;Discipline;Disease;Educational workshop;Ensure;Foundations;Funding;Goals;Growth;Health;Health Care;Health Care Systems;Heart Diseases;Home;Hospitals;Incidence;Industry;Inflammation;Infrastructure;Institution;Instruction;Investments;Jews;Kentucky;Lead;Malignant Neoplasms;Measures;Mentors;Mentorship;Metabolic Diseases;Monitor;Neurosciences;Nursing Research;Obesity;Pathogenicity;Patients;Process;Public Health;Rehabilitation Centers;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Rural;Rural Population;Scientist;Strategic Planning;Stroke;Students;Testing;Toxicology;Training;Translational Research;Transplantation;Universities;Urban Population;Vision;Workforce Development;biological research;career;community engagement;data management;data management center;design;healthcare partner;improved;learning network;member;metropolitan;microbiome research;outpatient facility;participant safety;programs;recruit;translational health science;translational research program;translational scientist;workforce needs

public_health_relevance:
Impact. With the successful implementation of LCTRC at UofL we will build and support an integrated and impactful local C&T research program that provides a single point of access to research resources; encourage community participation at all stages of C&T research; and build the ongoing infrastructure expertise and workforce to support the continued growth of local C&T research providing more treatment options for the diseases impacting Kentucky residents the most.


application_id: 11135173
project_number: 1R01AG093847-01
project_title: Lactate as a regulator of Alzheimer's pathology
administering_ic: NIA
award_notice_date: 2025-05-07
opportunity_number: PAR-22-093
application_type: 1
activity_code: R01
ic: AG
serial_number: 093847
program_official: OPANASHUK, LISA A
project_start_date: 2025-05-15
project_end_date: 2030-03-31
study_section: Special Emphasis Panel[ZRG1 AN-Z (55)]
contact_pi_person_id: 8504528
contact_pi: MACAULEY-RAMBACH, SHANNON L
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe goal of this proposal is to understand how shifts in microglial metabolism impact the progression ofAlzheimers disease (AD) and whether targeting metabolic flux reduces Alzheimers-related pathology. Workfrom our group and others now illustrates that alterations in glucose metabolism are central to Alzheimersdisease. While regional hypometabolism is a hallmark of later stage neurodegeneration recent studies suggestsubtle shifts in metabolism occur much earlier in presymptomatic AD. FDG-PET neuroimaging is the goldstandard for assessing brain glucose uptake in AD yet lacks the sensitivity to detect cell specific changes orthe fate of glucose following cellular uptake. This causes a fundamental gap in our knowledge regarding early-stage changes in metabolism what cell types drive these changes and whether these changes are protectiveor damaging to the brain. Microglia increase glucose uptake in response to amyloid-beta (A) and undergo ametabolic shift from oxidative metabolism to glycolysis with activation. We hypothesize that early metabolicadaptations in AD are driven by microglial activation causing increased glucose uptake and shifts in glucoseutilization toward a more glycolytic profile. Lactate is the metabolic end product of glycolysis and is produced inexcess during shifts from oxidative metabolism to glycolysis. Our preliminary data shows that brain andinterstitial fluid (ISF) lactate is chronically elevated in mice with amyloid plaques and blocking lactatemetabolism reduces ISF lactate and ISF A. While the role of lactate in the brain and in AD is widely debatedlactate has emerged as an essential metabolite and signaling molecule for the brain. However little is knownabout lactate as a regulator of immunometabolism and microglial activity in AD. Our preliminary data showsthat genes responsible for lactate production (Ldha) and lactate consumption (Ldhb) are highly expressed inmicroglia and Ldha expression is elevated surrounding amyloid plaques. Together this suggests that Aaggregation leads to excess lactate production which we hypothesize is due to changes in microglialmetabolism and function. While initially protective we hypothesize that these chronic shifts in microglialmetabolism exacerbate A aggregation neuroinflammation and functional deficits. In this proposal we willdetermine the relative contribution of microglia to brain metabolism lactate production and metabolic flux.Next we will use a pharmacological approach to block excess lactate as a novel target to reduce A pathologyand neuroinflammation. Lastly using a genetic approach we will selectively deplete lactate production inmicroglia to explore the impact of microglial derived lactate on brain metabolism microglia function Apathology and functional deficits.

project_terms:
Ablation;Acceleration;Acute;Affect;Alzheimer's Disease;Alzheimer's disease pathology;Amyloid;Amyloid beta-Protein;Anticonvulsants;Behavior;Behavioral;Bioenergetics;Brain;Brain Diseases;Cause of Death;Cd68;Cell Respiration;Cells;Chronic;Colony-Stimulating Factor Receptors;Complex;Consumption;Coupled;Data;Development;Disease;Disease Progression;Disease associated microglia;Endotoxins;FDA approved;Gene Expression;Genes;Glucose;Glycolysis;Goals;Hippocampus;Inflammatory;Injections;Intercellular Fluid;Knowledge;Lactate Dehydrogenase;Lactate Transporter;Lipopolysaccharides;Metabolic;Metabolism;Microdialysis;Microglia;Mitochondria;Monitor;Mus;Nerve Degeneration;Neurites;Neuroglia;Neuronal Dysfunction;Neurons;Pathology;Production;Role;Senile Plaques;Signaling Molecule;Sleep;Stimulus;Testing;United States;Waste Products;Work;abeta accumulation;beta amyloid pathology;brain metabolism;cell type;fluorodeoxyglucose positron emission tomography;genetic approach;glial activation;glucose metabolism;glucose uptake;in vivo;inhibitor;metabolomics;neuroimaging;neuroinflammation;novel;pharmacologic;programs;response;spatial transcriptomics;stable isotope;tau Proteins;therapeutic target;uptake

public_health_relevance:
PROJECT NARRATIVEAlzheimers disease is the 6th leading cause of death in the United States and is expected to triple by 2050. Workfrom our group and others now show that changes in metabolism are central to the development and progressionof Alzheimers disease. There is a critical need to understand what cell types in the brain drive early changes inmetabolism how this affects Alzheimers progression and whether these changes are a potential therapeutictarget for this devastating disease.


application_id: 11134418
project_number: 5R01MD016236-05
project_title: REsearching Sleep Time in Kentucky Communities (REST-KY)
administering_ic: NIMHD
award_notice_date: 2025-06-02
opportunity_number: PAR-20-164
application_type: 5
activity_code: R01
ic: MD
serial_number: 016236
program_official: GILLMAN, ARIELLE SAMANTHA
project_start_date: 2021-09-26
project_end_date: 2026-06-30
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 14786675
contact_pi: MOLONEY, MAIREAD
other_pis: MOGA, DANIELA CLAUDIA
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Insufficient sleep (habitual sleep duration of 6 hours) is a costly prevalent public health problem associated with numerous negative health outcomes. Prior research suggests that insufficient sleep is more prevalent among certain health populations (e.g. adults of low socioeconomic status) but our understanding of the mechanisms and consequences of sleep deficiencies in rural populations is limited. The present study REsearching Sleep Time in Kentucky Communities (REST-KY) focuses on Appalachian adults a population facing serious health problems including multiple health morbidities and premature mortality. Six of the counties with the highest concentration of insufficient sleep in the nation are in Central Appalachian Kentucky (KY) where 25-58% of adults report insufficient sleep 15+ nights/month. These counties are severely economically distressed yet nearby counties with comparable economic distress rurality and demographic homogeneity are not hotspots of insufficient sleep. Use of a mixed methods longitudinal design will allow us to evaluate mechanisms contributing to both sleep deficiencies and health in this rural community. Knowledge gaps include 1) Sparse insights into specific individual- social- and macro-level factors contributing to sleep deficiencies in Appalachian adults.; 2) It is not known if regional poor sleep and health outcomes share the same underlying mechanisms; and 3) Critical points of variance between hotspot and non-hotspot counties have not been examined. We will recruit a cohort of 400     adults from 6 insufficient sleep hotspot counties (n=200) in Appalachian KY and 6 similarly rural and economically distressed non-hotspot counties. Recruitment will be stratified across hotspot and non-hotspot counties by key demographic factors linked to sleep deficiencies (e.g. age sex) to promote county  cluster-level comparisons. Specific Aims. 1. Use mixed methods to compare how individual social and macro-level  factors linked to sleep deficiencies differ between insufficient sleep hotspot and non-hotspot counties. 2. Evaluate mechanisms driving sleep deficiencies and health outcomes over time. Bi-directional models of sleep and health outcomes will be examined. 3. Quantify day-to-day sleep reactivity (i.e. the degree to which daytime distress impacts sleep) and test if individual differences in sleep reactivity predict worsened health outcomes over time. Differences by sex and county cluster (hotspot vs. non-hotspot) will also be examined in Aims 2-3. Our multiple sophisticated objective and subjective data collection methods made possible by our interdisciplinary teams varied expertise will advance scientific knowledge about biological behavioral emotional and social contributions to sleep health. This holistic approach explicitly acknowledges the inseparable overlap between health and sleep. Our findings will offer unprecedented insight into the bi- directional relationships between sleep and health in an understudied rural population. Results will inform strategies to improve sleep health thus having strong potential for public health impact.

project_terms:
Address;Adult;Age;Alcohols;Anxiety;Appalachian Region;Attitude;Automobile Driving;Behavioral;Belief;Biological;Birds;C-reactive protein;Cardiovascular Diseases;Cardiovascular system;Caring;Child Sexual Abuse;Cirrhosis;Cognitive;Communities;County;Data Collection;Demographic Factors;Diabetes Mellitus;Diet;Disease;Disparity;Distress;Economics;Emotional;Equity;Ethnic Origin;Exercise;Eye;Face;Family;Financial Hardship;Glycosylated Hemoglobin;Glycosylated hemoglobin A;Health;Health Disparities Research;Health Status Indicators;Health behavior;Heart Diseases;Heart Rate;Hour;Immunologics;Individual;Individual Differences;Interview;Kentucky;Knowledge;Lead;Link;Malignant Neoplasms;Measurement;Measures;Mediating;Memory;Mental Depression;Mental disorders;Metabolic;Methods;Modeling;Morbidity - disease rate;Neurocognitive Deficit;Obesity;Outcome;Overdose;Participant;Perception;Physical activity;Predictive Factor;Premature Mortality;Process;Productivity;Public Health;Race;Recording of previous events;Reporting;Research;Risk;Rural;Rural Appalachia;Rural Community;Rural Population;Scientific Advances and Accomplishments;Series;Sex Differences;Sleep;Sleep Deprivation;Smoking;Social support;Societal Factors;Southeastern United States;Stress;Substance Use Disorder;Substance abuse problem;Suicide;Surveys;System;Task Performances;Testing;Time;Trauma;United States;United States National Institutes of Health;Violence;Well in self;Work;cognitive task;cohort;cost;demographics;design;economic impact;ethnic minority;health determinants;health disparity;health disparity populations;health inequalities;holistic approach;innovation;insight;interest;longitudinal design;low socioeconomic status;mortality;protective factors;racial minority;recruit;rural dwellers;rural health disparities;rurality;self reliance;sex;sleep health;sleep quantity;social;social determinants;social factors;substance use

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


application_id: 11133672
project_number: 1R56DK140148-01
project_title: Role of Hypothalamic Adgrl1 in Counteracting Hypoglycemia
administering_ic: NIDDK
award_notice_date: 2024-09-06
opportunity_number: PA-20-185
application_type: 1
activity_code: R56
ic: DK
serial_number: 140148
program_official: COOKE, BRAD
project_start_date: 2024-09-07
project_end_date: 2025-08-31
study_section: Pathophysiology of Obesity and Metabolic Disease Study Section[POMD]
contact_pi_person_id: 10526655
contact_pi: CHHABRA, KAVALJIT H
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:
The hypothalamus is a hub for counteracting dangerously low blood glucose levels by stimulating the counterregulatory response (CRR) to subsequently restore normal blood glucose levels. We recently identified hypothalamic Adhesion G-protein coupled receptor L 1 (Adgrl1) as a glucose receptor involved in energy and glucose balance. Adgrl1 is necessary in mediating a glucose-inhibited response in the ventromedial nucleus of the hypothalamus (VMH) neurons. Our preliminary findings show that Adgrl1 in the VMH is sufficient to restore the CRR to hypoglycemia in otherwise global Adgrl1 knockout mice. Moreover Adgrl1 deficiency specifically in the VMH causes an impairment in the glutamate responses to hypoglycemia. Remarkably Adgrl1 mRNA is decreased in the VMH in mouse models of diabetes a phenotype that may explain compromised CRR to hypoglycemia. Adgrl1-expressing neurons in the VMH demonstrate impaired neuronal activity following recurrent hypoglycemia. Based on these preliminary data we hypothesize: Adgrl1 in the VMH is essential for eliciting the counterregulatory response to hypoglycemia and the reduced function of VMH-Adgrl1 contributes to hypoglycemia-associated autonomic failure including compromised glutamatergic tone and impaired sympathoadrenal response. We will test the hypothesis with the following Aims: In Aim1 we will establish the contribution of VMH-Adgrl1 to eliciting the counterregulatory response to hypoglycemia. In Aim2 we will determine the involvement of VMH-Adgrl1 in regulating glutamatergic tone and adrenal sympathetic nerve activity in response to hypoglycemia to explain mechanisms underlying hypoglycemia-associated autonomic failure. Altogether this project will likely establish the contribution of the novel glucoreceptor Adgrl1 to counteracting hypoglycemia and attenuating hypoglycemia associated autonomic failure.

project_terms:
Adhesions;Adrenal Glands;Biological;Blood Glucose;Brain;Cell Nucleus;Chromaffin Cells;Closure by clamp;Continuous Glucose Monitor;Coupled;Dangerousness;Data;Deterioration;Diabetes Mellitus;Diabetic mouse;Electrophysiology (science);Equilibrium;Failure;Fiber;G-Protein-Coupled Receptors;Glucose;Glutamates;Homeostasis;Human;Hyperinsulinism;Hypoglycemia;Hypothalamic structure;Iatrogenesis;Impairment;Insulin;Insulin-Dependent Diabetes Mellitus;Knockout Mice;Measurement;Measures;Mediating;Messenger RNA;Methods;Modeling;Monitor;Mus;Nerve;Neurons;Pharmaceutical Preparations;Phenotype;Photometry;Procedures;Protocols documentation;Recurrence;Risk;Role;Streptozocin;Synapses;Synaptic Transmission;Testing;Time;blood glucose regulation;clinically relevant;defined contribution;glucose monitor;glucose receptor;improved;in vivo;mouse model;novel;prevent;real time monitoring;response;restoration;transmission process;vector

public_health_relevance:
How our brain senses and responds to changes in blood glucose levels is incompletelyunderstood. We have identified Adgrl1 as a glucoreceptor in the brain which appears tobe involved in counteracting hypoglycemia (dangerously low blood glucose levels).Through this study we will establish the contribution of Adgrl1 to glucose sensing in thebrain and its function in glucose homeostasis including counteracting hypoglycemia.Adgrl1 may emerge as a new target for preventing hypoglycemia or associatedautonomic failure in diabetes.


application_id: 11133015
project_number: 5R01HL171111-02
project_title: Functional Interactions Between Lipoproteins and Protease Inhibitors in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2025-04-21
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 171111
program_official: LIU, LIJUAN
project_start_date: 2024-07-01
project_end_date: 2028-04-30
study_section: Atherosclerosis and Vascular Inflammation Study Section[AVI]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryLipoproteins are dynamic complexes of lipid and protein in the circulation that are correlated withcardiovascular events. Lipoprotein particles can interact with over 100 different proteins in thecirculation. However except for a few core lipid-binding proteins (apolipoproteins) the functionalimplications of these protein-lipoprotein interactions are not known. We found that about 20% oflipoprotein-associated proteins are protease inhibitors. Proteases are enzymes that cleave otherproteins and they play important roles in many physiological pathways. In atherosclerosis their activityis often associated with inflammation and unstable lesions that may be more prone to rupture. Becauselipoproteins accumulate within atherosclerotic lesions and these particles are enriched with proteaseinhibitors we propose that lipoprotein-associated protease inhibitor activity may be a novel mechanismby which lipoproteins can suppress vascular inflammation and stabilize atherosclerotic lesions. Alpha-1-antitrypsin (AAT) is an abundant plasma serine protease inhibitor that is detected onboth low density and high-density lipoproteins (LDL and HDL respectively). AAT is an endogenousinhibitor of neutrophil elastase a protease generated by neutrophils and macrophages withinatherosclerotic lesions. Our central hypothesis is that lipoproteins can modulate AAT function and thiscontributes to lipoprotein-mediated effects on atherosclerosis by influencing vascular inflammation. Ourpreliminary data suggest a unique structural interaction between AAT and lipoproteins that results infunctional preservation of AAT activity. Aim 1 of our proposal will investigate this structure-functioninteraction in detail and will determine the mechanistic basis for this observation on LDL and HDL.These studies will utilize cross-liking mass spectrometry and detailed in vitro functional assays. Theliterature and our preliminary data support a potential role of AAT in various cardiovascular diseaseshowever the mechanistic contribution of AAT to vascular inflammation in atherosclerosis has not beenstudied. Aim 2 will determine the role of lipoprotein-associated elastase-inhibitor activity in vascularinflammation and atherosclerosis using in vivo mouse models of atherosclerosis. Furthermore we havedeveloped a novel lipoprotein-targeting elastase-inhibitor peptide for synthetic enhancement oflipoprotein-associated protease inhibitor activity. Aim 3 will utilize a newly generated AAT-deficientmouse model to examine the impact of AAT on hepatic lipid metabolism and atherosclerosis. Togetherthese studies will fill a significant knowledge gap in our understanding of how non-apolipoproteincomponents of lipoproteins can impact atherosclerosis risk by modulating the antiinflammatory potentialof lipoproteins. This work will also develop new tools for enhancement of lipoprotein function and dataon the potential of this approach for atherosclerosis prevention or stabilization of high-risk lesions.

project_terms:
Affect;Affinity;Anti-Inflammatory Agents;Apolipoproteins;Arterial Fatty Streak;Atherogenicity;Atherosclerosis;Binding;Binding Proteins;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Circulation;Complex;Coronary Arteriosclerosis;Data;Dyslipidemias;Elastases;Elasticity;Endothelium;Enzymes;Event;Fibrous Cap;Genes;Genetic Variation;Hepatic;High Density Lipoproteins;Human;In Vitro;Inflammation;Inflammatory;Infusion procedures;Investigation;Knowledge;Lesion;Lipid Binding;Lipids;Lipoprotein (a);Lipoprotein Binding;Lipoproteins;Literature;Low-Density Lipoproteins;Macrophage;Maps;Mass Spectrum Analysis;Measures;Mediating;Metabolism;Modeling;Morphology;Mus;Ontology;Paint;Pathway interactions;Peptide Hydrolases;Phenotype;Physiological;Plaque Instability;Plasma;Plasma Proteins;Play;Prevention;Protease Inhibitor;Protein Array;Protein C Inhibitor;Proteins;Proteomics;Risk;Role;Rupture;Serine Protease;Signal Transduction;Structure;Testing;Work;alpha 1-Antitrypsin;alpha 1-Antitrypsin Deficiency;atherogenesis;atheroprotective;atherosclerosis risk;biobank;cardiovascular risk factor;crosslink;density;elastase inhibitor;endothelial dysfunction;high risk;in vivo;lipid metabolism;lipid transport;mouse model;neutrophil;neutrophil elastase inhibitor;novel;particle;peptidomimetics;preservation;prevent;restoration;small molecule;synthetic peptide;tool;transcytosis;vascular inflammation;western diet

public_health_relevance:
Project NarrativeLipoproteins are dynamic complexes of lipid and protein in the circulation that are correlated withcardiovascular events. This project will examine a novel functional interaction between theantiinflammatory plasma protein alpha-1-antitrypsin and lipoproteins. These studies will test thehypothesis that lipoproteins influence the function of alpha-1-antitrypsin and this contributes toprotection against atherosclerotic cardiovascular disease by reducing vascular inflammation.


application_id: 11132222
project_number: 1R01NS138293-01A1
project_title: Function of sphingoid bases in brain health and disease
administering_ic: NINDS
award_notice_date: 2025-08-12
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 138293
suffix: A1
program_official: MORRIS, JILL A
project_start_date: 2025-08-15
project_end_date: 2030-05-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 9331158
contact_pi: SPASSIEVA, STEFANKA D
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
project_abstract:
Project SummarySphingolipid metabolism is fundamental for the function of the nervous system. Mutations in the enzymes ofsphingolipid metabolism lead to severe neurological disorders such as sphingolipidoses and hereditaryneuropathy underscoring the essential roles of sphingolipid metabolism in the brain. Ceramide synthase 1(CerS1) is the main neuronal isoform of the enzyme that synthesizes the common precursor for all sphingolipidsi.e. ceramide. Catalytically inactive CerS1 mutations in human and mice lead to serious neurological disordersmyoclonic epilepsy with mental retardation and cerebellar neurodegeneration with ataxia. Our previous work hasshown that neurotoxicity in CerS1 deficiency is due to the increased levels of sphingolipid basesdihydrosphingosine and sphingosine and their phosphates dihydrosphingosine-1-phosphate and sphingosine-1-phosphate. Importantly increased levels of the sphingolipid bases were shown in complex neurologicaldisorders such as Alzheimers disease. A critical knowledge gap and barrier to progress is the lack of a thoroughunderstanding of the mechanism underlying toxicity of those sphingolipid metabolites.To address this shortcoming we developed an innovative transgenic mouse model to investigate the mechanismunderlying sphingoid base-induced neurotoxicity in neurodegenerative diseases. In this transgenic model adifferent ceramide synthase isoform CerS2 is ectopically expressed in the neurons of the CerS1-deficient mice.The CerS2 transgene rescued the neurodegenerative phenotype and restored the physiological levels of thesphingoid bases and phosphates. The levels of the individual ceramide species in the CerS2 transgenic on theother hand were the same as in the CerS1 mutant. Using this mouse model we will pursue complementary invivo and in vitro approaches to dissect autonomous neuronal effects of sphingoid bases elevation on geneexpression and sphingolipid metabolism from trans-effects on glia both of which can contribute toneurodegeneration.In this proposal we will address the hypothesis that neuronal homeostasis of sphingoid bases and theirphosphate derivatives is essential for neuronal health and if dysregulated induces neuronal dysfunction andactivation of glia. We will: a) test that upregulation of the brain levels of sphingoid bases and phosphates inCerS1-deficient mutant mice alters the transcriptomes of neurons and glia over time by affecting neuronalmaturation leading to defective neuronal differentiation and the activation of glia (Aim 1); b) test how CerS1deficiency and sphingolipid base upregulation in neurons affect their intracellular membrane and lipid trafficking(Aim 2); and c) test that neuronal-induced sphingoid base phosphate signaling leads to the activation of glia (Aim3).

project_terms:
Address;Affect;Alzheimer's Disease;Anabolism;Ataxia;Brain;Brain Diseases;Cells;Ceramides;Cerebellar Ataxia;Cerebellum;Chimeric Proteins;Coculture Techniques;Communication;Complex;Cytoplasmic Granules;Data;Defect;Deposition;Dihydrosphingosine;Enzymes;Gene Expression;Genetic;Genotype;Goals;Harvest;Health;Homeostasis;Human;Impairment;In Vitro;Individual;Intracellular Membranes;Knowledge;Label;Lead;Lipofuscin;Mass Spectrum Analysis;Mediating;Membrane;Mental Retardation;Metabolic;Metabolism;Modeling;Mus;Mutant Strains Mice;Mutation;Myoclonic Epilepsies;Names;Nerve Degeneration;Nervous System Disorder;Nervous System Physiology;Neurodegenerative Disorders;Neuroglia;Neuronal Differentiation;Neuronal Dysfunction;Neurons;Niemann-Pick Diseases;Online Mendelian Inheritance In Man;Parkinson Disease;Pathway interactions;Physiological;Progressive Myoclonic Epilepsies;Prosencephalon;Protein Isoforms;Publishing;Reaction;Role;Sampling;Signal Transduction;Sphingolipidoses;Sphingolipids;Sphingosine;Sphingosine-1-Phosphate Receptor;Testing;Time;Toxic effect;Transgenes;Transgenic Mice;Transgenic Model;Transgenic Organisms;Transmembrane Transport;Ubiquitin;Upregulation;Work;analog;antagonist;base;brain health;dihydroceramide desaturase;dihydrosphingosine 1-phosphate;experimental study;glial activation;hereditary neuropathy;in vivo;innovation;inorganic phosphate;lipid transport;live cell imaging;mouse model;mutant;neurodegenerative phenotype;neurotoxicity;novel;single-cell RNA sequencing;sphingosine 1-phosphate;stable isotope;superresolution microscopy;trafficking;transcriptome

public_health_relevance:
PROJECT NARRATIVE:The role of biosynthesis of sphingolipid precursors for brain health is not well understood. Our preliminary datademonstrated that accumulation of the sphingolipid precursors the sphingoid bases and their phosphatederivatives results in neuronal damage and activation of glia leading to neurodegenerative disease. We areproposing to use unique mouse models to study the role of the sphingoid bases and their phosphate derivativesin brain health and disease.


