# projects

application_id: 11052505
project_number: 5R01CA278941-02
administering_ic: NCI
award_notice_date: 2025-02-17
opportunity_number: PAR-21-294
application_type: 5
activity_code: R01
ic: CA
serial_number: 278941
program_official: WANG, YISONG
project_start_date: 2024-03-08
project_end_date: 2029-02-28
study_section: Special Emphasis Panel[ZRG1-TIR-W(01)Q]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: GUO, HAIXUN
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
budget_start_date: 2025-03-01
project_title:
Understanding Pancreatic Cancer Immune Microenvironment and Treatment Response through Integrating in vivo Imaging with Immunophenotyping

project_abstract:
Project Summary Although cancer immunotherapy has been proclaimed a breakthrough in many types of cancer pancreaticductal adenocarcinoma (PDAC) responds poorly to immune checkpoint blockade (ICB) therapy. PDAC isclassified as immunologically cold tumor with pronounced presence of immunosuppressive myeloid cells.Therefore developing novel approaches to reprogram the PDAC tumor immune microenvironment (TiME) andpromoting immunotherapeutic efficacy are drastically needed. A key knowledge gap in understanding the PDAC TiME is a lack of tools to visualize and monitor theseimmunosuppressive myeloid cells during tumor progression and treatment. Molecular imaging approachesprovide such an opportunity through a specific cell-tracking strategy or targeting of surface molecules expressedon immune cells. In the preliminary studies we demonstrated that yeast-derived whole b-glucan particles (WGP)predominately traffic to the pancreas and incite massive infiltration of myeloid cells with trained immunityphenotype leading to a reduction in PDAC tumor progression and prolonged survival. Trained immunity isdefined as innate immune responses that can adapt and develop a memory-like phenotype of previous infectionor vaccination. Despite these successes mice treated with WGP eventually died even in combination with anti-PD-L1 therapy. The overarching goal of this proposal is to develop an integrated in vivo imaging withimmunophenotyping approach to understand PDAC immune evasion mechanisms and develop more efficacioustherapy for PDAC. Three Aims are proposed. Aim 1 will determine if induction of trained immunity reprogramspancreas myeloid cells thus reshaping their function in the PDAC TiME. We will utilize a radiolabeled WGP andan anti-CD11b probe to track WGP trafficking and influx of myeloid cells in the pancreas. We will also test thehypothesis that the abundance of pancreas tissue resident macrophages (TRMs) as measured by the lymphaticvessel endothelial hyaluronan receptor (LYVE-1) probe is a predictive marker for PDAC immune evasion andprogression. Aim 2 will determine whether combining trained immunity with anti-CD47 and/or anti-EGFR mAbtherapy promotes myeloid cell phagocytic/tumoricidal activity to maximize innate antitumor immunity. Targetedin vivo imaging will be used to monitor phagocytosis and EGFR levels within the PDAC TiME. Aim 3 willdetermine the ability of induction of trained immunity to recruit and stimulate adaptive T cells in the pancreas.We will also determine whether combining induction of trained immunity with anti-CD47 mAb therapy will furtherpotentiate anti-PD-L1 therapeutic efficacy in PADC. Immuno-imaging will be used to track CD8+ T cell infiltrationfunction and PD-L1 expression within the PDAC TiME. The successful completion of this proposal will likelyprovide a novel insight into understanding the mechanisms of PDAC immune evasion and treatment responseand resistance.

project_terms:
Anti-CD47;Biological Assay;CD44 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Control;Cancer Model;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Cytometry;Desmoplastic;Diagnosis;Disease;Eligibility Determination;Endothelium;Epidermal Growth Factor Receptor;Epigenetic Process;Excision;Exposure to;Glucans;Goals;Granzyme;ITGAM gene;Immune;Immune Evasion;Immune response;Immunity;Immunologic Memory;Immunologics;Immunophenotyping;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Infection;Infiltration;Innate Immune Response;Investigation;KPC model;Knowledge;Label;Liver;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mediating;Memory;Metabolic;Modeling;Monitor;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Organ;Pancreas;Pancreatic Ductal Adenocarcinoma;Paper;Particulate;Patients;Phagocytes;Phagocytosis;Phase;Phenotype;Publishing;Radiolabeled;Reporting;Research;Shapes;Signal Transduction;Solid;Solid Neoplasm;Stimulus;Surface;Survival Rate;Symptoms;T cell infiltration;T-Lymphocyte;Testing;Time;Tissues;Training;Treatment Efficacy;Tumor Immunity;Tumor-associated macrophages;Tumor-infiltrating immune cells;Vaccination;Visualization;Yeasts;anti-CTLA4;anti-PD-L1;anti-PD-L1 therapy;anti-PD1 antibodies;anti-tumor immune response;antitumor effect;cancer immunotherapy;cancer type;effective therapy;efficacious treatment;imaging approach;immune checkpoint blockade;immune imaging;improved;in vivo imaging;ineffective therapies;innate immune mechanisms;innovation;insight;intraperitoneal;lymphatic vessel;molecular imaging;mouse model;nanobiologic;novel;novel strategies;novel therapeutics;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;particle;predictive marker;programmed cell death ligand 1;programs;rational design;recruit;response;subcutaneous;success;therapy design;therapy resistant;tool;trafficking;transcriptomics;treatment response;tumor;tumor progression;tumor-immune system interactions;tumorigenic

public_health_relevance:
Project NarrativeThe overall goal of this proposal is to develop an integrated in vivo imaging with immunophenotypingapproach to understand the immune evasion mechanisms of pancreatic cancer and develop more effectivetherapies for this disease. The successful completion of this study may provide an innovative approach totreating pancreatic cancer and the knowledge gained from this study may also help us develop a rationallydesigned intervention for pancreatic cancer patients.


application_id: 11052468
project_number: 5R01HL163272-04
project_title: Extracellular Matrix Dynamics During Remodeling
administering_ic: NHLBI
award_notice_date: 2025-04-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163272
program_official: WONG, RENEE P
project_start_date: 2022-04-01
project_end_date: 2027-03-31
study_section: Integrative Myocardial Physiology/Pathophysiology B Study Section[MPPB]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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 SummaryInvestigations of ventricular remodeling have focused almost exclusively on changes in collagen depositionand matrix metalloproteinase activity. While such investigations have provided numerous insights into fibrillarchanges in the extracellular matrix (ECM) little attention has been paid to the non-fibrillar components of theECM. Indeed the ECM is composed of numerous soluble and bound factors. The roles of these various ECMcomponents are diverse but largely unknown. Moreover how these factors interact with existing parenchymalcells the changing and expanding populations of mesenchymal cells and the transitory leukocytes such asmacrophages remains to be examined carefully. Despite the complexity of the ECM our understanding of itremains primitive. In fact one of the most abundant components of the ECM hyaluronan (HA) functionsthrough largely cryptic or presumed mechanisms. Ultimately derived from glucose HA is synthesized by afamily of enzymes known as hyaluronan synthases (HAS). The role of HA may differ dynamically throughoutremodeling. Our preliminary data indicate that HA accumulates in the heart early after a myocardial infarction(MI) and its accumulation persists for weeks after MI. We also show that acutely activated fibroblasts contributeto HA production. Given that HA accumulates quickly following MI and activated fibroblasts can increase HAproduction this suggests a potential role for a fibroblast-HA axis in acute scar formation. Yet the persistentaccumulation of HA may provoke macrophage-dependent inflammation and contribute to adverse remodelingafter the scar has matured. Our preliminary data show that HA directly impairs macrophage function whichmay underlie non-resolving inflammation in the remodeling heart. We posit that the changing roles of HA in theacute post-MI setting versus chronic heart failure comprise major unappreciated events in ventricularremodeling. This insinuates that HA is neither purely pathologic nor purely adaptive. Rather the role of HA iscontext dependent. For these reasons we must understand the regulation of HA production in the failing heart.We posit that acutely after MI fibroblasts leverage metabolic changes to produce more HA and contribute toscar formation; however the inexorable accumulation of HA may transition into a contributor to pathology inthe chronic phases. Over the course of this project we will use a battery of gain- and loss-of-functionapproaches to test the central hypothesis that changes in fibroblast glucose metabolism drive hyaluronanproduction which acutely aids in scar formation but chronically prolongs inflammation and promotes adverseremodeling. Regardless of specific outcomes completion of this project will create fundamental mechanisticinsights into the causes and consequences of changes in the extracellular matrix during ventricular remodeling.

project_terms:
Abate;Acute;Anabolism;Attention;Binding;Biomechanics;CD44 Antigens;Cardiac;Cardiac Myocytes;Catabolism;Cells;Chronic;Chronic Phase;Cicatrix;Collagen;Collagen Fibril;Complex;Congestive Heart Failure;Coupled;Data;Dependence;Deposition;Disease;Embryo;Enzymes;Event;Extracellular Matrix;Family;Fibroblasts;Fibrosis;Glucose;Glycolysis;HAS2 gene;Heart;Heart failure;Hyaluronan;Hyaluronidase;Impairment;Inflammation;Inflammatory;Investigation;Knowledge;Leukocytes;Macrophage;Matrix Metalloproteinases;Mediating;Mesenchymal;Metabolic;Metabolism;Mus;Myeloid Cells;Myocardial Infarction;Outcome;Pathologic;Pathology;Pathway interactions;Phase;Population;Process;Production;Proliferating;Proxy;Regulation;Role;Shapes;Testing;Tissues;Ventricular Function;Ventricular Remodeling;cell type;gain of function;glucose metabolism;hyaluronan synthase 1;insight;loss of function;metabolomics;migration;response to injury;stable isotope;wound healing

public_health_relevance:
Project NarrativeThis project will address how the composition of the heart influences the trajectory of heart failure. In addition itwill elucidate new concepts relating metabolism to inflammation.


application_id: 11050014
project_number: 1R01HL172844-01A1
project_title: Mechanisms of Thrombosis in SARS CoV-2 Infection
administering_ic: NHLBI
award_notice_date: 2025-01-10
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 172844
suffix: A1
program_official: WARREN, RONALD Q
project_start_date: 2025-01-15
project_end_date: 2028-11-30
study_section: Special Emphasis Panel[ZRG1 IVBH-F (02)]
contact_pi_person_id: 9231243
contact_pi: WOOD, JEREMY P
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractMore than 100 million individuals in the United States have experienced Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Life-threatening thromboticevents are well-described in these patients and occur in 2-3% of hospitalized patients. However it is clear thata much greater number of patients experience microclots small thrombotic events capable of causing localizedtissue damage and that microclots associate with the development of long-term complications from COVID-19.We hypothesize that these microclots result from a combined procoagulant and antifibrinolytic state.Through our preliminary studies we have identified two novel regulatory mechanisms that lead to thehemostatic and fibrinolytic dysfunction and microclot formation: (1) Activated endothelial cells secrete vonWillebrand Factor (VWF) which binds and sequesters and inhibits protein S (PS) a critical plasmaanticoagulant; and (2) dyslipidemia and elevated plasminogen activator inhibitor-1 result in sequestration andinhibition of the fibrinolytic protein tissue plasminogen activator (tPA). This combination of impairedanticoagulant and impaired fibrinolytic activity results in the formation of stable microclots capable of blockingblood flow in microvascular beds and causing localized hypoxia and tissue damage. We hypothesize thatthese dysfunctions occur during the acute phase of COVID-19 infection and persist in a sub-populationof patients post-infection. As such these mechanisms contribute to both acute and post-acute COVID-19-associated coagulopathy. In the present study we will test these hypotheses and extend our previousfindings by following patients longitudinally from first diagnosis through 6-months post-infection to identify thechanges in the hemostatic and fibrinolytic systems directly assess the contributions of PS and tPA to thisprocess and their regulatory mechanisms and determine the correlation of dysfunctions in these systems withmicroclot formation and recovery post-infection. Finally we will perform similar analyses using samples from acohort of patients with post-acute sequelae of COVID-19 (PASC) long-term complications from their initialinfection. We hypothesize that these patients are individuals whose systems did not fully recover from the initialinfection and the proposed studies will allow us to compare the hemostatic and fibrinolytic systems betweenacute and PASC patients to evaluate this hypothesis with particular focus on PS and tPA. The results from thisstudy will inform on the mechanism(s) leading to COVID-19-associated coagulopathy and may determinebiomarkers that can be used to identify those patients at greatest risk.

project_terms:
2019-nCoV;Acute;Alteplase;Anticoagulants;Antifibrinolytic Agents;Binding;Binding Proteins;Biological Markers;Blood Coagulation Disorders;Blood Platelets;Blood coagulation;Blood flow;COVID-19;COVID-19 complications;COVID-19 patient;COVID-19 treatment;Cause of Death;Cell secretion;Centers for Disease Control and Prevention (U.S.);Clinical;Coagulation Process;Data;Development;Diagnosis;Dyslipidemias;Endothelial Cells;Endothelium;Event;Functional disorder;Goals;Health;Hematologist;Hemostatic Agents;Hospitalization;Hypoxia;Immunologist;Impairment;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Lead;Life;Lipoprotein Binding;Lipoproteins;Long COVID;Low-Density Lipoproteins;Measurement;Microcirculatory Bed;Modeling;Outcome;Pathology;Patients;Persons;Phase;Phenotype;Plasma;Plasmin;Plasminogen;Plasminogen Activator Inhibitor 1;Population;Post-Acute Sequelae of SARS-CoV-2 Infection;Predisposition;Prevalence;Process;Protein S;Protein S Deficiency;Proteins;Recovery;Regulation;Risk;SARS-CoV-2 infection;Sampling;Stimulus;Symptoms;System;Testing;Thrombosis;Time;Tissues;United States;Virus;activated Protein C;acute COVID-19;acute infection;cohort;experience;individual patient;insight;mortality;novel;patient subsets;response;severe COVID-19;therapeutic target;thrombotic;von Willebrand Factor

public_health_relevance:
Project NarrativeBlood clots are a leading cause of death in people with severe COVID-19 infection and are thought tocontribute to long-term complications from COVID-19 though the causes of these clots are not clear. Thegoals of this project are to understand how dysfunctions in the bodys hemostatic and fibrinolytic systems leadto the formation of clots. The results will have implications for the treatment of COVID-19 patients and mayprovide insight into the bodys responses to other serious infections which are commonly associated withthrombosis.


application_id: 11049177
project_number: 5R01MD016864-04
project_title: K-VAC: Kentucky Vaccinating Appalachian Communities
administering_ic: NIMHD
award_notice_date: 2025-07-13
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: MD
serial_number: 016864
program_official: JOSEPH, SUSAN KALAPURA
project_start_date: 2022-07-15
project_end_date: 2028-03-31
study_section: Special Emphasis Panel[ZRG1-HDM-V(90)]
contact_pi_person_id: 6914381
contact_pi: KIVINIEMI, MARC T
other_pis: CARDARELLI, KATHRYN MARIE
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTVaccination of adults is central to control of SARS-CoV-2/COVID-19 and multiple other infectious diseases.Failure to engage in vaccine uptake is a complex multilevel systems problem--individual factors such asfatalism lack of factual information medical and government mistrust and political affiliation are all knowninhibitors to vaccine uptake as are community factors such as lack of access limited delivery mechanismsand messages from untrusted communicators. Thus addressing vaccine hesitancy requires a multilevelintervention that aligns and addresses individual relational and structural elements to incorporate all of thenecessary and sufficient components to increase uptake. COVID-19 vaccine uptake among Appalachianresidents has been unacceptably low with rates plateauing months ago. Appalachian Kentucky encompassesa number of population characteristics that add up to a "perfect storm" for a vaccine hesitant population.Structurally the region is rural with many communities geographically isolated and lacking access to healthcare. This in addition to poverty low education and high levels of chronic disease place this population atsignificant risk of complications and mortality due to COVID-19 infection. In a population that historically hasdistrusted institutions vaccination interventions must leverage culturally appropriate community partnershipsand strategies. The purpose of this community-engaged study is to optimize SARS-CoV-2 vaccine uptake bythis highly vulnerable Appalachian Kentucky population. We will achieve three specific aims: Aim 1: Using acommunity-engaged approach elucidate: a) key themes for message content and framing that addressindividual-level factors b) trusted communicators to deliver culturally-sensitive messages and c) structuralbarriers to effective vaccine delivery as well determining to what degree such factors are community-specificversus more generalizable. Aim 2: Using a cluster randomized trial design assess the efficacy of a multilevelintervention that delivers individual-level target messaging tailored for theme and presentation by trusted localcommunicators AND that provides structural components to facilitate easy and acceptable access tovaccination delivery. Aim 3: Determine the process factors that affect reach acceptance and implementationfidelity for the intervention components as well as necessary adaptation components for broadertransferability dissemination and delivery of the intervention. Our long-term goal as a research team is todevelop effective multilevel intervention strategies that can be used to address vaccine hesitancy inAppalachian and similar rural populations for existing vaccination concerns.

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

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


application_id: 11048814
project_number: 5R01AI165521-04
project_title: Novel antiviral mechanisms of the interferon system
administering_ic: NIAID
award_notice_date: 2025-04-29
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 165521
program_official: SINGLETON, KENTNER L
project_start_date: 2022-05-25
project_end_date: 2028-04-30
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 10321717
contact_pi: CHATTOPADHYAY, SAURABH
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe respiratory viruses including coronaviruses the paramyxo/pneumoviruses and the influenza virus causelethal human diseases and the treatment options are limited or non-existent. The interferon (IFN) system is thefirst line of host defense against a wide range of viral infections. Viral infection is sensed by the cellular patternrecognition receptors which via a series of signaling proteins trigger the transcriptional induction of IFNs andIFN-stimulated genes (ISGs). The ISG-encoded proteins either alone or in combination with other ISGs inhibitone or more viral life cycle stages. The molecular mechanisms of these restriction factors many of whichfunction virus and cell-specifically are insufficiently understood. Furthermore IFN as antiviral therapy hasnumerous side effects. To identify viral restriction factors against paramyxoviruses we used a high throughputgenetic screen of a human ISG shRNA library. Our screen identified a novel viral restriction factor TDRD7which we demonstrated for the first time as an antiviral ISG. We reported that TDRD7 inhibits the virus-induced autophagy pathway which is required for the replication of paramyxoviruses (SeV HPIV3) as well asthe pneumoviruses (RSV). TDRD7 inhibits autophagy by suppressing the autophagy-initiating kinase AMP-activated kinase (AMPK). In support of this antiviral mechanism we recently demonstrated that TDRD7 inhibitsthe replication of herpesviruses which surprisingly require AMPK but not its autophagy branch. Therefore wediscovered a new antiviral mechanism of the IFN system mediated by TDRD7/AMPK. Currently the molecularmechanism by which TDRD7 inhibits the pro-viral AMPK and the contribution of TDRD7 to prevent viralpathogenesis is unknown. To investigate this we generated preliminary results to show that: (a) TDRD7interacts directly with AMPK to inhibit its activation (b) the ubiquitination of TDRD7 regulates its functions and(c) the newly-engineered conditional Tdrd7 KO mice and the derived primary cells show elevated viralreplication and pathogenesis. These compelling new results led to our hypothesis that TDRD7 a newly-identified viral restriction factor interacts directly with the pro-viral AMPK to inhibit its activation and respiratoryviral replication and pathogenesis and the TDRD7 functions are regulated by its ubiquitination. To test this wewill: SA1) determine the molecular mechanisms by which TDRD7 inhibits AMPK and SA2) evaluate thecontribution of TDRD7 to host antiviral responses. Our study is significant because we offer a novel conceptthat TDRD7-mediated inhibition of pro-viral AMPK is a new antiviral pathway of the IFN system withimplications beyond virus infection. Our study is innovative both conceptually and technically with a team ofcomplementary expertise. Based on the preliminary results our future studies will further reveal how TDRD7inhibits the lethal respiratory pathogen the influenza A virus. The results obtained will uncover novel cellularmechanisms to restrict virus infection and an AMPK-inhibitory function of the IFN system with broadertherapeutic implications in viral and non-viral diseases.

project_terms:
5'-AMP-activated protein kinase;Ablation;Address;Alveolar Macrophages;Anti-viral Response;Anti-viral Therapy;Autophagocytosis;Biochemical;Bone Marrow;C-terminal;CRISPR/Cas technology;Cells;Chemicals;Complex;Coronavirus;Dendritic Cells;Disease;Embryo;Engineering;Fibroblasts;Future;Genes;Genetic;Genetic Screening;Genetic Transcription;Goals;Herpesviridae;Host Defense;Human;Influenza A virus;Interferons;Knockout Mice;Knowledge;Libraries;Life Cycle Stages;Lung;Maps;Mediating;Microscopic;Modeling;Molecular;Morbidity - disease rate;Mus;Mutate;Nature;Para-Influenza Virus Type 3;Paramyxovirus;Pathogenesis;Pathway interactions;Pattern recognition receptor;Phosphotransferases;Pneumovirus;Proteins;Publishing;Regulation;Reporting;Role;Sendai virus;Series;Signaling Protein;Simplexvirus;System;Testing;Therapeutic;Time;Ubiquitin;Ubiquitination;Viral;Viral Load result;Viral Pathogenesis;Viral Physiology;Viral Respiratory Tract Infection;Virus;Virus Diseases;Virus Replication;Work;domain mapping;genetic approach;human disease;in vivo;influenzavirus;inhibition of autophagy;innovation;mortality;novel;novel strategies;prevent;respiratory;respiratory pathogen;respiratory virus;response;side effect;small hairpin RNA;tool;viral detection;virus host interaction

public_health_relevance:
Project NarrativeRespiratory viral infection contributes to a large amount of morbidity and mortality and in most cases thetreatment options are limited or non-existent. The proposal will address how a new viral restriction mechanismof the interferon system inhibits the cellular autophagy pathway to control paramyxovirus replication.Successful completion of the proposed work will reveal new facets of host-virus interaction leading to potentialtherapeutic strategies to inhibit virus replication and pathogenesis.


application_id: 11047986
project_number: 1R01HD114728-01A1
project_title: The MiLC Study: Moringa in Lactation and Early Childhood
administering_ic: NICHD
award_notice_date: 2025-09-18
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: HD
serial_number: 114728
suffix: A1
program_official: ROSS, SHARON A
project_start_date: 2025-09-25
project_end_date: 2030-06-30
study_section: Nutrition and Metabolism in Health and Disease Study Section[NMHD]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: 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:
Exclusive breastfeeding (EBF) for the first six months of life is estimated to save over 800000 child deathsunder 5 years. In low- and middle-income countries with high rates of child undernutrition the importance ofEBF increases further. Despite this there are limited proven medications or foods to increase milk volume. Weinvestigated the benefits of a nutrient-dense potential galactagogue the powdered leaf of the Moringa oleifera(moringa) in a pilot randomized controlled trial of moringa leaf powder supplementation in 50 mother-infantpairs in Western Kenya. We found that mothers consuming 20g of moringa daily for three months had doublethe volume of breast milk compared to controls with no dilution of protein and fat content. In addition infants ofmothers consuming moringa had increased growth-related hormone insulin-like growth factor-1 (IGF-1) andhemoglobin over controls. Our overall objective is to evaluate the effect of moringa on mothers ofundernourished infants on milk volume milk composition EBF rates and maternal and infant health. Wehypothesize that moringa supplementation to mothers of undernourished infants increases milk volumeenhances milk nutrients and improves select markers of maternal and infant health. These changes are drivenby maternal hormonal regulation of lactation longer duration of EBF and increased concentration of nutrientdelivery to mothers directly and to infants via breastmilk. Design: We will perform a cluster-randomized single-blinded controlled trial. Mothers of undernourished infants in Western Kenya will either receive 20g moringaleaf powder in corn porridge or corn porridge alone daily for six months with follow-up visits every 3 months fortwo years. Milk serum and urine samples dietary variables and a survey of perceptions of breastfeeding atbaseline and periodically throughout the study will be collected. We will perform anthropometrics and collectinformation on medical diagnoses and feeding practices at each visit. Aims: 1: Determine the impact ofmaternal moringa consumption on milk volume and infant milk consumption and investigate mechanismsdriving these effects. 2: Quantify the impact of maternal moringa supplementation on duration of EBF andconcentrations of selected nutrients in human milk. 3: Assess the effect of moringa supplementation onselected indicators of maternal and infant health. Primary outcomes: Comparing between groups we willexamine increases in milk volume prevalence and duration of EBF and infant growth via changes in IGF-1.Significance: This trial investigates the role of moringa in lactation and early childhood. This innovative studyintersects with the NICHD Pediatric Growth and Nutrition Branch priority on understanding how human milkaffects the health of the infant and lactating parent and will define the role of moringa in enhancing lactationand supporting maternal and child health in vulnerable populations.

project_terms:
Address;Affect;Antioxidants;Automobile Driving;Breast Feeding;Breastfed infant;Cessation of life;Child;Child Malnutrition;Childhood;Communicable Diseases;Communities;Consumption;Counseling;Deuterium;Diagnosis;Dietary Intervention;Droughts;Dryness;Enrollment;Exclusive Breastfeeding;Fatty acid glycerol esters;Feeding behaviors;Food;Goals;Growth;Harvest;Health;Hemoglobin;Home;Hormonal;Hormones;Hour;Human;Human Milk;Individual;Infant;Infant Health;Infant Mortality;Insulin-Like Growth Factor I;Intervention;Intervention Studies;Investigation;Iron;Kenya;Lactation;Lactose;Length;Life;Lipids;Macronutrients Nutrition;Malnutrition;Maternal Health;Maternal and Child Health;Measures;Medical;Methods;Micronutrients;Milk;Milk Proteins;Moringa;Moringa oleifera;Mothers;National Institute of Child Health and Human Development;Newborn Infant;Nutrient;Nutrition;Nutritional;Output;Parents;Perception;Pharmaceutical Preparations;Plant Leaves;Plants;Population;Powder dose form;Prevalence;Prolactin;Proteins;Pump;Randomized;Randomized Controlled Trials;Resistance;Resources;Role;Sampling;Satiation;Serum;Single-Blind Study;Source;Supplementation;Surveys;Trees;Urine;Visit;Vitamin A;Vulnerable Populations;Water;Weight;Woman;World Health Organization;comparison control;design;dietary;early childhood;experience;feeding;follow-up;hormone regulation;improved;infant morbidity/mortality;inflammatory marker;innovation;low and middle-income countries;milk intake;milk supply;milk volume;mortality;preservation;primary outcome;prospective;systemic inflammatory response;tool

public_health_relevance:
Undernutrition leads to up to 45% of deaths in children under five years and early cessation of breastfeedingwhether due to worry about or actual low milk supply contributes to this mortality. To evaluate the nutritionalimpact of Moringa oleifera (moringa) a plant that promotes increases in milk supply we will conduct a sixmonth randomized controlled dietary intervention study with two-year follow-up on Kenyan breastfeedingmothers and their undernourished newborn infants. Results on maternal milk volume and composition lengthof breastfeeding and benefits to maternal and child health have the potential to broadly impact thesevulnerable populations.


application_id: 11047774
project_number: 1R01HL173026-01A1
administering_ic: NHLBI
award_notice_date: 2024-12-30
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 173026
suffix: A1
program_official: ESPINOZA GRANDON, INGRID CECILIA
project_start_date: 2025-01-01
project_end_date: 2028-11-30
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 9353289
contact_pi: SHRIDAS, PREETHA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Investigating the Role of HDL-Associated Serum Amyloid A in Sepsis-Induced Acute Lung Injury and Mortality

project_abstract:
Abstract/Project SummarySepsis is a life-threatening condition caused by a dysregulated immune response to infection. The prognosis forsepsis remains poor with mortality rates exceeding 30% due to a lack of effective treatment options. Thus fardespite over 100 randomized controlled trials no treatments have shown a survival benefit and no specifictherapies are available for sepsis. One reason for the failed trials may be the lack of understanding of thepathways involved in the resolution of the immune response in sepsis. We have identified Serum Amyloid A(SAA) a family of acute phase proteins as required for sepsis survival. Our preliminary and published data showthat using two well-established sepsis mouse models SAA-deficient (TKO) mice had exacerbated lung injuryand increased mortality compared to wild-type (WT) mice in sepsis. Adenovirus-mediated overexpression ofSAA not only increased survival in TKO mice but also in WT mice. Lungs of TKO mice had significantly increasedneutrophils myeloperoxidase (MPO) activity and markers of leukocyte infiltration compared to WT mice. SAAand SAA-bound to high-density lipoprotein (SAA-HDL) decreased neutrophil transmigration through laminin-coated membranes in vitro. SAA in circulation is associated with HDL. Several clinical and animal studies indicatethat decreasing HDL levels is a risk factor for sepsis and raising HDL may be an effective therapy. SAA is thepredominant apoprotein on HDL during acute inflammation. Based on these findings we propose 2 specific aimswith the central hypothesis that systemic SAA-HDL resolves sepsis-induced lung injury and mortality byregulating neutrophil infiltration into the injured lung: (Aim 1) We will test the hypothesis that SAA mediates theresolution of sepsis by impeding neutrophil accumulation in injured lungs and we will identify molecular playersinvolved in SAA-neutrophil interaction. (Aim 2) We will demonstrate that SAA imparts HDLs sepsis protectiveeffects and decreasing systemic SAA-HDL negatively impacts sepsis outcomes. This study is significant andinnovative since it will refute the old paradigm that SAA promotes inflammation in an acute inflammatory settingand will establish for the first time that SAA mediates HDLs protective effects in sepsis by resolving sepsis-induced inflammation. The study is clinically relevant because many generalized anti-inflammatory therapiesmay decrease circulating SAA levels and thus inadverdently negatively impact sepsis outcomes. The results ofthis proposal will validate the importance of maintaining plasma SAA/SAA-HDL levels as one of the criticalparameters to be considered in developing any therapeutic strategy for this serious disease and developing SAAmemetic peptides as a therapeutic approach.

project_terms:
2019-nCoV;Acceleration;Accounting;Acute;Acute Lung Injury;Acute-Phase Proteins;Animal Model;Animals;Anti-Cytokine Therapy;Anti-Inflammatory Agents;Apolipoproteins;Apoproteins;Bacterial Infections;Binding;Biological Markers;Blocking Antibodies;Blood;Cells;Cholesterol Esters;Circulation;Clinical;Data;Death Rate;Disease;Extracellular Domain;Extracellular Matrix;Extracellular Matrix Proteins;FPR2 gene;Family;Functional disorder;High Density Lipoproteins;Hospital Costs;Human;Immune response;In Vitro;Individual;Infection;Infiltration;Inflammation;Inflammatory;Infusion procedures;Integrins;Investigation;Kinetics;Laboratories;Laminin;Leucocytic infiltrate;Life;Lipoprotein Binding;Lung;Mediating;Membrane;Migration Assay;Modeling;Molecular;Mus;Neutrophil Infiltration;Organ;Outcome;Pathway interactions;Patients;Peptides;Peroxidases;Phase;Plasma;Prognosis;Property;Proteins;Public Health;Publishing;Randomized Controlled Trials;Resolution;Risk Assessment;Risk Factors;Role;Sampling;Sepsis;Serum amyloid A protein;Site;Site-Directed Mutagenesis;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Virus Diseases;Wild Type Mouse;adenoviral mediated;clinically relevant;effective therapy;experimental study;high risk;improved;injured;innovation;lung injury;migration;mortality;mouse model;neutrophil;overexpression;protective effect;protein expression;receptor;sepsis mortality;sepsis survivor;septic patients;therapeutic target;tissue injury

public_health_relevance:
NarrativePreliminary studies show that Serum Amyloid A (SAA) protects mice from sepsis-induced mortality. Thisproposal will investigate the mechanisms and pathways by which SAA is protective in sepsis. Results areexpected to validate SAA-based peptides as therapeutics in sepsis and aid in developing new biomarkers foridentifying individuals at the highest risk for sepsis-induced mortality.


application_id: 11047739
project_number: 5R21CA290420-02
project_title: Dietary fructose and NASH/HCC progression
administering_ic: NCI
award_notice_date: 2025-03-14
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: CA
serial_number: 290420
program_official: KUMAR, AMIT
project_start_date: 2024-04-01
project_end_date: 2027-03-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 10972280
contact_pi: SONG, MING
other_pis: MITCHELL, ROBERT A
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 SUMMARYDietary fructose and NASH/HCC progression Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is emerging as a leadingrisk factor driving the development of hepatocellular carcinoma (HCC). Dietary fructose is a major risk factor forNAFLD and subsequent HCC progression. Fructose is primarily metabolized by ketohexokinase (KHK) and KHK-deficient mice or pharmacologic inhibition is protective against NAFLD but the underlying mechanismsresponsible are largely unexplored. We recently designed studies to investigate whether loss or inhibition of KHKimpacts HIF- protein stabilization by crossing HIF stabilization reporter (ODD-luc) mice with KHK-/- micediscovered that intestinal HIF-stabilization (as measured by luciferase activity) is significantly and consistentlyreduced by KHK-deficiency. Interestingly reduced HIF- stability in KHK-/- mice is fully rescued by the smallmolecule inhibitor of pyruvate kinase M2 (PKM2) suggesting that fructose/KHK-dependent HIF- stabilizationmay be mediated by the PKM2 inhibitory metabolite F1P. Consistent with the reduced HIF- stabilizationobserved in KHK-deficient mice intestinal expression of the HIF-2-induced iron transporter DMT1 is reducedin KHK-/- mice consistent with our observations that KHK-deficient mice exhibit spontaneous systemic irondeficiency. Because plasma iron is essential for maximal neutropoiesis coupled with the fact that KHK-deficiencyalso results in markedly reduced neutrophil numbers and percentages our overarching hypothesis is thatfructose facilitates increased intestinal iron absorption via a KHK/F1P/HIF-2 axis leading to pro-inflammatoryneutropoiesis that in turn contributes to the development of HCC. We will test this hypothesis using the followingtwo specific aims: Aim 1. Determine whether dietary fructose promotes intestinal iron absorption in a KHK F1Pand HIF-2-dependent manner. Aim 2. Determine whether dietary fructose promotes systemic inflammationleading to pro-tumorigenic liver microenvironments due to increased iron-dependent neutropoiesis.

project_terms:
Automobile Driving;Blood;Consumption;Coupled;Data;Development;Enzymes;Epithelial Cells;Exhibits;Fatty acid glycerol esters;Fructose;Gene Deletion;Genetic Transcription;Glucose;Goals;Hypochromic anemia;Hypoxia;Hypoxia Inducible Factor;Inflammation;Inflammatory;Intestines;Iron;Iron Chelating Agents;Iron Chelation;Ketohexokinase;Link;Liver;Liver diseases;Luciferases;Measures;Mediating;Metabolic;Mitochondria;Modeling;Mus;Oxygen;Pathologic;Pathology;Pathway interactions;Phosphoenolpyruvate;Physiological;Plasma;Prevalence;Primary carcinoma of the liver cells;Procollagen-Proline Dioxygenase;Proteins;Pyruvate;Pyruvate Kinase;Reporter;Research Design;Risk Factors;SLC11A2 gene;Streptozocin;Testing;Therapeutically Targetable;Work;dietary;fructose-1-phosphate;gastrointestinal system;inhibitor;intestinal epithelium;iron absorption;iron deficiency;liver inflammation;neutrophil;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutic intervention;pharmacologic;pyruvate carrier;small molecule inhibitor;stem;systemic inflammatory response;therapeutic target;tumorigenic;villin;western diet

public_health_relevance:
NARRATIVE Dietary fructose and NASH/HCC progression The rapid rise of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) hascorrelated with has a corresponding increase in the prevalence of hepatocellular carcinoma (HCC). Dietaryfructose is thought to be a major risk factor for NASHHCC progression but the mechanisms linking dietaryfructose to inflammation-dependent HCC progression are entirely unknown. This project seeks to investigate ahighly novel mechanistic pathway that links dietary fructose consumption to inflammation-dependent HCCprogression and will explore novel therapeutic approaches with which to target.


application_id: 11046586
project_number: 5R03MH136192-02
administering_ic: NIMH
award_notice_date: 2025-02-13
opportunity_number: PA-20-200
application_type: 5
activity_code: R03
ic: MH
serial_number: 136192
program_official: CORNELL, ASHLEY ROSE
project_start_date: 2024-03-01
project_end_date: 2026-02-28
study_section: Lifestyle and Health Behaviors Study Section[LHB]
contact_pi_person_id: 2106837
contact_pi: SPRANG, MARY V (GINNY)
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-03-01
project_title:
The Role of Social Supports in Mitigating the Effects of Adverse Childhood Experiences on Adolescent Psychopathology

project_abstract:
Project SummaryOver 61% of adults surveyed in 2017 across 23 states experienced at least one type of adverse childhood event(ACE). Black Indigenous and other Youth Of Color (BIYOC) are more likely to report having experienced fouror more types of ACEs than their White counterparts rendering it even more critical to understand the culturallyspecific protective mechanisms that buffer the negative impact of ACEs. Despite exposures to ACEs at-riskyouth still thrive; though a clear understanding of the underlying conditions that build resilience remains widelyunknown particularly for BIYOC youth. While the past 20 years of research has also shed light on the toll ACEshas on adolescent psychopathology most findings to date: (1) do not include samples from racially diversepopulations (2) disproportionately focus on adult populations and (3) do not capture an adequate number ofdata collection timepoints from early to late adolescence. The Adolescent Brain Cognitive Development studystarted collecting data on social behavioral physical and environmental factors that may affect health outcomesin 2016 when youth (N=11874) were between 9-10 years of age. This socio-demographically diverse nationalstudy of 21 research sites across the U.S. entails collecting data for 10 years until 2026. Utilizing these datawe aim to examine the following: 1) prevalence of ACEs among BIYOC 2) BIYOC's long-term impact of ACEson internalizing/externalizing behaviors from early to late adolescence and 3) whether social supports(caregiver peer neighborhood) buffer the long-term effects of exposures to ACEs on behavior. We will analyzelongitudinal data from BIYOC to identify the critical junctures by which trauma and social support impactbehavioral functioning. Relying upon a cross-lagged analytic approach we will generate an empirical modelelucidating the extent to which social supports influence the long-term effects of exposures to ACEs on behaviorsamong BIYOC. Results will identify how to cultivate and make accessible the specific types of social support thatmitigate the effects of ACEs.

project_terms:
10 year old;Adolescence;Adolescent;Adult;Affect;Age;Attention;Behavior;Behavioral;Black race;Brain;Buffers;Caregivers;Child;Childhood;Communities;Data;Data Collection;Development;Dose;Emotional;Environmental Risk Factor;Exposure to;Friends;Health;Indigenous;Long-Term Effects;Measures;Mental Health;Modeling;Neighborhoods;Outcome;Population;Population Heterogeneity;Poverty;Prevalence;Protocols documentation;Psychopathology;Public Health;Recommendation;Reporting;Research;Risk;Role;Sampling;Service provision;Site;Social Network;Social support;Surveys;Symptoms;Testing;Trauma;Trust;United States;Youth;adolescent mental health;adverse childhood events;behavioral outcome;children of color;cognitive development;cohort;experience;externalizing behavior;innovation;longitudinal analysis;minority children;participant enrollment;peer;promote resilience;racial disparity;racial diversity;resilience;response;social;sociodemographics;young adult

public_health_relevance:
Project NarrativeWith public health experts warning us of the increasing prevalence of adolescent mental health problems it is ofcritical importance to understand the effects of social supports on mitigating the effects of trauma particularly forminoritized youth whose experiences are less understood. By following the same cohort of socio-demographically diverse adolescents in the longitudinal Adolescent Brain Cognitive Development study we willidentify the critical junctures by which trauma and social support impact behavioral functioning. Findings will lendguidance on how to make accessible the specific types of culturally relevant social supports that minimizesymptoms of externalizing and internalizing behaviors due to adverse childhood experiences.


application_id: 11046290
project_number: 4R37CA234002-06
project_title: Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors
administering_ic: NCI
award_notice_date: 2025-07-23
opportunity_number: PAR-21-138
application_type: 4
activity_code: R37
ic: CA
serial_number: 234002
program_official: FORRY, SUZANNE L
project_start_date: 2025-07-01
project_end_date: 2027-06-30
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_abstract:
This extension request seeks to expand our understanding of CDK4/6 resistance in breast cancer building uponthe groundwork laid by the original grant. The primary focus of this proposal is to understand how alteredglutamine metabolism can be exploited as a vulnerability in breast cancer that has developed resistance toCDK4/6 inhibitors. Our central hypothesis is that the aberrant metabolism of glutamine serves to sustainresistance to CDK4/6 inhibition in breast cancer. The main goal is to leverage this identified vulnerability in orderto develop targeted therapies capable of eradicating drug-resistant forms of the disease. The specific aims ofthis extension involve a comprehensive exploration of the role of c-MYC in driving glutamine-induced resistance.This includes investigating c-MYC's role in global metabolic reprogramming understanding the dependency ofincreased glutamine metabolism on c-MYC and examining fuel dependencies following the loss of c-MYC.Additionally the metabolic fate of glutamine in CDK4/6-resistant cells will be examined. Furthermore theproposal aims to evaluate the therapeutic efficacy of a novel glutamine antagonist prodrug (JHU083) in patient-derived xenograft (PDX) models of palbociclib-resistant breast cancer. This extension request represents asignificant and logical progression from the initial grant introducing a pioneering evaluation of a novel glutamineantagonist prodrug to target glutamine addiction in ER+ CDK4/6-resistant breast cancer. Anticipating that ourstudies will yield crucial insights into overcoming drug resistance in breast cancer we aim to contributemeaningful therapeutic options for a subset of patients currently lacking effective treatment alternatives.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Address;Attenuated;Automobile Driving;Binding;Biological Availability;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;CDK4 gene;Cell Cycle;Cell Cycle Progression;Cells;Clinical;Clinical Trials;Cyclin D1;Cyclins;Dependence;Disabling;Disease;Drug resistance;ERBB2 gene;Enzymes;Estradiol;Estrogen receptor positive;Evaluation;FDA approved;Foundations;Fructose;Genetic;Genetic Transcription;Glucose;Glutamine;Glycolysis;Glycolysis Induction;Goals;Grant;Growth;In Vitro;Malignant Breast Neoplasm;Malignant Neoplasms;Mediating;Metabolic;Metabolism;Metastatic breast cancer;Oral;Pathway interactions;Patients;Phase;Phosphorylation;Prodrugs;Relapse;Resistance;Resistance development;Retinoblastoma Protein;Role;Testing;Therapeutic;Time;Treatment Efficacy;alternative treatment;antagonist;blood glucose regulation;c-myc Genes;cyclin D3;cyclin-dependent kinase 6;design;early phase clinical trial;effective therapy;efficacious treatment;glucose metabolism;glutamine addiction;hormone receptor-positive;hormone therapy;improved;in vivo;inhibitor;insight;mouse model;novel;novel strategies;overexpression;patient derived xenograft model;patient subsets;pharmacologic;prevent;research clinical testing;response;targeted treatment;therapy resistant;treatment response;tumor

public_health_relevance:
While clinical responses to CDK4/6 inhibition have shown remarkable efficacy metastatic breast cancerremains an unresolved challenge. The proposed studies aim to establish the mechanistic foundation fortargeting glutamine metabolism to eradicate CDK4/6-resistant estrogen receptor positive breast cancer. Theanticipated results are poised to pave the way for tailored therapeutic approaches that address the uniquechallenges posed by glutamine metabolism in the pursuit of more effective treatments for this subset ofpatients with limited options.


application_id: 11046032
project_number: 3R15MH113045-02S1
project_title: Cognitive and Contextual Factors in Suicide Ideation Persistence in Adolescents
administering_ic: NIMH
award_notice_date: 2024-09-03
opportunity_number: PA-23-189
application_type: 3
activity_code: R15
ic: MH
serial_number: 113045
suffix: S1
program_official: MURPHY, ERIC ROUSSEAU
project_start_date: 2018-08-01
project_end_date: 2025-04-30
contact_pi_person_id: 12499648
contact_pi: BRAUSCH, AMY MARIE
other_pis: Not Applicable
congressional_district: 02
department: PSYCHOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cognitive and Contextual Factors in Suicide Ideation Persistence in Adolescents. Deaths from suicide continueto be a major public health concern particularly among youth for whom suicide ranks as the second leadingcause of death. Recent suicide ideation is reported by almost 20% of high school students and the majority ofthose report persistent ideation of more than one year. If the factors that associate with persistent and remittingsuicide ideation can be identified then resources can be directed to those most at risk with a likely impact onrates of suicide. Depression hopelessness and psychiatric diagnoses have been studied as risk factors forover 50 years yet they are neither sufficient nor effective for understanding suicide risk. It is important toevaluate cognitive and contextual factors for suicide ideation which are understudied particularly for ruralyouth. Cognitive factors that may relate to suicide ideation are defeat entrapment grit and self-efficacy.Contextual factors with potential to make an impact on suicide ideation are socio-economic status access tolethal means social support food and housing security and access to health care. The parent grant(2R15MH113045-02) aims to fill these knowledge gaps through a 12-month longitudinal study of 225 non-clinical rural adolescents between the ages of 14 and 18 who report a history of suicide ideation. The parentgrant proposes that cognitive and contextual factors will differentiate adolescents with and without suicideideation history in the baseline sample. It is further expected that the cognitive factors defeat and entrapmentwill associate with persisting suicide ideation and self-efficacy and grit will associate with remitting suicideideation at follow-ups. Lastly it is expected that contextual factors will associate with persisting (low SES andaccess to lethal means) vs. remitting (social support food and housing security access to health care) suicideideation at follow-ups. This diversity supplement will augment the parent grant by supporting a second-yearmasters student trainee who will examine how sexual and gender minority (SGM) status associates with thesefactors and persistent suicide ideation. Adolescents in 9th-11th grades will be recruited to complete a researchprotocol of self-report and behavioral measures at their home schools at baseline (n=700); adolescents withsuicide ideation history (est. n=225) will be recruited into follow-up assessments at 6- and 12-months postbaseline. Teacher reports for the 225 adolescents with suicide ideation history will also be collected. ANOVAwill be used to determine how cognitive and contextual factors and suicide ideation history differ for SGM vs.cisgender heterosexual students. To test hypotheses about factors associating with suicide ideationpersistence and remittance and if these associations depend on SGM status moderation analyses will beused. SGM status will be tested as a moderator in the relationships between risk factors and suicide ideationpersistence. The supplement will also provide research and career mentoring for the trainee to assist inadvancing their goals of attending a Clinical Psychology PhD program and establishing a research career.

project_terms:
Adolescent;Age;Analysis of Variance;Cause of Death;Clinical Psychology;Cognitive;Development;Disease remission;Doctor of Philosophy;Early Intervention;Feeling hopeless;Feeling suicidal;Food;Future;Goals;Heterosexuals;High School Student;Home;Housing;Knowledge;Longitudinal Studies;Mental Depression;Mentors;Patient Self-Report;Protocols documentation;Psychiatric Diagnosis;Public Health;Recording of previous events;Remittance;Reporting;Research;Resources;Risk;Risk Factors;Rural;Sampling;Schools;Security;Self Efficacy;Sexual and Gender Minorities;Social support;Socioeconomic Status;Students;Suicide;Suicide attempt;Testing;Youth;behavior measurement;career;cisgender;contextual factors;eleventh grade;follow up assessment;gender minority status;gender minority youth;health care availability;ideation;intervention program;low socioeconomic status;parent grant;preventive intervention;programs;recruit;sexual minority youth;suicidal morbidity;suicidal risk;suicide rate;teacher

public_health_relevance:
Adolescents with persistent suicidal thoughts are at greater risk for future suicide attempts.Students identifying as gender and sexual minorities (SGM) are at even greater risk for suicide.Identifying factors that relate to diminishing suicide ideation will aid in the development ofprevention and early intervention programs for SGM youth.


application_id: 11045959
project_number: 3P20GM135004-05S1
project_title: Center for Cancer Immunology and Immunotherapy (CCII).
administering_ic: NIGMS
award_notice_date: 2024-05-24
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 135004
suffix: S1
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2025-08-31
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
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:
PROJECT SUMMARYResearch Question to be Addressed: The application of immunotherapies such as immune checkpoint inhibitors (ICIs) in the treatment ofcancer has led to significant improvements in long-term patient outcomes. However existing therapies are noteffective in all patients and our knowledge of the immunological factors that contribute to positive treatmentresponses and resistance remains limited. This demands targeted research efforts to more comprehensivelycharacterize immune profiles in patients receiving immunotherapies as a means to uncover biologicalmechanisms of action and identify more effective biomarkers of treatment response or resistance. Novel tumor-infiltrating lymphocyte (TIL) therapies hold great promise in the clinic for cancer patients that have provenrefractory to other treatment strategies. This proposal will take a multi-omic and data-driven approach to deeplycharacterize immunological signatures in blood and tumor tissues obtained from melanoma patients participatingin a clinical trial testing the efficacy of a novel TIL therapy. Our goal is to identify specific biomarkers thatassociate with treatment outcomes. This effort will result in unique and rich immunological datasets and noveltools and models for clinical outcome prediction and will drive the design of next-generation immunotherapies.Impact of Proposed Team Science: To effectively address the research questions posed we have assembled a team of researchers withdiverse expertise and skill sets. Our team builds from our parent COBRE drawing on the extensive expertise ofMPIs Chesney and Yan who are world leaders in cancer immunology and clinical research. Both will makecritical contributions through administrative oversight. Our research team includes three independentinvestigators with established research programs in cancer immunology (Yaddanapudi; Aim 1) genomics andimmunogenetics (Watson; Aim 2) and bioinformatics and data science (Park; Aim 3). Studies proposed in Aims1 and 2 are focused on the deep characterization of immunological profiles of melanoma patient tumors TILsand blood collected pre- and post-treatment using multi-omics approaches. These aims will delineateimmunological variables that vary between tissues and patients in the context of TIL therapy. Given the complexnature of the high-dimensional datasets to be generated in Aims 1 and 2 the activities planned for Aim 3 will becritical to advancing the overall objectives of the proposal. Specifically studies proposed in Aim 3 will focus onbuilding more streamlined pipelines and tools for processing and analysis of data generated in Aims 1 and 2. Inaddition the second major activity of Aim 3 will include the construction of novel machine learning models forpredicting therapy outcomes via the integration of datasets (from Aims 1 and 2) with the rich de-identified clinicaldata that will be collected as part of the trial. Critically the completion of the Aims outlined here will lead to afoundational compilation of integrated datasets and accompanying models that can be extended into the laterphases of this clinical trial and future efforts. These deliverables will also serve as key preliminary data forpursuing hypothesis-driven multi-PI R01 applications and advancing efforts for obtaining an NIH SPORE awardfocused on the treatment of melanoma.Goals of Parent COBRE Award: The overarching objective of the parent COBRE award was to establish the Center for CancerImmunology and Immunotherapy (CCII) a multidisciplinary research center of excellence focused on advancingdiscoveries in cancer immunology to improve the development of novel immunotherapies. The motivation forthis program was built around the 10-year successes of the UofL-Health-Brown Cancer Center in leading clinicaltrials of immunotherapeutic agents. Leveraging this long-term track record the CCII COBRE has focused onmore effectively integrating clinical and basic research endeavors across the School of Medicine. The CCII is aunique program being the only COBRE program exclusively focused on cancer immunology and immunotherapydevelopment. This is evidenced by the fact that in the initial funding period all scientific/research objectives ledby Junior Faculty and their mentors were centered around applying novel approaches to identifyingimmunological factors linked to cancer progression and/or treatment outcomes. Through these efforts ourCenter Investigators have been able to establish the infrastructure and resources including critical tools andmethodologies needed for generating large-scale genomic and immunological data in human and animal modelsystems. This success has laid a foundation for us to orient our research capabilities toward solving keyquestions in the clinic. Specifically this Team Science Development Project proposal will be focused onenhancing discoveries from a unique immunotherapy clinical trial currently being conducted at our Cancer Centerand seeks to capitalize on our successes by establishing a critically needed research team composed of COBREgraduates (Drs. Yaddanapudi and Watson) and additional faculty across the School of Medicine (Drs. ParkRouchka and Smith).

project_terms:
Address;Adoptive Cell Transfers;Advanced Malignant Neoplasm;Aftercare;Animal Model;Award;B-Lymphocytes;Basic Science;Binding;Bioinformatics;Biological;Biological Markers;Biological Models;Biopsy;Blood;Cancer Center;Cancer Patient;Cells;Cellular Assay;Centers of Research Excellence;Clinic;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Complex;Cytometry;Data;Data Analyses;Data Science;Data Set;Development;Disease remission;Faculty;Foundations;Funding;Future;Genetic;Genomics;Goals;Health;High-dimensional Modeling;Image;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune system;Immunogenetics;Immunogenomics;Immunohistochemistry;Immunologic Factors;Immunologics;Immunologist;Immunotherapeutic agent;Immunotherapy;Individual;Infiltration;Infrastructure;Infusion procedures;Interdisciplinary Study;Interleukin-15;Knowledge;Link;Malignant Neoplasms;Melanoma;Melanoma patient;Membrane;Mentors;Methodology;Methods;Mission;Modeling;Motivation;Myeloid Cells;Nature;Outcome;Parents;Participant;Patient Care;Patient Participation;Patient-Focused Outcomes;Patients;Peripheral;Phase;Phase I/II Clinical Trial;Population;Prediction of Response to Therapy;Predictive Factor;Proteins;Refractory;Research;Research Infrastructure;Research Personnel;Research Project Summaries;Resistance;Resolution;Resources;Science;Stress;Survival Rate;T-Cell Receptor;T-Lymphocyte;Targeted Research;Testing;Therapeutic;Time;Tissues;Training;Translational Research;Treatment Efficacy;Treatment outcome;Tumor Expansion;Tumor Immunity;Tumor Tissue;Tumor-Infiltrating Lymphocytes;Tumor-infiltrating immune cells;United States National Institutes of Health;Universities;Work;anti-CTLA4;anti-PD-1;anti-cancer;cancer cell;cancer immunotherapy;cancer therapy;data analysis pipeline;data integration;design;efficacy testing;genomic data;human model;immune checkpoint;immunotherapy clinical trials;improved;innovation;lymphocyte product;machine learning model;machine learning prediction;medical schools;multidimensional data;multidisciplinary;multiple omics;neoantigens;next generation;novel;novel strategies;novel therapeutics;outcome prediction;predict clinical outcome;profiles in patients;programs;receptor;response;single-cell RNA sequencing;skills;specific biomarkers;success;therapy outcome;therapy resistant;tool;transcriptome;transcriptomics;treatment response;treatment strategy;tumor;tumor immunology;tumor progression

public_health_relevance:
Decades of research have demonstrated that the immune system can eradicate cancer cells but only if immuneevasion mechanisms such as immune checkpoint proteins can be overcome. Multiple new immunotherapeuticapproaches have recently been developed that can induce durable remissions in patients with advanced cancers unfortunately the majority of patients still succumb to their cancers. The goal of this COBRE application is toestablish a new Center for Cancer Immunology and Immunotherapy that will focus on understanding immuneescape mechanisms developing new approaches to activate/reinvigorate anticancer immunity trainingpromising young cancer immunologists and improving the research infrastructure of the University of Louisville.


application_id: 11045781
project_number: 5R01HL150581-05
project_title: Epidural spinal cord stimulation and respiratory motor function after injury
administering_ic: NHLBI
award_notice_date: 2025-04-18
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: HL
serial_number: 150581
program_official: SOOD, BEENA G
project_start_date: 2021-05-01
project_end_date: 2027-02-28
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractRespiratory motor control deficit is the leading cause of morbidity and mortality in patients with spinal cordinjury. The long-term goal of this research is to develop a rehabilitation strategy for respiration in patients withspinal cord injury as a standard of care. Our previous findings demonstrate that respiratory function in patientswith chronic spinal cord injury can be improved by using our original inspiratory-expiratory pressure thresholdrespiratory training protocol. However the effectiveness of this intervention is limited by the levels of functionalcapacity preserved below the neurological level of injury. Our preliminary data obtained for this proposaldemonstrate that electrical spinal cord stimulation applied epidurally at the lumbar level in combination withrespiratory can activate and re-organize spinal motor networks for respiration. We propose to investigaterespiratory motor control-related responses to epidural spinal cord stimulation alone and in combination withrespiratory training. By characterization of respiratory muscle activation patterns using surfaceelectromyography in association with pulmonary functional and related cardiovascular measures we expect todetermine specific stimulation parameters needed to increase spinal excitability below level of injury toenhance responses to the input from supraspinal centers that remain after injury and to promote the neuralplasticity driven by the respiratory training. This hypothesis will be tested by pursuing two specific aims: 1)Evaluate the acute effects of epidural spinal cord stimulation on respiratory functional and motor controlproperties; and 2) Evaluate the effectiveness of epidural spinal cord stimulation combined with respiratorytraining.

project_terms:
Activities of Daily Living;Acute;Blood Pressure;Breathing;COVID-19;Cardiovascular system;Chronic;Clinical;Complication;Data;Development;Effectiveness of Interventions;Electromyography;Electrophysiology (science);Evaluation;Goals;Heart Rate;Human;Individual;Injury;Knowledge;Lead;Measures;Methods;Modality;Morbidity - disease rate;Motor;Muscle;Neurologic;Neuronal Plasticity;Neurostimulation procedures of spinal cord tissue;Patients;Pattern;Physiological;Population;Property;Protocols documentation;Public Health;Pulmonary function tests;Randomized Controlled Clinical Trials;Rehabilitation therapy;Research;Respiration;Respiration Disorders;Respiratory Muscles;Respiratory physiology;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Surface;Testing;Therapeutic Effect;Time;Training;Work;comparative;design;disability;effectiveness evaluation;evidence base;fighting;follow-up;functional improvement;functional outcomes;improved;kinematics;mortality;motor control;neural network;novel therapeutic intervention;preservation;pressure;pulmonary;rehabilitation strategy;respiratory;response;restoration;standard of care;voltage

public_health_relevance:
Project NarrativeRespiratory dysfunction after spinal cord injury in the primary public health concern. The proposed study isdesigned to test a novel therapeutic strategy to fight this complication by using respiratory training incombination with electrical spinal cord stimulation applied epidurally in patients with chronic spinal cord injury.This knowledge will help to reduce the burden of human disability.


application_id: 11045672
project_number: 5R21CA285253-02
project_title: Novel Strategy to Augmenting Immunotherapy against Melanoma
administering_ic: NCI
award_notice_date: 2025-03-14
opportunity_number: PAR-22-216
application_type: 5
activity_code: R21
ic: CA
serial_number: 285253
program_official: HU, ZHANG-ZHI
project_start_date: 2024-03-01
project_end_date: 2027-02-28
study_section: ZCA1-SRB-P(O2)S
contact_pi_person_id: 7598539
contact_pi: YANG, JIN-MING
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/ABSTRACTThe overarching goal of this R21 proposal is to explore the potential of nelfinavir a widely used antiviral agentas a modulator to significantly augment the efficacy of adoptive cell transfer (ACT) therapy against melanoma.Melanoma one of the most aggressive and fatal neoplasms is responsible for over 80% of skin cancer-relateddeaths. Despite recent advances in treatment for this devastating disease including surgical resectiontargeted therapy and chemotherapy the prognosis of patients with melanoma remains dismal. Cellular therapyusing ACT approach represents a particularly promising strategy to treatment of this malignancy; yet thetherapeutic outcomes remain elusive due to a variety of factors that limits the anti-tumor immunity. We recentlyrevealed the critical roles of eukaryotic elongation factor-2 kinase (eEF-2K) in promoting the survival andcytocidal activity of CD8+ T cells and in augmenting the antitumor activity of CAR-T therapy suggesting thepotential of manipulating this kinase in boosting immunotherapy against melanoma. eEF-2K belongs to thefamily of atypical -kinases and is an evolutionarily conserved regulator of protein synthesis. This kinasephosphorylates eEF-2 a 100 kDa protein that promotes ribosomal translocation from the A to the P-site thereaction that induces movement of mRNA along the ribosome during translation. Phosphorylated eEF2 isunable to catalyze ribosomal translocation thereby inhibiting peptide elongation. Notably studies showed thateEF-2K can be activated by nelfinavir an orally bioavailable antiviral agent that have been widely used inclinical treatment of human immunodeficiency virus infection such as HIV and AIDS and that activation of eEF-2K in tumor cells promotes tumor cell death and suppresses tumor progression. Thus based on ourobservation of the role of eEF-2K in reinvigoration of cytotoxic CD8+ T cells as well as the above studies wehypothesize that pharmacologic activation of eEF-2K by nelfinavir can be exploited as a novel and effectivetherapeutic approach to substantially augment the efficacy of ACT against melanoma. Addressing thishypothesis would provide a proof of concept and rationale for improving the efficacy of current anti-melanomatherapies through targeting eEF-2K by use of nelfinavir. To test this hypothesis we will characterize the effectsof nelfinavir on cytotoxic T lymphocytes including T cell functions persistence and stability and evaluate theimpact of nelfinavir on reinforcing the efficacy of ACT against melanoma through use of in vitro and in vivomelanoma models. Successful completion of this study may provide a rapid path to enter clinical trials ofnelfinavir in treatment of patients with immune poor-responsive melanoma yielding new therapeuticopportunities to significantly improve current melanoma treatment through use of nelfinavir.

project_terms:
Address;Adoptive Cell Transfers;Affect;Anti-viral Agents;Antibodies;Biological Availability;CAR T cell therapy;CD8-Positive T-Lymphocytes;Cell Death;Cell Line;Cell Physiology;Cell Therapy;Cell-Mediated Cytolysis;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Clinical Trials;Coculture Techniques;Cytotoxic T-Lymphocytes;Disease;EEF2 gene;Effectiveness;Excision;FDA approved;Family;Glycolysis;Goals;HIV;HIV/AIDS;HLA-A2 Antigen;Human;Immune;Immunologics;Immunotherapy;In Vitro;Malignant Neoplasms;Measures;Mediating;Melanoma;Melanoma Cell;Melanoma patient;Messenger RNA;Metastatic Melanoma;Modeling;Monitor;Movement;Mus;Mutation;Nelfinavir;Neoplasms;Operative Surgical Procedures;Oral;PDL1 inhibitors;Patients;Peptides;Phosphorylation;Phosphotransferases;Pluripotent Stem Cells;Protein Biosynthesis;Proteins;Reaction;Retroviral Vector;Ribosomes;Role;Site;Skin Cancer;T cell therapy;T-Lymphocyte;Testing;Therapeutic;Translations;Tumor Immunity;Tumor Promotion;Virus;Virus Diseases;calmodulin-dependent protein kinase III;chemotherapy;cytotoxic CD8 T cells;cytotoxicity;fatty acid oxidation;feasibility testing;improved;in vivo;melanoma model;neoplastic cell;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;patient prognosis;pharmacologic;programmed cell death protein 1;response;targeted treatment;therapeutically effective;therapy outcome;treatment strategy;tumor;tumor progression

public_health_relevance:
Project NarrativeThis proposal is aimed at evaluating and defining nelfinavir an FDA-approved and commonly usedantiviral agent as an immune-sensitizer for enhancing cell-based therapy against melanoma. Thisstudy may lay groundwork and provide rapid path to enter clinical trials of nelfinavir for treatment ofpatients with immune poor-responsive melanoma an aberrantly aggressive and fatal disease.


application_id: 11045175
project_number: 3R01DK135885-02S1
administering_ic: NIDDK
award_notice_date: 2024-05-22
opportunity_number: PA-23-189
application_type: 3
activity_code: R01
ic: DK
serial_number: 135885
suffix: S1
program_official: CENTER, MAUREEN MONAGHAN
project_start_date: 2023-04-01
project_end_date: 2025-03-31
study_section: Health Promotion in Communities Study Section[HPC]
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: KRUSE-DIEHR, AARON
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_title:
Diversity Supplement for Courtney Ortz: Older Adults Using Social Support to Improve Self-Care (OASIS): Adaption Implementation and Feasibility of Peer Support for Older Adults with T2DM in Appalach

project_abstract:
PROJECT SUMMARYApproximately 34.1 million (13%) adults in the US have type 2 diabetes (T2D). The prevalence of T2D is 17%higher in rural dwellers compared to their urban counterparts and the prevalence of T2D increases with agewith an estimated 25% of older adults ( 65 years) diagnosed. Appropriate self-care is necessary for optimalclinical outcomes and variability in self-care accounts for 90% of the variance in glycemic control. Overall T2Dself-care is consistently poor among the general population but is even worse in rural-dwellers and older adults.This is particularly true in rural Kentucky where up to 23% of adults in Appalachian communities have beendiagnosed with T2D and of those 26.8% are older adults. To attain optimal clinical outcomes socialenvironmental factors including social support are integral when promoting T2D self-care. Specifically peersupport has shown to be efficacious in improving T2D self-care behaviors; it provides emotional supportinstrumental support and education while also helping individuals develop new skills. Similarly peer support hasalso been shown to improve clinical and psychosocial outcomes related to T2D; however there is literature thatalso suggests self-selected social support can be obstructive when trying to engage in healthful activities.Currently available evidence-based interventions (EBIs) using peer support have not been used specifically toprioritize older adults especially those living in rural communities. To address this gap in research we haveconducted formative research with regional practitioners leaders of service organizations in Appalachia andresidents and through that process we collaboratively identified an acceptable and feasible peer support EBIpeer health coaching (PHC)that has resulted in improved clinical and psychosocial T2D-related outcomesamong participants who did not reside in rural communities nor were 65 years. Through these communityconversations we also determined necessary a priori adaptations to the EBI to ensure its cultural and contextualrelevance to regional needs and values. Because PHC is a community-based and low-cost intervention it holdspromise to be a sustainable and scalable model across Appalachian Kentucky where resources are often scantbut community bonds are valued. Informed by literature and feedback from stakeholders the goal of theproposed study is to use a 2x2 factorial design to test the adapted PHC components and determine theirpreliminary effectiveness to promote self-care behaviors and improve glycemic control among older adults livingin Appalachian Kentucky. The main components of the factorial design will be how peer coaches are selectedfor participants (self-selected vs matched) and frequency of contact with coach (once per week vs every 2weeks). To achieve this goal we will (1) determine which EBI components are associated with improved T2D-related outcomes in older adults living in Appalachia Kentucky and (2) evaluate the pragmatic implementabilityof the adapted EBI.

project_terms:
Address;Adult;Age;Appalachian Region;Behavior;Clinical;Clinical Trials;Communities;Community Health;Data;Diagnosis;Dimensions;Disease;Education;Effectiveness;Emotional;Ensure;Environmental Risk Factor;Evidence based intervention;Familiarity;Feedback;Frequencies;General Population;Glycosylated hemoglobin A;Goals;Health;Individual;Intervention;Kentucky;Literature;Measures;Mission;Modeling;Monitor;Morbidity - disease rate;National Institute of Diabetes and Digestive and Kidney Diseases;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Overutilization of Health Services;Participant;Practical Robust Implementation and Sustainability Model;Prevalence;Process;Psychosocial Factor;Questionnaires;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Research;Resources;Rural;Rural Appalachia;Rural Community;Self Care;Social support;Source;Structure;Testing;Vulnerable Populations;acceptability and feasibility;cost;design;diabetes self-management;glycemic control;human old age (65+);implementation evaluation;implementation outcomes;implementation strategy;improved;intervention cost;mortality;older adult;peer;peer coaching;peer support;post intervention;primary outcome;psychosocial;psychosocial outcome;response;rural dwellers;rural residence;service organization;skills;social;trustworthiness

public_health_relevance:
PROJECT NARRATIVEWe aim to use a 2x2 factorial design to test an acceptable and feasible peer support evidence-based intervention(EBI)peer health coachingto determine the preliminary effectiveness of different implementation strategiesas well as the overall EBI at promoting self-care behaviors and improving glycemic control among older adultswith type 2 diabetes living in Appalachian Kentucky. The main components of the factorial design will be howpeer coaches are selected for participants (self-selected vs matched) and frequency of contact with coach (onceper week vs every 2 weeks). Guided by the Practical Robust Implementation and Sustainability Model (PRISM)we will collect quantitative and qualitative data to assess PRISM domains and give context to both anticipatedand unanticipated EBI adaptations.


application_id: 11044136
project_number: 5R01GM150200-03
project_title: Study of PTPRF-Mediated Regulation of Wnt Signaling
administering_ic: NIGMS
award_notice_date: 2025-06-09
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 150200
program_official: SALAZAR, DESIREE LYNN
project_start_date: 2023-06-01
project_end_date: 2027-03-31
study_section: Cellular Signaling and Regulatory Systems Study Section[CSRS]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Protein phosphorylation defines one of the most important and pervasive regulatory mechanisms in cellsignaling. A precise control of the balance between phosphorylation and dephosphorylation is crucial for livingorganisms to maintain normal physiological functions. While protein kinases have attracted a significant amountof attention given the promise of developing inhibitors for targeted therapies significant knowledge gaps existon the opposing actions of protein phosphatases. The overall objective of this study is to investigate themolecular mechanisms by which PTPRF a receptor-type tyrosine phosphatase regulates Wnt signaling andnormal intestinal homeostasis. A large body of evidence indicates that Wnt signaling is required for themaintenance of normal intestinal stem cells; and dysregulation of Wnt signaling is often the first step leading tothe development of colorectal cancer. In our efforts to investigate the regulatory mechanisms of Wnt signalingwe identified PTPRF a receptor protein tyrosine phosphatase as a novel positive regulator in the Wnt pathwaythat promotes the activation of Wnt signaling upstream of the -catenin destruction complex. To further determinethe functional importance of PTPRF we utilized Ptprf knockout mice to investigate if Ptprf-loss alters Wntsignaling and the proliferation and differentiation of intestinal stem cells in vivo. Our exciting new data showedthat intestinal crypts isolated from Ptprf knockout mice have reduced ability to form organoids which coincideswith decreased expression of Wnt target genes. In addition we found that PTPRF interacts and co-localizes withLRP6 and caveolin upon Wnt stimulation; and CRISPR/Cas9-mediated knockout of PTPRF in 293T cellsattenuates Wnt-stimulated TOP-Flash reporter activity as well as LRP6 phosphorylation. Moreover we identifiedNEDD4L as a novel E3 ligase that controls PTPRF ubiquitination and degradation. Collectively the centralhypothesis driving this proposal is that that PTPRF positively regulates Wnt signaling by promoting theformation of Wnt signalosome and the expression of PTPRF sustains intestinal stem cell function. The followingspecific aims are proposed: 1) to delineate the molecular mechanisms underlying PTPRF-mediated regulationof Wnt signaling; 2) to determine the role of NEDD4L in controlling PTPRF protein stability; and 3) to define thefunctional importance of PTPRF in regulating the proliferation and differentiation of intestinal stem cells in vivo.Results from our studies will fill an important knowledge gap on how protein phosphatases are involved inregulating complex biological processes. To ensure the success of this study we have assembled a stronginvestigative team with collective expertise in protein phosphatases Wnt signaling and intestinal epithelial cellbiology. Ultimately by providing new mechanistic insights into PTPRF-dependent regulation of Wnt signalingour findings will help identify new strategies for treating Wnt-driven diseases by using PTPRF as a target.

project_terms:
3-Dimensional;Attention;Attenuated;Automobile Driving;Bioinformatics;Biological Process;CRISPR/Cas technology;Caveolins;Cell Differentiation process;Cell Proliferation;Cell membrane;Cells;Cellular biology;Colon;Colon Carcinoma;Colorectal Cancer;Complex;Data;Development;Disease;Endocytosis;Ensure;Epithelium;Equilibrium;Genes;Goals;Human;Human body;In Vitro;Internal Ribosome Entry Site;Intestines;Investigation;Knock-out;Knockout Mice;Knowledge;LGR5 gene;Maintenance;Mediating;Modeling;Molecular;Mus;Mutation;Nedd4L;Oncogenic;Organism;Organoids;PTPRR gene;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Physiology;Play;Process;Proliferating;Protein Dephosphorylation;Protein Kinase;Protein Tyrosine Phosphatase;Protein phosphatase;Proteins;Regulation;Reporter;Role;Sampling;Signal Transduction;System;Technology;Testing;Tissues;Ubiquitination;Villus;WNT Signaling Pathway;beta catenin;cancer cell;colon cancer patients;colon tumorigenesis;in vivo;inhibitor;insight;intestinal crypt;intestinal epithelium;intestinal homeostasis;intestinal stem cells;knock-down;novel;novel therapeutic intervention;receptor;self-renewal;single-cell RNA sequencing;stem cell fate;stem cell function;stem cell proliferation;success;targeted treatment;tumor growth;ubiquitin-protein ligase

public_health_relevance:
PROJECT NARRATIVE Wnt signaling is a rapidly evolving and important field of investigation and new regulators involved in thiscascade are continuously being identified. Our study focuses on developing a mechanistic understanding ofPTPRF-mediated regulation of Wnt signaling and intestinal stem cell function. Results from our studies will helpidentify new therapeutic strategies for treating Wnt-driven diseases by using PTPRF as a target.


application_id: 11042252
project_number: 5R01DC007176-20
project_title: Regulation of taste neuron morphology and function
administering_ic: NIDCD
award_notice_date: 2025-02-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2027-02-28
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
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:
Project Summary:Taste-transducing cells detect chemicals in our food and communicate this information to peripheral tasteganglion neurons (taste neurons) which carry this information to the brain. The axons of taste neurons vary inbranching characteristics some branching little and others branching a great deal. However it is unclear howthese differing morphologies underly plasticity and/or function. Our goal here is to clarify the relationship betweentaste neuron morphology plasticity genetic type and function in order to gain insight into the peripheralorganization of the taste system. Taste neuron morphology may underlie differences in connectivity but is alsolikely regulated by plasticity. Even in adults taste receptor cells undergo continuous renewal and must constantlyattract and connect to nerve fibers and some variation in neuron morphology likely occurs as part of this process.Additionally differences between neurons in their branching likely have functional importance. For examplesimply branched neurons can only connect with a few taste-transducing cells while heavily branched neuronslikely connect to many more taste-transducing cells. Currently the significance of these differences inconvergence are unclear. In this project we propose to investigate factors that regulate differences in tasteneuron morphology and branching characteristics between neurons and relate these factors to neuron function.Specifically in Aim 1 we will determine which aspects of the axon morphologies of taste neurons are stable andwhich change over time. In Aim 2 we will determine which aspects of neuron morphologies are determined byan intrinsic factor (i.e. cell type) and how this factor correlates with function. Finally in Aim 3 we will determinewhich aspects of neuron morphologies are determined by extrinsic (i.e. neurotrophins) developmental factorsand how these features relate to neuron function. We hypothesize that branching inside the taste bud is regulatedby plasticity while branching outside the taste bud is regulated by a combination of intrinsic and extrinsicfeatures which influence taste neuron sensitivity and breadth of tuning.

project_terms:
Address;Adult;Anatomy;Axon;Brain;Brain-Derived Neurotrophic Factor;Calcium;Characteristics;Chemicals;Citric Acid;Communication;Development;Disease;Epithelium;Food;Functional Imaging;Ganglia;Gene Expression;Genetic;Goals;Health;Hour;Image;Individual;Intrinsic factor;Label;Link;Measurement;Measures;Methods;Morphology;Mus;Nerve Fibers;Neurons;Pattern;Peripheral;Persons;Population;Process;Quality of life;Receptor Cell;Regulation;Role;Stimulus;Structure;Taste Bud Cell;Taste Buds;Taste Disorders;Taste Perception;Temperature;Time;Variant;Wild Type Mouse;cell type;cellular transduction;experimental study;functional plasticity;in vivo;insight;intravital imaging;life span;neurotrophic factor;overexpression;preproenkephalin;proenkephalin;reconstruction;sensory system;taste stimuli;taste system;taste transduction;two photon microscopy

public_health_relevance:
Project Narrative. Taste disorders can have detrimental effects on a person's health and qualityof life. The underlying mechanisms of these disorders are not understood but may result fromdisruption of the connections between taste buds and the neurons carrying taste information tothe brain. Here we are exploring the relationship between taste neuron structure connectivityand function to elucidate the role of connectivity in taste disorders.


application_id: 11041026
project_number: 5R01AG061111-05
administering_ic: NIA
award_notice_date: 2025-01-23
opportunity_number: PAR-18-175
application_type: 5
activity_code: R01
ic: AG
serial_number: 061111
program_official: CLARKE, AKANNI YAO
project_start_date: 2019-02-01
project_end_date: 2026-11-30
study_section: Special Emphasis Panel[ZRG1-BBBP-Z(55)R]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
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: 2024-12-01
project_title:
Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging (SMArTHS)

project_abstract:
Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampalsclerosis of aging (HS-Aging). A major subtype of Alzheimer's disease and related dementia (ADRD)HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable ADor AD-type dementia in the clinical setting. Unfortunately there currently is no validated biomarker todiagnose HS-Aging during life and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging based on our prior work elucidatinga pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drugused clinically to treat chronic heart failure in the elderly population. Pharmacologically Nicorandil isan agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Agingpathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind randomized placebo-controlled clinical trial of nicorandil in 62participants (both sexes >75 years old CDR 0.5 or 1 with HS-Aging profile in CSF and MRIbiomarkers [amyloid and phospho-tau negative with evidence for hippocampal atrophy; A-/T-/N+])over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly atrisk for HS-aging (this is the primary outcome measure) that will inform future trial design; and c.Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure)cognitive tests and CSF levels of nicorandil tau phospho-tau and A(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by:a. Refining MR imaging analysis (including hippocampal volumetric assays arterial spin labeling(ASL) diffusion tensor imaging (DTI) magnetic resonance spectroscopy (MRS) techniques that maydistinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performingproteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers tocomplement the A/T/N framework utilizing our prospective cohort with A(1-42) phospho-tau andneurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directlytest and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state;and c. Following our published and replicated neurocognitive testing marker that is associated withHS-Aging pathology we will optimize the clinical and neurocognitive criteria for disease diagnosisbased on the prospects of a relatively long-running (96 week) early-phase clinical trial.

project_terms:
3-Dimensional;ABCC9 gene;Affect;Age;Age related pathologies;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimers disease biomarker;Amyloid;Amyloid beta-Protein;Autopsy;Biological Assay;Biological Markers;Brain;Cardiovascular system;Clinical;Clinical Trials;Cognition;Complement;Congestive Heart Failure;Data;Degenerative Disorder;Dementia;Diagnosis;Differential Diagnosis;Diffusion Magnetic Resonance Imaging;Disease;Double-Blind Method;Elderly;Future;Genes;Genetic;Heart failure;Hippocampus;Human;Impaired cognition;Individual;Kentucky;Life;Link;Longitudinal cohort;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Metabolic;Morbidity - disease rate;Nerve Degeneration;Neurocognitive;Neurofibrillary Tangles;Nicorandil;Outcome Measure;Participant;Pathway interactions;Persons;Pharmaceutical Preparations;Pharmacotherapy;Phase;Placebo Control;Placebos;Population;Populations at Risk;Prevention trial;Probability;Prospective cohort;Proteins;Proteomics;Publishing;Randomized;Research;Risk;Running;Safety;Techniques;Testing;Universities;Urea;Work;aging biomarker;aging mechanism;aging population;arterial spin labeling;biomarker validation;cognitive testing;cohort;cost;design;disease diagnosis;drug discovery;drug repurposing;early phase clinical trial;efficacy outcomes;genetic risk factor;high risk;hippocampal atrophy;hippocampal sclerosis;late life;magnetic resonance imaging biomarker;neurocognitive test;neuroimaging;neuropathology;novel;novel therapeutics;pharmacologic;prevent;primary endpoint;primary outcome;randomized placebo-controlled clinical trial;rational design;receptor;safety testing;sex;tau Proteins;tau-1;treatment duration;trial design;volunteer

public_health_relevance:
NarrativeThis proposal seeks (through drug repurposing) a novel drug therapy as a potential treatment forhippocampal sclerosis dementia. There is no current treatment for this disease that affects approximately1/4th of the elderly but which is seldom recognized clinically because it mimics Alzheimer's disease. As suchthe proposed study represents a cutting-edge data-driven low-cost exploration of a novel disease relevantpathway that may hold promise for our global efforts targeting late life dementia.


application_id: 11040627
project_number: 1R61HL177474-01
project_title: Liposomal azithromycin to treat cardiac inflammation
administering_ic: NHLBI
award_notice_date: 2025-03-18
opportunity_number: RFA-HL-23-011
application_type: 1
activity_code: R61
ic: HL
serial_number: 177474
program_official: DANTHI, NARASIMHAN
project_start_date: 2025-03-18
project_end_date: 2027-02-28
study_section: Special Emphasis Panel[ZHL1 CSR-E (O1)]
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
other_pis: ABDEL LATIF, AHMED ;FEOLA, DAVID
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Coronary artery disease is the leading cause of morbidity and mortality in the US leading to over 1 millionmyocardial infarctions (MI) annually. The inflammatory response associated with MI leads to an influx ofcirculating immune cells particularly neutrophils monocytes and macrophages into the myocardium. Thisresponse is crucial for removing dead tissue and initiating the healing process. However exacerbatedinflammation following MI and other cardiomyopathies can be detrimental and is associated with infarctexpansion poor cardiac remodeling and adverse clinical outcomes. Modulating inflammation represents aparadigm shift in the treatment of MI but clinical translation has not been realized. Therapeutic transition ofmacrophages to a reparative phenotype represents a promising strategy to reduce the damage responsible forheart failure after MI. To address this we have prepared a liposomal formulation containing azithromycin (AZM)a clinically approved antibiotic that has been shown to modulate immune responses to favor repair. The overallgoal of this project is to advance the preclinical development of liposomal AZM (L-AZM) for clinical translation.The rationale for this proposed research is based on the need to identify treatments with improved therapeuticindex to minimize the inflammation and fibrosis associated with adverse cardiomyopathies including MI.Encouraged by strong preliminary data our goals are based on clear milestones that address current gaps inknowledge to further de-risk the technology and position it for clinical translation. The R61 phase will becompleted through the following specific aims: 1) Determine the optimal dose initiation and formulationparameters that enhance the therapeutic index of AZM and 2) Determine the optimal duration and dose of ourlead L-AZM formulation to reduce myocardial inflammation. The R33 phase will be completed through thefollowing specific aims: 1) Determine the efficacy of the optimal L-AZM regimen in murine and porcine modelsof cardiac inflammation and 2) Determine the pharmacokinetic parameters in murine and porcine animal models.Completion of both milestone-driven phases of the award will result in the data necessary to advance thetechnology toward IND-enabling studies for eventual clinical translation. The milestones of this proposal arewell-defined to advance pre-clinical development of L-AZM focused on identifying a treatment regimen thatresults in a survival benefit in animals. The approach is innovative and addresses an unmet need due to: 1)the repurposing of AZM in liposomes to polarize phagocytes toward a reparative phenotype to preserve cardiacmuscle post-MI and 2) our approach to assess formulations in an in vivo model with the goal of improving thetherapeutic index of AZM. There are currently no therapies approved to treat the post-MI inflammatory response.This research is significant as the proposed aims are low risk yet high impact and focus on improving ourunderstanding of AZM in a liposomal formulation to reduce the pathological inflammation in patients post-Ml.Project Summary/Abstract

project_terms:
Address;Animal Model;Animals;Antibiotics;Award;Azithromycin;Biological Markers;Cardiac;Cardiac Myocytes;Cardiac Output;Cardiomyopathies;Cells;Cicatrix;Clinical;Clinical Trials;Complex;Coronary Arteriosclerosis;Data;Dose;Drug Kinetics;Equilibrium;Exhibits;FDA approved;Family suidae;Fibrosis;Formulation;Future;Glucocorticoids;Goals;Heart Injuries;Heart failure;Immune;Immune Targeting;Immune response;Immunologics;Immunosuppression;In Vitro;Infarction;Inflammation;Inflammatory;Inflammatory Response;Injury;Ischemia;Knowledge;Lead;Lesion;Liposomes;Long QT Syndrome;Macrolides;Macrophage;Mediator;Miniature Swine;Modeling;Morbidity - disease rate;Mus;Myocardial;Myocardial Infarction;Myocarditis;Myocardium;Outcome;Pathologic;Pathology;Patients;Phagocytes;Phase;Phenotype;Play;Positioning Attribute;Preclinical data;Process;Property;Regimen;Reperfusion Therapy;Research;Risk;Role;Safety;Serum;Technology;Therapeutic;Therapeutic Index;Time;Tissues;Toxic effect;Treatment Efficacy;Treatment Protocols;biophysical properties;burden of illness;clinical translation;coronary fibrosis;design;efficacy evaluation;functional improvement;healing;heart damage;heart function;heart preservation;immunoregulation;improved;in vivo Model;inflammatory milieu;inflammatory modulation;innovation;liposomal formulation;monocyte;mortality;mouse model;neutrophil;novel therapeutics;optimal treatments;porcine model;preclinical development;preclinical efficacy;primary outcome;repaired;response;screening;secondary outcome;sudden cardiac death;therapy duration;tissue injury;treatment duration;uptake

public_health_relevance:
PROJECT NARRATIVEThis proposal seeks to continue preclinical development of a liposomal formulation containing azithromycin as atherapeutic strategy to modulate the inflammatory immune response associated with myocardial infarction. Theobjectives of this proposal will improve our understanding of the dosing regimen targeting of immune cellssafety and efficacy of our current lead formulation to continue pre-clinical development. These data will serveas the basis for future clinical translation to reduce the burden of cardiac inflammation in patients.


application_id: 11040506
project_number: 1UG3NS140971-01
project_title: Gastric Electrical Stimulation for Pain in Gastroparesis
administering_ic: NINDS
award_notice_date: 2025-06-09
opportunity_number: PAR-21-315
application_type: 1
activity_code: UG3
ic: NS
serial_number: 140971
program_official: HUDAK, ERIC MICHAEL
project_start_date: 2025-07-01
project_end_date: 2026-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: CHEN, JIANDE
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:
Abdominal pain affects almost 25% of the general population and results in more than 15 million clinical visits each year. Gastroparesis (Gp) defined as delayed stomach emptying and affecting 5 million American is a major health burden with limited treatment options. About 50% of patients with Gp are on narcotics for pain but narcotics delay gastric emptying and thus worsen symptoms of nausea and vomiting. Gastric electrical stimulation (GES) via an implantable pulse generator (a device called Enterra) has been approved by the FDA as a humanitarian method to treat nausea and vomiting in patients with Gp. However its effect on abdominal pain is largely unknown.  In this project we propose using GES in two ways to help elucidate its role in attenuating abdominal pain: using a special set of parameters Pp derived from pre-clinical studies and using modified Enterra parameters Pm derived from a clinical algorithm. Both methods will be compared with the nominal Enterra setting Pn.  During the UG3 Phase we will modify the Enterra software to allow multiple settings at different times of a 24-h period develop an IRB protocol meet with FDA and obtain IRB approval for the final study protocol that incorporates inputs from FDA. During the UH3 Phase we will conduct a 3-center randomized double-blinded and placebo controlled clinical study to investigate the effect of the proposed GES methods (two novel parameter settings). To make such an early clinical study feasible we will enroll only those patients with gastroparesis who are under the treatment of nausea and vomiting using an implantable Enterra device. The clinical study will be performed in 150 Gp patients with abdominal pain randomized to receive one of three treatments: GES with the nominal parameters Pn serving as control GES with special parameters Pp and GES with modified Enterra parameter Pm. The primary outcome will be the 7-day average of daily worst pain; the secondary outcomes will include change in use of pain medications percent of responders and gastroparesis cardinal symptom index.  The PIs have assembled a comprehensive and competitive team with expertise in all areas of this research. The PIs are world leaders in neuromodulation GES and Gp. The project is easy to implement (simply changing the parameter setting) but may lead to novel therapies for visceral pain. The likelihood of success is high due to promising preclinical findings availability of patients and extensive experience of the team.

project_terms:
Abdominal Pain;Affect;Algorithms;Alternative Therapies;American;Analgesics;Anti-emetics;Anxiety;Area;Back;Blinded;Blood Vessels;Chronic;Clinical;Clinical Data;Clinical Research;Computer software;Devices;Diabetes Mellitus;Double-Blind Method;Dyspepsia;Electric Stimulation;Enrollment;FDA approved;Feasibility Studies;Funding;Gastric Emptying;Gastroparesis;General Population;Health;Helping to End Addiction Long-term;Hyperalgesia;Implant;Institutional Review Boards;Intestines;Irritable Bowel Syndrome;Medical center;Mental Depression;Methods;Michigan;Modality;Modification;Monitor;Narcotics;Nausea and Vomiting;Neuropathy;Neurostimulation procedures of spinal cord tissue;Opioid;Pain;Pain Disorder;Pain in lower limb;Pain management;Patients;Pharmaceutical Preparations;Phase;Physiologic pulse;Placebo Control;Placebos;Population;Preclinical data;Preparation;Protocols documentation;Publishing;Quality of life;Randomized;Reporting;Research;Risk;Rodent Model;Role;Safety;Severities;Stomach;Symptoms;Syndrome;Testing;United States National Institutes of Health;Universities;Visceral pain;Visit;addiction;chronic pancreatitis;cohort;daily pain;diabetic;efficacious treatment;experience;improved;indexing;meetings;member;neuroregulation;novel;novel therapeutics;open label;opioid use;pain relief;pain score;preclinical study;primary outcome;secondary outcome;side effect;success;systematic review

public_health_relevance:
Gastroparesis (Gp) defined as delayed gastric emptying represents a major health burden with limited treatment options. Gp symptoms are also common in functional dyspepsia (FD) that affects 10-20% of general population and is present in about 20-50% of patients with diabetes (7-11% of general population). This proposal will test a new method of GES for treating pain in patients with gastroparesis and functional dyspepsia.


application_id: 11040320
project_number: 5R01ES033531-02
project_title: Vascular Toxicity of Benzene
administering_ic: NIEHS
award_notice_date: 2024-12-03
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: ES
serial_number: 033531
program_official: SCHUG, THADDEUS
project_start_date: 2024-02-21
project_end_date: 2028-11-30
study_section: Environmental Determinants of Disease Study Section [EDD]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
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:
Abstract:Benzene is a ubiquitous environmental pollutant. Natural sources of benzene include gasemissions from volcanos and forest fire. Benzene is also one of the top 20 chemicals generatedby industrial sources in the United States. While levels of benzene in the ambient air are usuallyin low ppb range amount of benzene in automobile exhaust and tobacco smoke can exceed 50ppm and occupational exposure to benzene can be as high as several hundred ppm. Peopleliving near hazardous waste sites gasoline refineries petrochemical industries and gasolinefueling stations may also have high exposure to benzene. Emerging data suggest that benzenecan exert cardiovascular toxicity. Our preliminary studies show that exposure to benzeneexacerbates atherosclerosis the underlying cause of most cardiovascular disease and stroke. Invitro studies show that benzene metabolite tt-muconaldehyde induces endothelial activation(expression of adhesion molecules leukocyte adhesion and their trans-endothelial migration andendothelial cell apoptosis). Using RNA-seq approach we identified several molecular targets(eNOS SOD1 HO-1 COX-2 ATF3 etc.) by which benzene and its metabolites can exert adverseeffects on endothelial functions. We also observed that heat shock proteins HSPA1A andHSPA1B induced by benzene exposure could play a protective role in benzene-inducedendothelial dysfunction and atherosclerosis. Based on these observations we hypothesize thatHSPA1A and HSPA1B prevent benzene-induced exacerbation of atherogenesis by inhibitingvascular inflammation and injury. To test this hypothesis we propose two specific aims: Aim 1will examine how HSPA1A and HSPA1B affect benzene-induced endothelial functions (vascularrelaxation leukocyte rolling and adhesion to vascular endothelium apoptosis) and Aim 2 willexamine how endothelial cell specific overexpression of HSPA1A and HSPA1B affects benzene-induced atherosclerosis (lesion size composition and nature). Successful completion of thisproject will establish a mechanistically validated model of benzene-induced endothelialdysfunction and atherosclerosis. This will provide a strong rationale to examine the association ofbenzene exposure with vascular dysfunctions and atherosclerosis in humans.

project_terms:
Adhesions;Adverse effects;Affect;Air;Air Pollution;Aorta;Apoptosis;Arterial Fatty Streak;Arteries;Atherogenicity;Atherosclerosis;Automobile Exhaust;Benzene;Benzene Exposure;Benzoquinones;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Adhesion Molecules;Cell Physiology;Cells;Cessation of life;Chemicals;Cytoskeleton;Data;Deposition;Disease;Dose;Dyslipidemias;Endothelial Cells;Endothelium;Environmental Pollutants;Environmental Pollution;Evaluation;Exposure to;Failure;Fibrosis;Foam Cells;Gases;Gasoline;Hazardous Waste Sites;Health;Heat shock proteins;Hematopoietic;Human;Hydroquinones;In Vitro;Individual;Industrialization;Industry;Inflammation;Inflammation Mediators;Inflammatory;Innate Immune Response;Insulin Resistance;Knockout Mice;LDLR gene;Lesion;Leukocyte Rolling;Leukocytes;Lipid-Laden Macrophage;Lipoproteins;Low-Density Lipoproteins;Matrix Metalloproteinases;Mediating;Metals;Modeling;Molecular;Molecular Chaperones;Molecular Target;Mus;Myocardial Ischemia;Natural Source;Nature;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Occupational Exposure;Ozone;PTGS2 gene;Particulate Matter;Persons;Petroleum;Play;Process;Protein Overexpression;Proteins;Rattus;Relaxation;Role;Rupture;Small Interfering RNA;Smooth Muscle Myocytes;Source;Stimulus;Stroke;Structure;Testing;Time;Tobacco smoke;Toxic effect;Toxin;Trichloroethylene;United States;Vascular Diseases;Vascular Endothelium;activating transcription factor 3;air filter;atherogenesis;chronic inflammatory disease;cytokine;drinking water;endothelial dysfunction;forest fires;high efficiency particulate air filter;immunotoxicity;leukemia;migration;overexpression;pollutant;premature;prevent;protein expression;protein folding;recruit;response;sex;superfund site;superoxide dismutase 1;transcriptome sequencing;vascular inflammation;vascular injury;volatile organic compound;volcano;western diet

public_health_relevance:
Narrative: Benzene is a ubiquitous environmental pollutant and a known hematopoietic toxin butlittle is known about the effect of benzene exposure on cardiovascular disease. The proposedstudy will examine the effect of benzene exposure on atherosclerosis the underlying cause ofmost cardiovascular disease and stroke and delineate the associated molecular mechanisms.


application_id: 11039999
project_number: 5R01CA284532-02
project_title: Fatty Acid Synthase as a Novel Molecular Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2025-02-17
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 284532
program_official: CHEN, WEIWEI
project_start_date: 2024-03-01
project_end_date: 2029-02-28
study_section: Mechanisms of Cancer Therapeutics C Study Section [MCTC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Altered metabolism is recognized as a common hallmark of cancer. Dysregulation of glucose metabolismhas been extensively studied; however the role of fatty acid (FA) metabolism in tumorigenesis and diseaseprogression as well as treatment resistance remains poorly understood. Following our initial discovery of FASNa key enzyme of de novo lipid biosynthesis as an important regulator or tumor progression in colorectal cancer(CRC) studies from our group and others have firmly established an oncogenic role of FASN in multiple tumortypes. Increased fatty acid biosynthesis is needed not only to accommodate high rates of proliferation byproviding building blocks for membrane synthesis but also to enhance cancer cells ability to defend againstoxidative stress- or chemotherapy-induced cell death by changing membrane lipid composition. Given the strongrationale for targeting FASN in cancer therapy a new class of potent and selective small molecule inhibitors ofFASN (TVBs) have been developed and characterized in pre-clinical and clinical investigations. Our group hasconducted a double-blind randomized placebo-controlled window trial with TVB-2640 in patients with resectablecolon and other cancers. Results from the interim analysis of this ongoing clinical investigation revealed thatshort-term oral TVB-2640 therapy demonstrates excellent on-target inhibition of de novo lipogenesis andmanageable safety profile. However our preclinical studies using CRC patient-derived xenografts (PDXs)showed that FASN inhibitors only modest reduce tumor growth despite a significant decrease in lipogenesis invivo. Thus targeting FASN alone is unlikely to be sufficient to eradicate cancer cells. In exciting new findingswe showed that FASN inhibition potentiates chemotherapy drug-induced DNA damage in colon cancer cells asa result of altered histone acetylation. In addition we discovered that FASN inhibition promotes the activation ofthe cGAS/STING pathway and downstream type I interferon (IFN) response. The overall objective of this studyis to identify novel mechanisms that can enhance the antitumor efficacy of FASN inhibitors in CRC. The centralhypothesis driving this proposal is that a combination treatment strategy which includes FASN inhibition willprevent chemoresistance by blocking DNA damage response and potentiating the activation of innate immunesignaling via epigenetic mechanisms. The following Specific Aims are proposed: 1) to define the molecularmechanisms by which FASN inhibition blocks DNA repair pathways; 2) to delineate the functional significanceof FASN inhibition on modulating tumor immune microenvironment; and 3) to determine the impact of FASNinhibition on enhancing the efficacy of CRC therapies in vivo. Our highly collaborative group has the requisiteexpertise innovative model systems state-of-the-art technology and novel inhibitors to make rapid progressthat will potentially provide novel treatment options to improve patient outcome.

project_terms:
Acetyl Coenzyme A;Attenuated;Automobile Driving;Binding;Biological Models;Cancer Etiology;Cancer Patient;Cell Death Induction;Cessation of life;Chemoresistance;Clinical Trials;Colon;Colon Carcinoma;Colorectal Cancer;Combined Modality Therapy;Cytoplasm;DNA Damage;DNA Repair Pathway;Data;Development;Disease Progression;Double-Blind Method;Drug resistance;Enzymes;Epigenetic Process;Fatty Acids;Fatty-acid synthase;Goals;Histone Acetylation;Immune checkpoint inhibitor;Immune signaling;In Vitro;Interferon Type I;Investigation;Malignant Neoplasms;Malonyl Coenzyme A;Mediating;Membrane Lipids;Metabolic Control;Metabolism;Modeling;Molecular;Molecular Target;Nucleosomes;Oncogenic;Oral;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Placebo Control;Preclinical data;Proliferating;Protein Acetylation;Publishing;Randomized;Regulation;Resectable;Role;Safety;Signal Pathway;Signal Transduction;Site;Specimen;Stimulator of Interferon Genes;T-Lymphocyte;Technology;Testing;Therapeutic;anti-cancer;antitumor effect;cancer cell;cancer therapy;chemotherapeutic agent;chemotherapy;clinical investigation;clinically relevant;colon cancer patients;colon cancer treatment;colorectal cancer treatment;digital;epigenetic regulation;fatty acid biosynthesis;fatty acid metabolism;glucose metabolism;immune activation;improved;in vivo;inhibitor;innovation;irinotecan;lipid biosynthesis;lipid metabolism;membrane synthesis;multidisciplinary;novel;patient derived xenograft model;placebo group;pre-clinical;preclinical study;prevent;recruit;response;small molecule inhibitor;stressor;therapy resistant;treatment strategy;tumor;tumor growth;tumor metabolism;tumor progression;tumor xenograft;tumor-immune system interactions;tumorigenesis;uptake

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the second most common cause of cancer death in the U.S. Increased FASN-dependentde novo lipid biosynthesis drives tumorigenesis and progression. Our study will identify novel mechanisms thatcan enhance the antitumor efficacy of FASN inhibitors and provide the necessary preclinical data for thedevelopment of a new combination treatment strategy to improve patient outcome.


application_id: 11039990
project_number: 5R25ES036039-02
administering_ic: NIEHS
award_notice_date: 2025-01-06
opportunity_number: PAR-21-168
application_type: 5
activity_code: R25
ic: ES
serial_number: 036039
program_official: HUMBLE, MICHAEL C
project_start_date: 2024-03-01
project_end_date: 2028-12-31
study_section: ZES1-BWD-W(25)1
contact_pi_person_id: 8531285
contact_pi: NEAL, RACHEL ELIZABETH
other_pis: ABOLINS-ABOLS, MIKUS ;CORBITT, CYNTHIA
congressional_district: 03
department: 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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-01-01
project_title:
KEEP: Kentucky Environmental Education Pipeline A program to retain a diverse and equitable scientific trainee pipeline

project_abstract:
ABSTRACTThe KEEP: Kentucky Environmental Education Pipeline will create a paid immersive undergraduateenvironmental health focused summer research experience that targets enrollment by URM and economicallydisadvantaged students. Nearly 60% of students who enter college with the goal of majoring in a STEM field endup graduating in a non-STEM field or leaving without a degree. This attrition is especially severe in students fromunderrepresented and historically marginalized communities. Among the major reasons for such a high dropoutfrom STEM programs are limited career counseling limited institutional support and an academic culture that isunwelcoming or outright hostile to unique circumstances and lived experiences. The KEEP program will facilitatethe development of student identity as scientists create lasting support structures and connect student researchto local communities. The KEEP program will focus on the following Specific Aims: Aim 1: Create and administer a 10-week on-site summer undergraduate research program for UofLstudents in the broad field of environmental health sciences. The KEEP program includes mentored research aswell as a community led environmental sampling bootcamp (all mentors also invited) weekly instruction inbiostatistics concepts and methodologies and dissemination via undergraduate research day participation aswell as Posters-At-The-Capital and regional Ohio Valley Society of Toxicology meeting participation. Aim 2: Enrich undergraduate student development through continuing academic and careermentoring professional development activities (ex: resume building and personal statement construction)exposure to a broad variety of environmental health research seminars and weekly cohort building activities. Aim 3: Evaluation of student outcomes including recruitment participation satisfaction and trackingof academic progress toward matriculation. We will utilize existing infrastructure associated with the UofL CIEHSand Office of Undergraduate Research and Creative Activities as well as the UofL Cards Analytics office.

project_terms:
Abattoirs;Academic support;Air;Appalachian Region;Arts;Back;Biology;Biometry;Black race;Capital;Chemicals;Chemistry;Coal;Communities;Community Outreach;County;Creativeness;Data;Degree Completion;Development;Discipline of Nursing;Dropout;Economics;Education;Enrollment;Environmental Health;Environmental Monitoring;Equity;Evaluation;Excision;Exposure to;Fellowship Program;Foundations;Funding;Goals;Health;Health Personnel;Health Sciences;Home;Huntington Disease;Incentives;Information Sciences;Infrastructure;Institution;Instruction;Justice;Kentucky;Latino;Link;Lived experience;Medical Students;Medicine;Mental Health;Mentors;Mentorship;Methodology;National Institute of Environmental Health Sciences;Ohio;Organization and Administration;Outcome;Participant;Pollution;Postdoctoral Fellow;Public Health;Reporting;Research;Research Personnel;Research Training;Running;STEM field;STEM program;STEM student;Sampling;Schools;Science;Scientist;Site;Societies;Statistical Data Interpretation;Structure;Students;Superfund;Toxicology;Training;Training Programs;Training and Education;Underrepresented Students;Universities;Vocational Guidance;bridge to the baccalaureate;cancer health disparity;career;cohort;college;community partners;cost;disabled;disadvantaged student;economic disparity;experience;faculty mentor;field trip;innovation;manufacture;marginalized community;marginalized population;matriculation;meetings;posters;programs;recruit;satisfaction;skills;skills training;soil sampling;student research;summer research;superfund site;technical college;transfer student;undergraduate research;undergraduate research experience;undergraduate student;undergraduate summer research

public_health_relevance:
NARRATIVE:KEEP: Kentucky Environmental Education Pipeline program will recruit and train undergraduate studentresearchers from historically marginalized populations for careers within the field of environmental healthsciences. Key to the mentorship associated with this summer research opportunity program we will offer accessto specialized skills training sessions via boot camps including a community-embedded air/soil sampling fieldtrip with integrated report back organized and administered via the NIEHS funded Center for IntegrativeEnvironmental Health Sciences Community Outreach core. Faculty mentors and/or program directors willcontinue to provide career coaching and personalized mentorship until matriculation so that participants are fullyintegrated into an ongoing supportive community focused on degree completion timely application to competitivegraduate and professional school programs and ultimately biomedical careers in environmental health sciences.


application_id: 11039226
project_number: 3R01MH131633-02S1
administering_ic: NIMH
award_notice_date: 2024-08-20
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: MH
serial_number: 131633
suffix: S1
program_official: CHAVEZ, MARK RAY
project_start_date: 2023-09-01
project_end_date: 2028-06-30
study_section: Adult Psychopathology and Disorders of Aging Study Section[APDA]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: SMITH, APRIL ROSE
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Longitudinal Personalized Dynamics Among Anorexia Nervosa Symptoms Core Dimensions and Physiology Predicting Suicide Risk

project_abstract:
ABSTRACTAnorexia nervosa (AN) is a severe mental illness with the highest mortality rate of any psychiatric disorder withsuicide as the second leading cause of death. Despite extremely high rates of suicide risk factors for suicidalideation (SI) and behaviors/attempts (SA) in this high-risk population are not well understood. While there isevidence that threat reactivity stress-response over-arousal emotion dysregulation and agitation contributeto suicide risk the dynamic relations among these processes have not been characterized on acomprehensive momentary basis. Our scientific premise developed from our past work is that the applicationof ideation-to-action and network theories will enable the identification of dynamic longitudinal interactionsamong core dimensions (e.g. arousal threat) AN symptoms and SI/SA both between and within individuals.Our study goals are to (1) identify symptom and dimension risk interactions of co-occurring AN and SI/SAbetween and within persons (2) differentiate which risk factors predict SI vs SA and (3) test if these risk factorspredict onset of SI/SA. These goals will ultimately identify which factors should be targeted in novel preventionand treatment efforts. We will use a multiple units of analysis approach combined with novel cutting-edgeadvances in suicide and network science. We will collect intensive real-time data on AN and suicide behaviorsanxiety over-arousal emotion regulation and agitation using mobile technology as well aspsychophysiological assessment of emotion regulation (via heart-rate variability) and arousal (viaelectrodermal activity characterizing over-arousal and acceleration characterizing the sleep-wake cycle) from230 individuals with a diagnosis of AN/Atypical AN (AAN). At 1-month 6-month and one year follow-up we willtest if individual risk factors predict SI/SA. We expect 35-58 participants will have SA across our study period.The purpose of this supplement is to provide staff support for our research operations and cover additionalcosts for sensor bands to collect real-time objective physiological data during the 3-week period thatparticipants complete ecological momentary assessment data. This supplement will ensure that we reach ourrecruitment milestones and collect physiological data in a timely fashion. In turn this work will help to identifyrisk factors for the overlap between eating disorders and suicide which will lead directly to novel preventionand treatment efforts.

project_terms:
Acceleration;Administrative Supplement;Agitation;Anorexia Nervosa;Anxiety;Arousal;Cause of Death;Data;Death Rate;Diagnosis;Dimensions;Eating Disorders;Ecological momentary assessment;Ensure;Equipment;Feeling suicidal;Goals;Individual;Lead;Mental disorders;Operations Research;Participant;Persons;Physiological;Physiology;Predictive Factor;Prevention;Process;Psychophysiology;Research Support;Risk;Risk Factors;Science;Sleep Wake Cycle;Suicide;Symptoms;Testing;Time;Work;biological adaptation to stress;cost;emotion dysregulation;emotion regulation;follow-up;heart rate variability;high risk population;ideation;mobile computing;novel;recruit;sensor;severe mental illness;suicidal behavior;suicidal risk;suicide rate;theories

public_health_relevance:
PROJECT NARRATIVEThis project is an administrative supplement to provide support for research staff and equipment. This supportwill ensure that we reach our recruitment milestones and collect physiological data in a timely fashion. I n turnthis work will help to identify risk factors for the overlap between eating disorders and suicide which will leaddirectly to novel prevention and treatment efforts.


application_id: 11038048
project_number: 5R25NS130963-03
project_title: UKNeu-PREP: University of Kentucky Neuroscience Postbaccalaureate Research Education Program
administering_ic: NINDS
award_notice_date: 2025-08-21
opportunity_number: RFA-NS-22-035
application_type: 5
activity_code: R25
ic: NS
serial_number: 130963
program_official: MATTHEWS, MARGUERITE
project_start_date: 2023-03-15
project_end_date: 2028-02-28
study_section: ZNS1-SRB-D(21)
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: BRADLEY, LUKE H
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:
Nationally there is a critical need for a pipeline of promising young scientists interested in earning life science doctorate degrees. While the foundation for the development of biomedical Ph.D. and MD/Ph.D. graduates primarily focuses on the recruitment of younger students gaps in the Ph.D. or MD/Ph.D. pipeline still underscore the need for enhanced pools of potential post-baccalaureate students to pursue exceptional doctoral training. Nationally the step between undergraduate and graduate school is often a barrier in the biomedical doctoral degree pipeline. This barrier is exacerbated by limited access to substantive biomedical research opportunities to prepare for graduate school. To address this critical need in our region and beyond the University of Kentucky (UK) Neuroscience - Postbaccalaureate Research Education Program (UKNeu- PREP) is uniquely positioned to provide access to an extensive biomedical research experience in neuroscience while preparing program Participants through educational and professional development opportunities to acquire the knowledge research experience communication skills and confidence to successfully navigate the admissions process into a strong neuroscience graduate program. UKNeu-PREP will leverage existing state regional and national networks to recruit Participants to become integrated into campus student supports active research programs and pipeline programs. Existing pipeline programs include our associated T32 training program Neurobiology of CNS Injury and the All Access Research Training Scholars (AARTS) summer program through the Spinal Cord and Brain Injury Research Center. Collectively UKNeu-PREP will train Participants to be lifelong career scientists while creating opportunities for those who have completed bachelors degrees at institutions with limited research infrastructure. UKNeu-PREP will contribute to innovation and excellence in research environments and strengthen the entire research training enterprise.

project_terms:
Address;Admission activity;Bachelor's Degree;Biological Sciences;Biomedical Research;Communication;Communities;Degree Completion;Development;Discipline;Doctor of Philosophy;Doctor's Degree;Education;Educational process of instructing;Educational workshop;Electronic Mail;Employment;Enrollment;Ensure;Environment;Foundations;Goals;Graduate Education;Health;Individual;Institution;Kentucky;Knowledge;Knowledge acquisition;Letters;Medicine;Mentors;Mission;Modeling;Neurobiology;Neurosciences;Neurosciences Research;Outcome;Output;Participant;Pathway interactions;Patient Recruitments;Positioning Attribute;Postbaccalaureate;Postdoctoral Fellow;Preparation;Process;Publications;Qualifying;Recruitment Activity;Research;Research Infrastructure;Research Training;Resources;STEM career;Scholars Program;Schools;Scientist;Student recruitment;Students;Surveys;Talents;Telephone;Training;Training Programs;Training and Infrastructure;Universities;Videoconferencing;Work;career;central nervous system injury;education research;empowerment;expectation;experience;graduate school;graduate school preparation;graduate student;higher education;improved;innovation;interest;meetings;peer;programs;recruit;role model;skills;social media;spinal cord and brain injury;stem;success;summer program;symposium;technological innovation;undergraduate student;university student

public_health_relevance:
The goal of the University of Kentucky Neuroscience Postbaccalaureate Research Education Program (UKNeu-PREP) is to serve individuals who lack substantive research opportunities. The realization of this mission is the development of a robust pool of well-trained postbaccalaureate participants that transition into strong neuroscience and research-focused higher degree doctoral programs. An expanded scientific community and workforce are vital for increasing the quality of higher education medicine scientific research and technological innovation to solve health-related problems and challenges.


application_id: 11038024
project_number: 5P20GM125504-08
administering_ic: NIGMS
award_notice_date: 2025-02-24
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2025-06-30
study_section: ZGM1-RCB-3
subproject_number: 5221
contact_pi_person_id: 10933857
contact_pi: TENG, YUN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-03-01
project_title:
Edible Plant-derived exosome-like nanoparticles (ELNs) and phage inhibit brain inflammation by targeting microglia and  gut microbiota

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

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


application_id: 11038022
project_number: 5P20GM125504-08
project_title: The role of sugar transport in C. difficile colonization and disease
administering_ic: NIGMS
award_notice_date: 2025-02-24
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3
subproject_number: 5220
contact_pi_person_id: 14774031
contact_pi: COLLINS, JAMES TRISTAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractClostridioides difficile infection (CDI) is still the most common cause of healthcare-associated infection despitea concerted effort to reduce the incidence. Increasingly C. difficile is found in the community among personswith no recent healthcare contact. The long-term goal of this project is to identify novel therapeutic targets whichcan be exploited to treat CDI and control the spread of C. difficile. The overall objectives in this application areto (i) elucidate the specificity and redundancy of the sugar transporters under positive selection in C. difficile (ii)determine their role in disease and iii) examine the impact of dietary sugar on asymptomatic carriage. Thecentral hypothesis is that C. difficile has evolved to better occupy niche space within the gastrointestinal tract(GIT) by taking advantage of the modern sugar-rich diet. The rationale for this project is that determining thespecificity and importance of sugar transporters and downstream metabolism in C. difficile carriage and infectionsets up a robust scientific framework whereby new prophylaxis and treatment strategies can be developed. Thecentral hypothesis will be tested by pursuing three specific aims: 1) Elucidate the specificity redundancy andinfluence on toxin production of evolving sugar transport genes 2) Determine the effect of evolving sugartransport genes on community invasion and disease and 3) Investigate the role of sugars in niche establishmentand asymptomatic carriage. Under the first aim clean deletions of sugar transporters previously shown to beunder positive selection in epidemic C. difficile will be generated and their effect on growth and toxin productionassessed. The second aim will determine the role of sugar transport in invasion using a novel in vitro bioreactorassay and disease by utilizing a mouse model of CDI. Finally aim three will assess the role of sugar availabilityin asymptomatic C. difficile colonization by using toxin negative C. difficile strains and a novel 13 strain mousemicrobiota colonization model. The research proposed in this application is innovative because it focuses onthe metabolic adaptation of C. difficile to carbohydrates and their role in asymptomatic carriage as well asdisease. This focus has the potential to lead to novel prophylactic strategies that can be used against C. difficilebefore the emergence of the disease. The proposed research is significant as it will provide a solid scientificjustification for the continued examination of metabolism as a virulence mechanism in C. difficile and provide aframework for the future study of novel prophylactic intervention and treatment options.

project_terms:
Accounting;Adult;Antibiotics;Biological Assay;Bioreactors;Carbohydrates;Clostridium difficile;Communities;Data;Development;Diet;Dietary Sugars;Disease;Enabling Factors;Environment;Environmental Risk Factor;Epidemic;Future;Gastrointestinal tract structure;Genes;Goals;Growth;Health Care;Horizontal Disease Transmission;Hospitalization;Hospitals;Human;In Vitro;Incidence;Infection;Inflammation;Intake;Intervention;Intestines;Invaded;Link;Metabolic;Metabolism;Modeling;Modernization;Mouse Strains;Nutrient;Nutrient availability;Organism;Outcome;Pathogenicity;Persons;Population;Process;Production;Prophylactic treatment;Research;Role;Severity of illness;Shapes;Solid;Specificity;System;Testing;Toxic effect;Toxin;Trehalose;Virulence;Work;colonization resistance;dysbiosis;evidence base;gut microbiota;health care associated infections;host microbiota;innovation;insight;microbiome research;microbiota;mouse model;new therapeutic target;novel;old age;pathogen;prevent;prophylactic;sugar;treatment strategy


application_id: 11038015
project_number: 5P20GM125504-08
project_title: Functional Microbiomics Core
administering_ic: NIGMS
award_notice_date: 2025-02-24
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3
subproject_number: 5218
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractIn this Phase 2 of the Functional Microbiomics Inflammation and Pathogenicity COBRE the primary goal of theFunctional Microbiomics Core (FMC) is unchanged. We will sustain and enhance the well-established integratedservice center that functions as a critical resource for the Research Project Leaders (RPLs) as a priority andsecondarily for all investigators of the Center. Since all new COBRE projects also utilize mouse models to explorethe inter-relationships between inflammation and pathogenesis and the contribution of microbiota to thisprocess our well-established germ-free and gnotobiotic mice facility (GMF) will continue to play a central role inservices provided by the FMC. We will continue to provide anaerobic culturing of mixed and/or mono bacterialstrains to facilitate the specific colonization of the germ-free mice. 16S ribosomal DNA will be profiled with thein-house developed Oxford nanopore sequencing as well as PacBio-long read sequencing tools andbioinformatic support provided. Our most extensively used resource; multiplex-based analysis of inflammatorymediators in biological samples will continue to function using the Bio-Plex 200 (Bio-Rad) multiplex system. Inaddition several recent advances allow us to augment the services provided by the FMC. First the recentlydeveloped highly successful rederivation service of transgenic and KO mouse models as germ-free will greatlyexpand the scope and utility of the GMF. Related to this service is the development of a new area of researchon the role of microbiota in Alzheimers Disease (AD) supported by an administrative supplement to the FMCfrom NIA/NIGMS. The GMF has already rederived several AD mouse models. For this project the FMC alsodeveloped a suite of mouse behavior analysis models including the Morris Water Maze and Novel ObjectRecognition tests. These services will support all future ageing related research at the center including a newproject on the role of edible-plant derived exosomes in restoring the integrity of the Blood Brain Barrier. We alsonow include imaging support in particular Multiphoton Intravital Microscopy for imaging of live tissue and an InVivo Imaging System (IVIS) for live mouse imaging. Besides functioning as a service center another major goalof the FMC is to promote the education and training of researchers primarily the RPLs. The FMC will also interactwith other Core facilities at the University of Louisville such as the Genomics Metabolomics and Bioinformaticscore facilities established with the support of other highly successful COBRE/INBRE programs. In particular thenewly funded Cancer Immunology and Immunotherapy COBRE-operated Functional Immunomics Core (FIC)facility also directed by Dr. Bodduluri has several joint initiatives with the FMC including the establishment of ahistopathology service center. The FMC will work with these and other UofL resources in order to avoidduplication of equipment and to train individual investigators in specific protocols foster innovative protocoldevelopment and integrate analysis of data.

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


application_id: 11038011
project_number: 5P20GM125504-08
project_title: FMIP COBRE Administrative Core
administering_ic: NIGMS
award_notice_date: 2025-02-24
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3
subproject_number: 5217
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract The University of Louisville (UoL) COBRE in Functional Microbiomics Inflammation and Pathogenicity (FMIP) comprises a multidisciplinary group of investigators addressing thematic aspects that span the human microbiome host inflammatory responses and disease outcomes. The purpose of the Administrative Core is to provide a formal governance structure for the administrative fiscal and scientific oversight of this Phase 2 COBRE. Following on from the success of Phase 1 we are well-positioned to transition to Phase 2 and maintain a coordinated and efficient administrative structure. The departments of Oral Immunology and Infectious Diseases (OIID) and Microbiology and Immunology (M&I) are the main contributors to the cross-disciplinary nature of the program. These units have established records of federal funding mentoring junior faculty graduate student training and collaborative interactions across campus. We will continue mutually supportive horizontal interactions with other NIH-funded programs at UoL including the Hepatobiology and Toxicology COBRE and the KY-INBRE which will enhance the overall research profile of UoL. The activities of the COBRE will help recruit retain and diversify the faculty. The application is led by well-qualified and well-funded Center Directors. Governance and evaluation are supported by an Internal Advisory Committee (IAC) and an External Advisory Committee (EAC) comprised of five international experts in the thematic area of research. There are three outstanding Research Project Leaders (RPLs) with senior established funded mentoring teams with a track record in developing the careers of junior faculty through to independent funding status and further career devlopment. We have developed comprehensive mentoring and career development plans with milestones and evaluative metrics. Similarly mentors and the COBRE program are evaluated formatively and summatively. We have a strong commitment of support from the UoL which will ensure sustainability beyond the NIH-funded period. The Specific Aims are: to provide the formal governance structure which allows coordination direction and prioritization of all activities including budget issues thus ensuring the quality of all functions and growth of research goals; to administer the process for mentoring and career development of junior faculty and accelerate their transition to independence; coordination of the evaluative processes of the COBRE by the IAC and EAC; budget management including budget reconciliation and preparing and submitting RPPRs and FFRs; resolution of any conflicts as they arise; management of mechanisms to replace RPLs as they become independent and replacement other key personnel as necessary; administration of the Pilot Program to help maintain a pipeline of investigators; coordination of institutional support; support of clinical translational and commercialization potential of research projects; provision of biostatistical support; to disseminate pertinent information resulting from the COBRE activities; and ensuring compliance with all relevant regulations and guidelines. All projects and cores will utilize the Administrative Core.

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


application_id: 11038010
project_number: 5P20GM125504-08
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2025-02-24
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
program_official: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3(C2)
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractIn the past few decades the fields of microbiology and immunology have undergone a renaissance driven inpart by technological advances establishing that the human microbiome can play a role in a number offundamental aspects of human health and disease in many instances through the interface with host innateimmunity. The immune system functions to restrict the potential for damage caused by the microbiota whilesimultaneously minimizing destructive inflammatory responses. Disruption of the intensity duration or physicallocation of inflammation however can contribute to disease. Advances in our understanding of the microbiomeand its regulation by environmental factors along with a realization that inflammatory processes are at the coreof a number of common diseases necessitates a cross-disciplinary perspective that accommodates the host-microbe interaction in toto. The major goal of this Phase 2 Cobre is to continue to develop and expand ourthematic multidisciplinary research center for the study of the interface between the microbiome inflammationand pathogenicity within a framework to develop the careers of junior investigators. We have assembled a teamof junior investigators with complementary expertise and outstanding potential and have partnered these projectleaders with well-qualified and dedicated mentors. An integrated set of projects will make novel connectionsbetween inflammatory processes and bacterial pathogenicity and establish the basis for the development ofnovel therapeutics and delivery methods. We will create a multidisciplinary program in research trainingmentoring and career development that will facilitate and accelerate the transition of junior faculty to independentextramural funded status. Research will be support by a Functional Microbiomics Core that will provide germfree animal facilities anaerobic culture capability microbiome sequencing and bioinformatics assay ofinflammatory markers along with whole animal imaging and intravital microscopy. An Administrative Core willco-ordinate activities and provide additional biostatistical support along with a Pilot Project program to ensure apipeline of investigators. Institutional commitment through a university funded Center will ensure sustainabilityof the thematic research program.

project_terms:
Acceleration;Autoimmune Diseases;Basic Science;Bioinformatics;Biological Assay;Biometry;Career Mobility;Centers of Research Excellence;Chronic;Communities;Complex;Dedications;Development;Disease;Ensure;Environment;Environmental Risk Factor;Evaluation;Extramural Activities;Faculty;Funding;Germ-Free;Goals;Health;Health Transition;Homeostasis;Human;Human Microbiome;Human body;Immune response;Immune system;Immunologics;Immunology;Infection;Inflammation;Inflammatory;Inflammatory Response;Infrastructure;Institution;Interdisciplinary Study;International;Location;Mentors;Methods;Microbiology;Mucous Membrane;Natural Immunity;Outcomes Research;Pathogenicity;Pathway interactions;Phase;Pilot Projects;Postdoctoral Fellow;Process;Qualifying;Regulation;Renaissance;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Scientist;Site;Specificity;Structure;System;Talents;Technology;Therapeutic Agents;Tissues;Training;Universities;animal facility;career;career development;design;experience;graduate student;host-microbe interactions;imaging capabilities;immune system function;inflammatory marker;innovation;interdisciplinary approach;intravital microscopy;microbial;microbial community;microbiome;microbiome research;microbiome sequencing;microbiota;multidisciplinary;novel;novel therapeutics;pathogen;programs;recruit;research and development;response;senior faculty;success;synergism;whole animal imaging

public_health_relevance:
Project NarrativeThe University of Louisville COBRE in Functional Microbiomics Inflammation and Pathogenicity is a uniquethematic research center. COBRE scientists comprise a multidisciplinary group of senior mentors and juniorinvestigators on a pathway to independence who are focusing on diseases that involve complex interactionsbetween microbial challenge and host inflammatory responses. Outcomes of this research may lead to thedevelopment of novel therapeutic agents and delivery systems to protect against a number of chronic and difficultto treat conditions.


application_id: 11037922
project_number: 5R61MH132722-02
project_title: Using Exercise to Enhance Consolidation of Exposure-Based Therapeutic Learning in PTSD
administering_ic: NIMH
award_notice_date: 2025-04-07
opportunity_number: PAR-21-135
application_type: 5
activity_code: R61
ic: MH
serial_number: 132722
program_official: TUMA, FARRIS KEITH
project_start_date: 2024-02-16
project_end_date: 2027-01-31
study_section: ZMH1-ERB-N(06)
contact_pi_person_id: 10372293
contact_pi: BADOUR, CHRISTAL L.
other_pis: ADAMS, THOMAS G;CISLER, JOSHUA M
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe proposed R61/R33 project would build on our published pilot data and animal models to demonstrate thatmoderate intensity physical exercise delivered after exposure therapy engages fear circuitry and enhances theconsolidation of therapeutic safety learning thereby enabling enhanced symptom reduction for PTSD. In theR61 target engagement phase adults with PTSD related to interpersonal violence (IPV) exposure wouldcomplete an initial session of imaginal exposure to traumatic memory cues adapted for an MRI setting. Thiswould be followed by 30-mins of moderate intensity exercise or low intensity walking control. Participantswould return 24-hrs later to complete a second session of imaginal exposure with MRI. We hypothesize greaterbetween-session reductions in fear responding and fear circuit activation to traumatic memory cues 24-hrslater among those who exercised following the first session compared to those in the walking control condition.The R33 phase will build upon successful target engagement and adapt a brief version of prolonged exposure(PE) therapy to include moderate-intensity exercise or walking control after imaginal exposure. We hypothesizethat PE with exercise will result in more rapid and larger reductions in PTSD symptoms and reduced fear-related neurocircuitry activation and affective arousal to trauma cues compared to PE plus walking control.Overall this project is designed to demonstrate that a novel intervention (moderate intensity exercise) engageskey mechanisms of therapeutic exposure thereby enhancing the efficacy of exposure therapy.

project_terms:
Acute;Adult;Aerobic Exercise;Affective;Aftercare;Amygdaloid structure;Animal Model;Anterior;Anxiety;Arousal;Biological Markers;Brain-Derived Neurotrophic Factor;Cardiovascular Diseases;Clinical assessments;Cues;Diagnosis;Disease;Dorsal;Emotional;Event;Exercise;Exercise Test;Exposure to;Extinction;Fright;Functional Magnetic Resonance Imaging;Heart Rate;Insula of Reil;Interpersonal Violence;Intervention;Knowledge;Learning;Magnetic Resonance Imaging;Measures;Mediating;Mental Depression;Monitor;Neurobiology;Participant;Patient-Focused Outcomes;Peripheral;Phase;Physical Exercise;Post-Traumatic Stress Disorders;Psyche structure;Psychopathology;Psychophysiology;Psychotherapy;Publishing;Randomized;Reporting;Safety;Signal Transduction;Symptoms;Testing;Therapeutic;Trauma;Visit;Walking;Writing;anxiety reduction;anxious;candidate marker;comorbidity;data modeling;design;exercise intensity;follow-up;heart rate monitor;improved;indexing;learning extinction;neural;neural circuit;novel;prevent;psychoeducation;psychologic;reduce symptoms;self-reported anxiety;therapy outcome;trauma exposure;trauma memories;traumatic event;treadmill;treatment planning;violence exposure

public_health_relevance:
Project NarrativeThe proposed project would explore the viability of moderate intensity exercise delivered following exposuretherapy as a novel means of enhancing consolidation of therapeutic safety learning and exposure therapies.This knowledge has the potential to increase therapy outcomes for patients with PTSD and related disorders.


application_id: 11037395
project_number: 1R01DA061996-01
administering_ic: NIDA
award_notice_date: 2024-09-23
opportunity_number: RFA-DA-22-040
application_type: 1
activity_code: R01
ic: DA
serial_number: 061996
program_official: JENKINS, RICHARD A
project_start_date: 2024-09-30
project_end_date: 2029-07-31
study_section: Special Emphasis Panel[ZDA1 TXT-E (A1)]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-30
project_title:
Optimizing PrEP Care Delivery through Adaptive Intervention Strategies for Underserved Rural People who Inject Drugs

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

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

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


application_id: 11037157
project_number: 3P30ES030283-05S1
project_title: University of Louisville Center for Integrative Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2024-03-15
opportunity_number: PA-21-071
application_type: 3
activity_code: P30
ic: ES
serial_number: 030283
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The University of Louisvilles (UofL) Center for Integrative Environmental Health Science (CIEHS) bringstogether a multidisciplinary group of investigators working together to develop a framework to understand thecomplexities of and to integrate the interactions between environmental toxicants life style factors life stagegenetics and gender and their roles in human health and disease. The CIEHS is uniquely positioned to buildtransdisciplinary teams to tackle these problems by virtue of the multidisciplinary expertise of its members andits geographic location. The Louisville Regional Community composed of Metropolitan Louisville and thecounties of western Kentucky is a unique mix of urban and rural environments with industrial and agriculturalexposures that is a microcosm of the United States. The region is plagued by rates of chronic disease (e.g.cardiovascular diabetes cancer etc.) all with environmental etiologies that are among the highest in thenation. The CIEHS facilitates research and training focused on: (1) exposure to industrial chemicals present inthe urban and rural KY environments (metals VOCs PCBs vinyl chloride etc.) (2) lifestyle factors (dietalcohol socioeconomic stressors obesity etc.) and the modifications to response by life stage genetics andgender in development of chronic adult diseases. CIEHS is organized into three multi-disciplinary researchinterest groups (multi-organ toxicology cancer and neurodevelopmental toxicology). The Integrated HealthScience Facility Core promotes translation of basic science including assistance with both adult and pediatricclinical trials. The Community Engagement Core promotes multi-directional communication between CIEHSinvestigators and community groups with special focus on rural health care providers and youth groups. ThePilot Project Program provides resources supporting new environmental health investigators collaborationsbetween CIEHS members and established investigators bringing new skill sets to environmental healthproblems new avenues of environmental health research by CIEHS members and community-engaged andcommunity-led research in collaboration with CIEHS members. A Career Development Program providesmentorship and support to new junior as well as mid-level investigators. These activities are supported by twofacility cores (biostatistics and informatics and integrated toxicomics and environmental measurements). TheCIEHS provides leadership in environmental health research promotes investigation of the interactions ofchronic exposure to environmental toxicants and lifestyle factors in pathogenesis and develops the nextgeneration of environmental health researchers. Our studies utilize model systems in the laboratory the largerecosystem by investigation of pollution effects on wildlife and the human laboratory provided by the LouisvilleRegional Community in collaboration with community partners.

project_terms:
Adult;Agriculture;Alcohol consumption;Alcohols;Area;Basic Science;Biological Models;Biometry;Cardiovascular system;Chemicals;Childhood;Chronic;Chronic Disease;Clinical;Clinical Trials;Clinical Trials Unit;Collaborations;Communication;Communities;Complex;Core Facility;County;Development;Diabetes Mellitus;Diet;Disease;Disease Outcome;Ecosystem;Education;Environment;Environmental Health;Environmental Risk Factor;Etiology;Exposure to;Funding;Gender;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Industrialization;Informatics;Interdisciplinary Study;Interest Group;Intervention;Investigation;Kentucky;Knowledge;Laboratories;Leadership;Life;Life Style;Malignant Neoplasms;Measurement;Mental disorders;Mentors;Mentorship;Metals;Modification;Obesity;Organ;Pathogenesis;Persons;Pilot Projects;Play;Pollution;Polychlorinated Biphenyls;Positioning Attribute;Predisposition;Prevention strategy;Program Development;Research;Research Personnel;Resources;Role;Rural;Strategic vision;Toxic Environmental Substances;Toxicant exposure;Toxicology;Training;Translating;Translations;United States;Universities;Vinyl Chloride;Youth;addiction;built environment;career development;citizen science;community based participatory research;community based research;community collaboration;community engagement;community partners;design;health science research;improved;lifestyle factors;man;member;metropolitan;multidisciplinary;next generation;pollutant;programs;recruit;response;rural environment;rural healthcare;skills;socioeconomics;stressor;tobacco exposure;tobacco products;toxicant interaction;urban setting

public_health_relevance:
The goal of the University of Louisville Center for Integrative Environmental Health Sciences isto understand how exposure to environmental toxicants interacts with life style factors and howthese co-exposures impact human health and disease as modified by life stage and gender.This knowledge will provide better prevention and intervention strategies to improve the healthof the people in western Kentucky.


application_id: 11035846
project_number: 3P20GM125504-07S1
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2024-06-07
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 125504
suffix: S1
program_official: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1(C2)
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
AbstractThe primary objective of the Functional Microbiomics Inflammation and Pathogenicity (FMIP) CoBRE at theUniversity of Louisville (UofL) is to establish a comprehensive and interdisciplinary research center focused onexploring the intricate relationship between the microbiome inflammation and pathogenicity. Over the past sixyears we have successfully brought together a group of promising junior investigators each possessing uniqueexpertise and paired them with highly qualified and dedicated mentors. Through a collaborative effort a cohesiveset of complementary projects has been developed forging innovative connections between inflammatoryprocesses and bacterial pathogenicity. This has led to successful graduation of six junior faculty with NIH R01awards and three of these investigators are still at UofL and are transitioning into mentoring roles whileestablishing their own strong scientific programs. These achievements were supported and facilitated by theFunctional Microbiomics Core which provides essential resources such as germ-free animal facilities anaerobicculture capabilities microbiome sequencing bioinformatics support and the assay of inflammatory markers.For Phase I and II of the FMIP CoBRE we have made significant commitment to expand our microbiomics corecapabilities by developing anerobic culture germ free gnotobiotic and advanced imaging facilities. Many of ourRPLs and their mentors are now experiencing a growing need for the capability to swiftly and easily identify andquantify small molecules such as host and microbial metabolites from various sources. Here we propose tofurther expand microbiome area into metabolomics by purchasing the TSQ Quantis Triple-Stage QuadrupoleMass Spectrometer from Thermo Scientific. This mass spectrometer provides reliability and sensitivity and willbe a significant addition to our CoBRE core facility. This supplement application is requesting partial funding fromto acquire and establish the CoBRE-Metabolomics facility at the UofL that focuses on microbial and hostmetabolites. This core will support the research of large number of faculty working in the areas of microbiotainflammation and pathogenesis.

project_terms:
Achievement;Alzheimer's Disease;Area;Award;Bioinformatics;Biological Assay;Core Facility;Dedications;Faculty;Funding;Germ-Free;Gnotobiotic;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Interdisciplinary Study;Link;Malignant Neoplasms;Mentors;Pathogenesis;Pathogenicity;Periodontal Diseases;Phase;Play;Process;Qualifying;Regulation;Research Personnel;Research Support;Resources;Role;Source;United States National Institutes of Health;Universities;animal facility;experience;forging;human disease;imaging facilities;inflammatory marker;innovation;mass spectrometer;metabolomics;microbial;microbiome;microbiome research;microbiome sequencing;microbiota;programs;small molecule

public_health_relevance:
NarrativeHost and microbial metabolites play a crucial role in the regulation of inflammation and are linked to the onset ofdiverse human diseases such as periodontal disease inflammatory bowel disease cancer and Alzheimersdisease. This proposal aims to establish a CoBRE-Metabolomics facility under Functional Microbiomics Core bypurchasing TSQ Quantis Triple-Stage Quadrupole Mass Spectrometer. This facility will enable identification andquantification of both targeted- and untargeted metabolites across various pathophysiological conditions.


application_id: 11035234
project_number: 5R01ES034389-03
project_title: Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2025-03-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: ES
serial_number: 034389
program_official: NADADUR, SRIKANTH
project_start_date: 2023-05-01
project_end_date: 2028-02-29
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 12651681
contact_pi: SANSBURY, BRIAN EDWARD
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:
Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular disease. Although the mechanismsby which PM induces pervasive multi-organ injury are still under investigation evidence strongly implicateschronic inflammation as a primary driver of pathology. Whether exposure to fine PM (PM2.5) specifically impairsthe endogenous pathways that promote the resolution of inflammation is not known. Therefore the long-termgoal of this project is to determine how exposure to PM impacts the resolution of inflammation and whether thiscontributes to PM exposure-exacerbated atherosclerosis. In work in progress we discovered that in miceexposed to concentrated PM (PM2.5) for 30 days circulating erythrocytes expressed markers of premature agingand oxidative damage. In the spleens of these mice there was an expansion of the population of cells responsiblefor erythrocyte disposal red pulp macrophages while pathways related to erythrocyte turnover hememetabolism and iron cycling were upregulated. Additionally we found that several factors related tohematopoiesis were induced in the tissue. These alterations were accompanied by a marked decrease in theabundance of specialized lipid mediators that promote resolution (SPMs) and their receptors. The changes inspleen are particularly critical because the spleen plays a central role in regulating immune response dynamics.It houses an important and distinct reservoir of monocytes which can be rapidly mobilized and deployed inresponse to various insults. In addition to coordinating immune function the spleen acts as a filter to removesenescent and damaged erythrocytes. Though patients survive following splenectomy they are more likely tocontract serious and life-threatening infections and have heightened risk of developing hematologicalmalignancies and coronary artery disease among other disorders. Our preliminary studies suggest that exposureto PM2.5 may disrupt splenic homeostasis with targeted impacts on red pulp macrophages. As macrophages arethe critical facilitators of erythrophagocytosis maintenance of the splenic hematopoietic niche and SPM actionsour central hypothesis is that PM2.5 exposure increases splenic macrophage erythrophagocytosis whichsuppresses SPM production and permits local myelopoiesis thereby enhancing monocyte egress andexacerbating vascular inflammation. To test this hypothesis we will examine the effects of PM2.5 exposure onsplenic macrophages determine the impact of PM2.5 exposure on the splenic hematopoietic niche and delineatethe contribution of splenic myelopoiesis to PM2.5-exacerbated atherosclerosis. This project will elucidate theeffects of PM on the resolution of inflammation and will provide a new mechanism by which exposure to PMestablishes a state of chronic non-resolving inflammation that affects multiple organs and processes.

project_terms:
Acceleration;Address;Adoptive Transfer;Affect;Air Pollution;Apolipoprotein E;Applied Research;Arachidonate 15-Lipoxygenase;Atherosclerosis;Biological;Cardiovascular Diseases;Cells;Chronic;Complex;Contracts;Coronary Arteriosclerosis;Development;Disease;Disease Progression;Engraftment;Enzymes;Erythrocytes;Erythrophagocytosis;Event;Excision;Exposure to;FPR2 gene;Genetic Transcription;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Heme;Homeostasis;Homing;Immune response;Immunity;Impairment;Individual;Infection;Inflammation;Inflammation Process;Inflammatory;Interruption;Investigation;Iron;Knockout Mice;Lead;Leukocytes;Life;Link;Macrophage;Maintenance;Maps;Measures;Mediating;Mediator;Metabolism;Mus;Myelogenous;Myelopoiesis;Organ;Particulate;Particulate Matter;Pathology;Pathway interactions;Patients;Phase;Play;Population;Premature aging syndrome;Process;Production;Property;Resolution;Risk;Role;Signal Transduction;Site;Spleen;Splenectomy;Splenic Red Pulp;Stimulus;Systemic disease;Testing;Tissues;Upregulation;Work;cardiovascular disorder risk;cardiovascular risk factor;cell type;cytokine;exhaustion;fine particles;fundamental research;immune function;in vivo;interest;life span;lipid mediator;monocyte;multiorgan injury;oxidative damage;prevent;programs;receptor;response;senescence;single-cell RNA sequencing;spleen transplantation;uptake;vascular inflammation

public_health_relevance:
Chronic exposure to ambient particulate matter (PM) leads to systemic inflammation andcardiovascular disease. Promoting the endogenous active mechanisms of resolution mayinterrupt persistent inflammatory inputs induced by PM. Here we will assess the impacts of PMexposure on the cellular facilitators of resolution and determine whether their response to PMgoverns systemic immunity.


application_id: 11035183
project_number: 5T35ES014559-19
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2025-06-04
opportunity_number: PA-20-162
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2021-08-13
project_end_date: 2027-02-28
study_section: ZES1-VSM-S(T)
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: CAVE, MATTHEW C;CONKLIN, DANIEL JOSEPH
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:
This proposal is a competing renewal application for a T35 short term medical student summer training program in environmental health science research that has been funded by NIEHS for 15 years. The Specific Aims are: 1) To provide hands-on training in basic and clinical environmental health-based research to medical students in a structured mentored environment; 2) To provide an interactive educational experience that introduces medical students to the fundamental skills necessary for basic translational and clinical Environmental Health Sciences-based research. The Distinction in Research Track (DIR) a feature added in the previous award period enhances training for our students to function as environmental health sciences specialists in an academic health center setting. This NIEHS T35 training program encourages students to participate in the DIR for a continued longitudinal research experience in the 2nd  4th years of medical training allowing them to develop research-oriented skills to complete a clinical or translational research project in the third/fourth years. Publication of peer-reviewed articles as some trainees have achieved as well as the strength of residency training and first permanent position as physician-scientists are tracked as outcomes. The program will support training of 6 second year medical students in environmental health sciences research topics related to chemical exposure induced chronic diseases including diabetes non-alcoholic fatty liver disease obesity cancer and hormonal regulation of metabolism. UofL medical students in the top half of the first year class choose from research projects submitted by 23 mentors in the Schools of Medicine and Public Health and Information Science. Trainees to be appointed to the T35 training grant are selected after in- person meetings between trainees and mentors to assure fit. During the summer training students work with mentors on their research project in clinical or laboratory settings and complete training in the Responsible Conduct of Research (topics include: reproducibility fabrication and falsification of data plagiarism managing scientific data publication practices mentorship responsible authorship stewardship conflict of interest). Trainees working with human subjects complete human subject and IRB training prior to beginning their research. Trainees who use vertebrate animals in mentors labs complete and pass IACUC training courses. All trainees will attend a weekly Environmental Health Sciences Conference designed to introduce clinical and translational research in environmental health sciences to T35 trainees. The conference culminates with each Trainee presenting his/her research project to peers and mentors. Trainees also present the results of their research as posters with peers at a School of Medicine week-long research celebration that includes nationally recognized physician-scientists as keynote speakers. Poster contest Winners are eligible to attend the National Student Research Forum the following Spring.

project_terms:
Authorship;Award;Chemical Exposure;Chronic Disease;Clinical;Clinical Research;Conflict of Interest;Data;Diabetes Mellitus;Education;Eligibility Determination;Environment;Environmental Health;Funding;Grant;Health;Health Sciences;IACUC;Information Sciences;Institutional Review Boards;Laboratories;Malignant Neoplasms;Medical;Medical Students;Mentors;Mentorship;Metabolism;National Institute of Environmental Health Sciences;Obesity;Outcome;Peer Review;Persons;Physicians;Plagiarism;Positioning Attribute;Public Health;Publications;Reproducibility;Research;Research Project Grants;Residencies;Scientist;Specialist;Structure;Students;Training;Training Programs;Training Support;Translational Research;Vertebrates;Work;design;experience;fabrication;health science research;hormone regulation;human subject;medical schools;meetings;non-alcoholic fatty liver disease;peer;posters;programs;responsible research conduct;skills;student research;summer student;symposium

public_health_relevance:
NarrativeThis NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is to request annual supportfor 8 medical student trainees for a 10 week training experience for the next 5 years. The overarching scientifictheme of research that links our faculty to this T35 Training Grant is the common interest of the faculty inresearch training of medical students in our laboratories in elucidating the health outcomes of exposure ofnormal and obese individuals to various environmental chemicals. In addition we will use the T35 TrainingGrant to entice our medical students into our Distinction in Research Track designed to allow students topursue research interests throughout the years 2-4 of medical school curriculum with an eye toward building apipeline of diverse translational clinician-researchers in the future.


application_id: 11032914
project_number: 1K01HL177045-01
project_title: Circadian Regulation of Cardiomyocyte Size and Function
administering_ic: NHLBI
award_notice_date: 2024-12-30
opportunity_number: RFA-HL-22-011
application_type: 1
activity_code: K01
ic: HL
serial_number: 177045
program_official: WANG, WAYNE C
project_start_date: 2025-01-01
project_end_date: 2029-12-31
study_section: Special Emphasis Panel[ZHL1 CSR-A (O1)]
contact_pi_person_id: 12589366
contact_pi: BLAIR, CHEAVAR
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 SUMMARYThe overall objectives of this study are to 1) establish hiPSC-CMs as robust models for mechanistic studies ofhow intrinsic circadian regulation impacts cardiomyocyte size and function and 2) determine whether mutationsthat impact cellular size and function also disrupt cardiomyocyte clock rhythms.In the heart disruptions in circadian rhythms stemming from irregular sleep jet lag or shift work can lead toheart attacks arrhythmias and cardiac dysfunction. Prior research shows that disrupting the clock via Bmal1knockout in mouse cardiomyocytes induces age-dependent hypertrophic cardiomyopathy (HCM) with adversemyocardium remodeling marked by enlarged cardiomyocytes. These data underscore the importance ofstudying circadian regulation on cardiomyocyte size and function.Most of our current understanding of how circadian clock disruption leads to cardiac abnormalities is derivedfrom animal studies influenced by the suprachiasmatic nucleus (SCN) pacemaker. Consequently ourunderstanding is limited to how intrinsic cardiomyocyte circadian clocks function independently of the SCN. Toaddress this gap developing an in vitro cell model will be crucial. Such a model would enable circadian regulationof cardiomyocyte size and function to be studied separately from SCN influence providing valuable insights intohow the intrinsic clock autonomously governs cellular processes. Understanding these mechanisms is essentialfor unraveling the intricate relationship between circadian rhythms and cardiac health at the cellular level.Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as invaluable diseaseand drug screening models. These cells also offer a unique opportunity to investigate the circadian regulation ofcardiomyocyte size and function in a controlled in vitro environment independent of SCN influence. Due to theirinherent immaturity interventions targeting clock function in these cells at an early stage can elucidate themechanisms by which circadian rhythms influence changes in cell size and function. Moreover hiPSC-CMsserve as established models for inherited genetic mutations offering a distinctive chance to explore how inheritedgenetic disorders such as hypertrophic cardiomyopathy which results in enlarged cardiomyocytes andhypercontractile function disturb circadian rhythms.The results of these aims will 1) establish hiPSC-CM as a model to obtain critical new information on how theintrinsic cardiomyocyte clock impacts cell size and function and 2) inform us of the potential of targeting the clockto treat genetic cardiomyopathy. The training provided in this K01 will enable the candidate to become an expertin circadian regulation of cardiomyocyte size and function and establish an independent research career.

project_terms:
ARNTL gene;ATAC-seq;Acceleration;Address;Adult;Affect;Animals;Arrhythmia;Behavior;Biological Clocks;Cardiac Myocytes;Cardiac health;Cell Differentiation process;Cell Physiology;Cell Size;Cell model;Cells;ChIP-seq;Circadian Dysregulation;Circadian Rhythms;Communication;Data;Development;Disease;Drug Screening;Environment;Forskolin;Functional disorder;Genes;Genetic;Growth;Heart;Heart Abnormalities;Heart Hypertrophy;Hereditary Disease;Hypertrophic Cardiomyopathy;Hypertrophy;In Vitro;Inherited;Intervention;Jet Lag Syndrome;Knock-out;Knowledge;Mentors;Modeling;Mus;Mutation;Myocardial Infarction;Myocardial dysfunction;Myocardium;Organ;Pacemakers;Peripheral;Physiological;Physiology;Proteins;Regulation;Research;Sarcomeres;Sleep disturbances;Stimulus;Techniques;Temperature;Time;Traction Force Microscopy;Training;Work;age related;beta-Myosin;career;cell growth;cell type;circadian pacemaker;circadian regulation;embryonic stem cell;human induced pluripotent stem cells;induced pluripotent stem cell derived cardiomyocytes;inherited cardiomyopathy;insight;overexpression;shift work;stem;stem cells;suprachiasmatic nucleus;therapy development;transcriptome sequencing;transcriptomics

public_health_relevance:
Project NarrativeThe results of this study will establish human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CM)as a model to obtain critical new information on how the intrinsic cardiomyocyte clock impacts cell size andfunction. These data will also inform our knowledge of whether inherited genetic mutations that lead tohypertrophic cardiomyopathy resulting in increased cardiomyocyte size and contractile dysfunction can disruptcircadian rhythms. The impact of this study is that it will provide a mechanistic understanding of the interplaybetween the circadian clock and its regulation of cardiomyocyte size and function while also answering thequestion of whether the circadian clock in the heart is altered during hypertrophic states.


application_id: 11032054
project_number: 7K01MD015304-05
project_title: Geographic and Racial Disparities in Mammography Screening and Barriers to Receiving Care
administering_ic: NIMHD
award_notice_date: 2024-08-02
opportunity_number: PA-19-126
application_type: 7
activity_code: K01
ic: MD
serial_number: 015304
program_official: STINSON, NATHANIEL
project_start_date: 2020-08-10
project_end_date: 2026-07-31
study_section: ZMD1-DRI(M1)
contact_pi_person_id: 14376529
contact_pi: MOORE, JUSTIN XAVIER
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis K01 proposal entitled Geographic and Racial Disparities in Mammography Screening and Barriers toReceiving Care describes the career development and research plan that will be instrumental in thedevelopment of Dr. Justin Xavier Moores transition into an independent investigator in the field of breastcancer disparity and community-based participatory research. Dr. Moore has a background in epidemiologyand cancer prevention and control that includes training in quantitative methods research design geospatialanalysis and social epidemiology. However this grant will provide Dr. Moore with additional needed training inBayesian methodology and inference qualitative and mixed-methods health communication participantrecruitment and community-participatory research through a combination of courses independent studies withhands on focus and mentoring. Dr. Moores interdisciplinary mentors include researchers with achievements inbreast cancer disparities research cancer health communication through community-based participatoryresearch qualitative and mixed methods approaches as indicated through their multiply funded NIH awards.Further their expertise will provide the necessary support for the career development and research activities ofthe study proposed in this application by Dr. Moore.The proposed research will provide valuable insight to the field of breast cancer disparities and address keypublic health questions of relevance to racial and geographic disparities in breast cancer using innovativeanalytical methods. It will combine Dr. Moores expertise in spatial and cancer epidemiology with the mentorsexpertise in large intervention studies on breast cancer health communication and community-basedparticipatory research and mixed-methods analysis to understand the individual interpersonal communityfacilitators of mammography screening among minority (Hispanic and Black) women living in the highest riskcommunities of the United States. The research includes specific aims that be will achieved usinginterdisciplinary research methods including Bayesian methodology for small-area estimates of mammographyscreening semi-structured interviews and survey research among those recruited within the pilot study. Theaims include: (1) identifying areas of low mammography screening among Black and Hispanic women usingnovel small-area estimation; 2) quantifying a novel index of high-risk counties for breast cancer among Blacksand Hispanics and 3) performing a pilot study among Black and Hispanic women stratified among the novelindex to understand the personal interpersonal and community barriers on intentions to receivingmammography screening. Through the proposed research the investigator will understand culturally specificbarriers and develop a strong rapport within high-risk communities using a community-based approach that willprovide a foundation to develop a larger longitudinal study with sustainable interventions.

project_terms:
Achievement;Address;Affect;Area;Award;Bayesian Analysis;Bayesian Method;Behavioral Risk Factor Surveillance System;Black Populations;Black race;Breast;Breast Cancer Early Detection;Breast Cancer Risk Factor;Cancer Control;Caring;Communities;County;Data;Development;Diagnosis;Disparity;Epidemiology;Ethnic Origin;Foundations;Funding;Goals;Grant;Hispanic;Hispanic Populations;Hispanic Women;Hot Spot;Individual;Interdisciplinary Study;Intervention;Intervention Studies;Interview;Longitudinal Studies;Malignant Breast Neoplasm;Malignant Neoplasms;Mammographic screening;Mammography;Maps;Mentors;Methodology;Methods;Minority;Minority Women;National Health Interview Survey;Outcome;Patient Recruitments;Pattern;Pilot Projects;Population;Prevalence;Public Health;Publications;Publishing;Race;Racial Segregation;Reporting;Research;Research Activity;Research Design;Research Methodology;Research Personnel;Resources;Risk;Sampling;Socioeconomic Factors;Structure;Surveys;Training;United States;United States National Institutes of Health;White Women;Woman;Work;advanced breast cancer;analytical method;black women;cancer epidemiology;cancer health disparity;cancer prevention;career development;community barrier;community based participatory research;ethnic minority;experience;follow-up;geographic difference;geographic disparity;health communication;high risk;indexing;innovation;insight;mortality;mortality risk;multidisciplinary;novel;racial difference;racial disparity;racial minority;recruit;research and development;screening;social epidemiology;social health determinants;spatial epidemiology;uptake

public_health_relevance:
PROJECT NARRATIVERacial/ethnic minorities are disproportionately affected by breast cancer outcomes as Black and Hispanicwomen are 20% more likely than White women to be diagnosed with advanced stage breast cancer; and haveup to 70% and 14% increased risk of death respectively. This K01 project aims to identify areas of lowmammography screening and to elucidate the racial/ethnic specific barriers on the uptake of adequatemammography screening for Black and Hispanic women within the defined high-risk areas. The long-term goalof this research trajectory is to contribute to the reduction of racial and geographic disparities in breast canceroutcomes.


application_id: 11031970
project_number: 5R24OD010435-23
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2025-02-14
opportunity_number: RFA-OD-19-027
application_type: 5
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2027-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-G(55)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: SMITH, JERAMIAH JAMES
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This application proposes to develop fundamental genomic and bioinformatic resources that will better enablestudies of the axolotl (Ambystoma mexicanum). The axolotl provides the best model for identifying mechanismsof regeneration that can translate to humans. This is because it can regenerate multiple damaged body partsincluding whole limbs spinal cord and brain and because it shares tetrapod biology with human. Understandinghow axolotls regenerate complex tissues may reveal mechanisms to activate stem cells within human tissues toorganize and reform damaged tissues. Beyond regeneration the axolotl presents many untapped diseasemodels that were identified and rigorously examined with traditional developmental approaches before thegenetics/genomics era. With our recent development of the first chromosome-scale assembly of the axolotlgenome these and new models that will be created in coming years through genome editing can be advancedfor the first time to significantly impact biomedical research. However to advance these models improvementsof the genome assembly are needed along with new datasets to enable genome-wide studies of the large axolotlgenome. To accomplish these objectives we propose three specific aims. In Aim 1 we will resolve inter- andintra-specific variation within the current assembly and resolve complex repetitive regions that have hamperedthe placement of ~6 Gb of the 32 Gb genome. Specifically we will employ a powerful trio binning strategy thattakes advantage of long read sequencing of DNA from axolotl x tiger salamander (A. tigrinum) hybrids. Thisapproach leverages decades of experience in generating interspecific hybrids to resolve assembly gaps/errorsand accurately place gene models within their non-coding regulatory environments. Additionally we will analyzesequence data from 10 AGSC axolotls from branches of the pedigree that optimally sample laboratory geneticdiversity. In Aim 2 we will perform Chip-Seq to identify changes in histone post-translational modifications duringtail and limb regeneration. Characterization of epigenetic marks for embryo larval and adult models ofregeneration will provide new resources for regeneration research and advance community efforts in performinggenome wide studies. Aim 3 will address significant community needs user-friendly access to large scalegenomic datasets and improvement of genomic and bioinformatic capabilities of investigators in the axolotlcommunity. Accomplishment of these aims will significantly advance axolotl as an animal model for biomedicalresearch.

project_terms:
Achievement;Adult;Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Area;Base Sequence;Bioinformatics;Biology;Biomedical Research;Body part;Brain;ChIP-seq;Chromatin;Chromosomes;Communities;Complex;DNA Binding;DNA sequencing;Data;Data Set;Development;Embryo;Enhancers;Ensure;Environment;Epigenetic Process;Funding;Gene Expression;Generations;Genes;Genetic;Genetic Transcription;Genetic Variation;Genome;Genomics;Growth;Haploidy;Histones;Human;Hybrids;Laboratories;Limb structure;Methods;Modeling;Molecular;Natural regeneration;Phase;Positioning Attribute;Post-Translational Protein Processing;Protocols documentation;Publishing;Reagent;Recommendation;Regenerative research;Repetitive Sequence;Research;Research Personnel;Resources;Salamander;Sampling;Site;Spinal Cord;System;Tail;Tetrapoda;Tigers;Time;Tissues;Translating;Untranslated RNA;Variant;bioinformatics resource;cell type;data dissemination;data integration;data sharing networks;design;disease model;empowerment;experience;genetic pedigree;genome browser;genome editing;genome resource;genome-wide analysis;genomic data;histone-binding proteins;human tissue;improved;innovation;knowledgebase;limb regeneration;long-read sequencing;promoter;regeneration model;stem cells;tissue regeneration;user-friendly;web portal

public_health_relevance:
The project will develop critical resources to enhance research efforts using the laboratory axolotl(Ambystoma mexicanum). Improvements to the axolotl genome assembly will be made epigenetic datawill be generated for limb and tail regeneration and all data from the project will be made publiclyavailable. Studies using the axolotl may reveal strategies to achieve endogenous tissue regeneration inhumans.


application_id: 11031926
project_number: 5R01AI155545-04
project_title: Anti-inflammatory functions for non-transcriptional IRF3
administering_ic: NIAID
award_notice_date: 2025-01-03
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 155545
program_official: VAZQUEZ-MALDONADO, NANCY
project_start_date: 2021-02-08
project_end_date: 2027-01-31
study_section: Special Emphasis Panel[ZRG1-IMM-T(02)M]
contact_pi_person_id: 10321717
contact_pi: CHATTOPADHYAY, SAURABH
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe innate immune response is the first line of defense against microbial infection. Virus infection causes rapidinduction of interferon (IFN) and IFN-induced genes which are critical for antiviral defense. IFN regulatoryfactor 3 (IRF3) expressed ubiquitously is the key transcription factor for the induction of IFN and the antiviralgenes. Therefore IRF3 deficiency leads to susceptibility to a wide range of virus infections. We havediscovered that IRF3 in addition to its transcriptional activity has a non-transcriptional (nt) function to kill thevirus-infected cells by a pro-apoptotic pathway RIPA. Knock-in mice expressing nt-Irf3 mutant can mountantiviral protection in the absence of antiviral genes. Recently we demonstrated that nt-Irf3 functionscontribute to alcoholic and non-alcoholic liver diseases further strengthening the physiological significance ofnt-Irf3. In the current proposal we present a new function for nt-Irf3 to inhibit the NF-B activity and theinflammatory gene induction. We termed this anti-inflammatory activity of IRF3 as Repression of IRF3-mediated NF-B Activity RIKA. Our strong preliminary results demonstrate that: (a) IRF3-/- cells in responseto viral or non-viral stimulation express elevated levels of NF-B-induced inflammatory genes compared to theWt cells (b) IRF3 interacts with the NF-B subunit to inhibit its transcriptional activity and (c) the Irf3-/- micethat are susceptible to respiratory virus infection exhibit higher levels of NF-B-induced genes in the lungs.These results led to our central hypothesis that nt-IRF3 activated by either RIPA or transcription-independentpathway binds to p65 inhibiting the NF-B-induced genes and suppressing inflammatory pathogenesis. Toaddress this using cellular and conditional knockout mouse models and respiratory virus pathogenesis weformulate two specific aims: (SA1) Investigate the molecular mechanisms by which IRF3 functions in RIKAand (SA2) Evaluate the contribution of RIKA to prevent inflammatory responses and viral pathogenesis.Successful completion of these aims will delineate a new anti-inflammatory function of Irf3 that contributes toits antiviral functions. Our research is innovative because it uses the novel in vitro and in vivo models to studythe molecular mechanism of RIKA and its cell type-specific contribution to protect against inflammatorypathogenesis. Our results will be significant as delineating a new anti-inflammatory function for IRF3 thatcontributes to its antiviral innate immune responses will advance the field with a new functional branch of IRF3that has implications in preventing inflammatory pathogenesis beyond viral infection.

project_terms:
Address;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-viral Response;Apoptosis;Apoptotic;Binding;Biochemical;Cells;Cytosol;Dimerization;Engineering;Epithelial Cells;Exhibits;Gene Expression;Genes;Genetic Transcription;Goals;Human;IRF3 gene;Immune response;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Influenza;Innate Immune Response;Interferons;Knock-in Mouse;Knockout Mice;Knowledge;Location;LoxP-flanked allele;Lung;Macrophage;Maps;Measures;Mediating;Microscopic;Modeling;Molecular;Mus;Natural Immunity;Nuclear Translocation;Pathogenesis;Pathway interactions;Phosphorylation;Physiological;Predisposition;Property;Proteins;Repression;Research;Research Personnel;Role;Sendai virus;Stimulus;TNF gene;TNFRSF5 gene;Testing;Therapeutic;Ubiquitination;Viral;Viral Genes;Viral Pathogenesis;Viral Physiology;Virus;Virus Diseases;airway epithelium;cell type;conditional knockout;design;disease model;domain mapping;fatty liver disease;gene induction;genetic approach;immunoregulation;in vivo;in vivo Model;innovation;microbial;mouse model;mutant;non-alcoholic fatty liver disease;novel;p65;prevent;problem drinker;respiratory infection virus;respiratory virus;response;three dimensional structure;transcription factor

public_health_relevance:
Project NarrativeViral infection often leads to unregulated inflammatory responses which contribute to the viral pathogenesis.The proposal will reveal novel anti-inflammatory functions for the host transcription factor IRF3 in modulatingimmune responses to inflammatory stimulus e.g. respiratory virus infection. The results will lead to deeperunderstanding of how viral as well as non-viral inflammation is controlled with potential therapeuticsignificance.


application_id: 11030847
project_number: 5R01NS112693-05
project_title: Mitochondrial Uncoupling Prodrug as a Translational Therapy for TBI
administering_ic: NINDS
award_notice_date: 2025-09-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 112693
program_official: AWWAD, HIBAH OMAR
project_start_date: 2020-03-15
project_end_date: 2026-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: KILBAUGH, TODD JUSTEN
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:
Traumatic brain injury (TBI) results in cognitive impairment which can be long-lasting after moderate to severeTBI. Currently there are no FDA-approved therapeutics to treat the devastating consequences of TBI andimprove recovery. A wealth of experimental evidence shows that mitochondrial dysfunction is poised to be apivotal link in the neuropathology of brain injury. We previously have targeted bioenergetic impairment withmitochondria-directed therapeutics including mild mitochondrial uncouplers which have shown to beneuroprotective. These uncouplers facilitate the movement of protons from the mitochondrial inner-membranespace into the mitochondrial matrix thereby reducing the mitochondrial membrane potential (). Whilecomplete uncoupling of mitochondria would be detrimental we have published data showing that transient ormild uncoupling confers neuroprotection in preclinical models of TBI. Recently we demonstrated that a prodrugof 24-dinitrophenol (DNP) MP201 a mitochondrial uncoupler with better pharmacodynamic properties includinghigher tolerability and extended elimination time rescues acute mitochondrial bioenergetics reduces oxidativedamage increases brain-derived neurotropic factor (BDNF) and is neuroprotective. We hypothesize that theoptimal dosage and timing of therapeutic intervention of MP201 is neuroprotective across species following focalcontusion brain injury. Our proposed studies will explore how MP201 administration can improve acutelongitudinal and chronic outcomes paired with critical biomarkers including platelet physiology andneurochemical profiles. To achieve this we will use innovative techniques across multiple institutions to assesssynaptic and non-synaptic mitochondria in both porcine and murine models of TBI. Additionally we will extendour findings to examine therapeutic efficacy measuring longitudinal cortical morphology (T2/DTI scanning)neurometabolite profiles (MRS scanning) platelet signature (as a novel biomarker and biosensor) and cognitivebehavior. Finally we will explore the underlying mechanism behind the long-term neuroprotection imparted byMP201 after TBI examining BDNF levels and mitochondrial restoration. With strong preliminary data and utilizingmany innovative and clinically-relevant techniques we anticipate this proposal will generate ground-breakingdata. Overall this proposal will highlight highly translatable therapy by MP201 to alleviate negative outcomes ofTBI.

project_terms:
24-Dinitrophenol;Acute;Address;Adult;Aging;Anxiety;Axon;Behavior;Bioenergetics;Biological Assay;Biological Markers;Biosensor;Blinded;Blood Platelets;Brain;Brain Contusions;Brain Injuries;Chronic;Clinical Pharmacology;Clinical Treatment;Cognition;Cognitive;Cognitive deficits;Contusions;Data;Dinitrophenols;Dose;Drug Kinetics;FDA approved;Family suidae;Female;Goals;Health Care;Homeostasis;Huntington Disease;Impaired cognition;Impairment;Individual;Injury;Inner mitochondrial membrane;Institution;Intervention;Link;Measures;Mediating;Membrane Potentials;Mitochondria;Mitochondrial Matrix;Morphology;Motor Activity;Movement;Mus;Neurons;Outcome;Oxidative Stress;Pediatric Hospitals;Pharmacodynamics;Pharmacology;Pharmacotherapy;Philadelphia;Physiology;Pre-Clinical Model;Prodrugs;Production;Property;Protons;Publishing;Randomized;Reactive Oxygen Species;Recovery;Rodent;Scanning;Stroke;Synapses;TBI treatment;Techniques;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Tissues;Translating;Translational trial;Translations;Traumatic Brain Injury;Traumatic Brain Injury recovery;Treatment Efficacy;United States;Women's cohort;Work;behavior measurement;behavioral outcome;biosignature;clinically relevant;cognitive testing;design;dosage;efficacy evaluation;experimental study;improved;in vivo;innovation;male;mitochondrial dysfunction;mitochondrial membrane;mouse model;neurochemistry;neuroimaging;neurological recovery;neuropathology;neuroprotection;neurotropic;novel;novel marker;novel strategies;oxidative damage;pharmacologic;porcine model;pre-clinical;preclinical efficacy;primary endpoint;repaired;residence;response;restoration;severe injury;sex;spinal cord and brain injury;therapeutic evaluation;translational therapeutics

public_health_relevance:
Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacologicaltreatments currently approved for clinical intervention; improved TBI treatment options are urgently needed. Toaddress this problem we are proposing to use a novel 24-dinitrophenol prodrug MP201 across multiple TBIplatforms and at different institutions to define its dose-response and therapeutic window of intervention. Thisproposal is designed to lay the groundwork for translation of MP201 to ameliorate recovery after TBI.


application_id: 11030769
project_number: 5R01AG084670-02
administering_ic: NIA
award_notice_date: 2025-03-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 084670
program_official: LI, TONG
project_start_date: 2024-02-15
project_end_date: 2029-01-31
study_section: Special Emphasis Panel[ZRG1-AN-Q(55)]
contact_pi_person_id: 12103073
contact_pi: SELENICA, MAJ-LINDA B
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-02-01
project_title:
Emerging role of PAD4 mediated TDP-43 citrullination in the neuropathology of LATE and Alzheimers Disease Related Dementias

project_abstract:
ABSTRACTTAR DNA-binding protein 43 (TDP-43) pathology is associated with a spectrum of clinicaldementias. Despite the enormous risk that TDP-43 proteinopathies present to public health thereis a lack of strategies against TDP-43 pathology. Our laboratory has discovered that peptidylarginine deiminase 4 (PAD4) induces the conversion of arginine (positive) to citrulline (neutral) anovel and irreversible posttranslational modification of TDP-43. We identified elevated PAD4expression and TDP-43 citrullination (citR) at the outset of Limbic-Predominant Age-related TDP-43 Encephalopathy (LATE) and in AD Related Dementias (ADRDs). We cross-validated ourfindings in a novel TDP-43 mouse model and will utilize it to investigate the mechanistic impactof PAD4 on TDP-43 phenotype. To date we know very little about the role of PAD4 in theprogression of LATE and ADRD. Notably as citR TDP-43 remains elusive our studies suggestdomain-specific effects of citR moieties on TDP-43 nuclear import cytoplasmic accumulation andphase-separation dynamics. We will address the significant gap and define mechanisms ofCa2+-coordinated PAD4 activity on TDP-43 toxic gain-of-function in the human brain mousemodels and neuronal cells. We state that PAD4-mediated TDP-43 citrullination impairs TDP-43 nucleocytoplasmic shuttling and accelerates cytoplasmic accumulation ultimatelyleading to neuropathology and cognitive decline in LATE. In Aim 1 we will establish howgenetic PADi4 (gene) gain- and loss-of-function regulates TDP-43 nuclear import and cytoplasmicaccumulation and determine PAD4-restricted TDP-43 epitopes in primary neurons. We will alsoassess how neuronal PADi4 expression or deletion promotes TDP-43 phenotype synapticdysfunction and neurobehavioral deficits in a mouse model. Aim 2 will investigate the directeffects of NLS and LCD-directed pseudo-citR mimetics on TDP-43 nuclear import accumulationand solubility in primary neurons. We will also determine how these citR moieties regulate TDP-43 liquid-solid separation kinetics. Lastly we will determine the functional role of pseudo-citRmimetics on the TDP-43 phenotype in vivo. Aim 3 will determine if PAD4 activity and citR TDP-43 epitope restriction signatures follow regional vulnerability of the human brain in LATE andADRD. The proposed studies will elucidate how PAD4 activity and this novel PTM definefunctional consequences that lead to the neuropathogenesis of TDP-43 proteinopathies.

project_terms:
Acceleration;Affect;Alzheimer's disease related dementia;Animal Model;Antibodies;Arginine;Arginine deiminase;Biochemical;Biological Markers;Biology;Brain;Brain region;Cells;Chronic;Citrulline;Clinical;Cognitive deficits;Custom;Cytoplasm;DNA-Binding Proteins;Data;Dementia;Epitopes;Fostering;Functional disorder;Genes;Genetic;Human;Impaired cognition;Impairment;In Vitro;Kinetics;Laboratories;Liquid substance;Mass Spectrum Analysis;Mediating;Neurons;Neuropathogenesis;Nuclear Import;Outcome;Pathologic;Pathology;Phase;Phase Transition;Phenotype;Phosphorylation;Post-Translational Protein Processing;Proteins;Public Health;Recombinants;Risk;Role;Solid;Solubility;Spectrum Analysis;Synapses;TDP-43 aggregation;TDP43 proteinopathy;Testing;Work;aging population;comorbidity;digital;gain of function;human tissue;in vivo;indexing;limbic-predominant age-related TDP-43 encephalopathy;loss of function;mimetics;mouse model;neurobehavioral;neuropathology;novel;nucleocytoplasmic transport;protein TDP-43;protein aggregation;protein function;response

public_health_relevance:
NARRATIVEWe discovered a new posttranslational modification of TDP-43 citrullination (citR) and confirmed itsaccumulation in Limbic-Predominant Age-related TDP-43 Encephalopathy (LATE) human brain and TDP-43animal models. We state that the "coordinated activation state of peptidyl arginine deiminase 4 (PAD4) inducescitrullination of TDP-43 impairs protein function promotes cytoplasmic accumulation and aberrant proteinphase-separation dynamics. This application will unravel mechanisms of PAD4-mediated citrullination implicatedin TDP-43 pathogenesis that characterize LATE and ADRDs.


application_id: 11030721
project_number: 5R01AA028246-05
administering_ic: NIAAA
award_notice_date: 2025-03-19
opportunity_number: PA-18-390
application_type: 5
activity_code: R01
ic: AA
serial_number: 028246
program_official: FREEMAN, ROBERT
project_start_date: 2021-03-15
project_end_date: 2027-01-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14470701
contact_pi: RAY, ANNE ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-02-01
project_title:
Cross-Tailoring Integrative Alcohol and Risky Sex Feedback for College Students: A Hybrid Type 1 Effectiveness-Implementation Trial

project_abstract:
PROJECT SUMMARY/ABSTRACTAlcohol misuse and related risky sexual behavior (RSB) are significant public health concerns among collegestudents. Two-thirds of students are current drinkers at least 1 in 3 report past month binge drinking (5+ drinksin a row) and 1 in 10 report high intensity drinking (10+ drinks in a row). Greater student alcohol consumptionand heavy drinking on a given day is linked to increased sexual activity and RSB (e.g. unprotected sexunplanned hook-ups). This puts students at risk for negative health outcomes (e.g. STIs) and is a pathway tosexual victimization and escalated drinking. The first few weeks of college or the red zone present a criticalwindow of opportunity to intervene for escalated alcohol use and associated risks which can result in a potentiallyhigh public health and clinical impact. However individual-level prevention strategies for college students tendto focus on students alcohol use patterns and consequences more broadly with little to no integration of contenton the relationship between alcohol use and RSB an important gap in the literature and a priority area for NIAAA.Our team previously established the short-term efficacy of a personalized feedback intervention (PFI) a goldstandard intervention approach with integrated content on alcohol and RSB. We propose to extend ourintegrated PFI to include a cross-tailored dynamic feedback (CDF) component which leverages technology toincorporate daily assessments of student behavior and provide users with dynamic weekly feedback over 12weeks to amplify the effectiveness of the integrated PFI and to be easily implemented on college campuses. Theproject utilizes a multisite hybrid type 1 effectiveness-implementation study design to (1) evaluate the impact ofCDF for at-risk first-year college students and (2) identify implementation factors critical to its success to facilitatefuture scale-up in campus settings. The first aim is to conduct a multi-level stakeholder-engaged adaptation ofthe integrated alcohol and risky sex PFI through the development and inclusion of CDF. The second aim is toconduct a randomized controlled trial (RCT) of the enhanced intervention (PFI+CDF) in a sample of 600 first-year college students who report recent binge drinking and are sexually active. Our primary hypothesis is thatparticipants who receive the PFI+CDF intervention will report less alcohol use fewer risky sexual behaviors andfewer consequences relative to those who receive a PFI supplemented with generic health information at follow-up (1 2 3 6 and 13 months). Our third aim seeks to identify factors critical to PFI+CDF implementation incampus settings through conducting focus groups with a subset of students from the RCT and with local andnational systems-level stakeholders. The intervention has strong potential for widespread dissemination andtargets a group at high risk for alcohol misuse and RSB.

project_terms:
Alcohol consumption;Alcohols;Area;Behavior;Behavior Therapy;Behavioral;Clinical;Data;Data Collection;Development;Effectiveness;Ensure;Event;Feedback;Focus Groups;Future;Health;Heavy Drinking;Hybrids;Individual;Intervention;Link;Literature;Mind;Monitor;Motivation;National Institute on Alcohol Abuse and Alcoholism;Nature;Outcome;Participant;Pathway interactions;Pattern;Persons;Prevention strategy;Process;Public Health;Randomized Controlled Trials;Reporting;Research;Research Design;Risk;Sampling;Self Efficacy;Sex Behavior;Site;Students;System;Target Populations;Technology;Testing;Time;Universities;Unsafe Sex;Work;alcohol misuse;alcohol prevention;behavior change;binge drinking;college;commercialization;design;diaries;drinking;eHealth;effectiveness evaluation;effectiveness/implementation design;effectiveness/implementation study;effectiveness/implementation trial;evidence base;experience;flexibility;follow-up;formative assessment;group intervention;high intensity drinking;high risk;high risk sexual behavior;implementation determinants;implementation intervention;improved;innovation;intervention effect;online delivery;post implementation;programs;response;scale up;sex;sexual victimization;sexually active;success;university student;usability;web-based assessment

public_health_relevance:
PROJECT NARRATIVEAlcohol misuse and related risky sexual behavior are significant public health concerns among college students.This project involves (1) adapting and evaluating a technology-delivered behavioral intervention that is designedto reduce alcohol misuse and related risky sexual behavior among first-year college students while also (2)examining factors important to intervention implementation in college settings. If effective the intervention maybe widely disseminated and has the potential to make a positive impact on college student health.


application_id: 11030698
project_number: 5U01CE003394-04
administering_ic: NCIPC
award_notice_date: 2024-06-28
opportunity_number: RFA-CE-21-006
application_type: 5
activity_code: U01
ic: CE
serial_number: 003394
project_start_date: 2021-09-30
project_end_date: 2025-09-29
study_section: ZCE1-MLW(06)R
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-30
budget_end_date: 2025-09-29
project_title:
CE-21-006: RCT to evaluate Bystander-informed See it Stop it (BiSiSi) to Prevent Child Sex Trafficking in Kentucky Middle Schools

project_abstract:
The strongest risk factor for child sexual exploitation and trafficking (CSE/T) is a dysfunctional familyenvironment characterized by violence and parental substance use. In Kentucky familial sex trafficking is themore common form of CSE/T. Kentucky leads the nation with the highest rates of sexual violence (SV) andpartner violence and we rank 4th in opioid overdose deaths. Based on Kentuckys need we propose aclustered randomized controlled trial (RCT) in response to Priority area 4 preventing CSE/T using abystander-informed intervention among middle school staff as interventionists. As highlighted by CDCs STOP-SV bystander programming shows promise to reduce SV. Our research team conducted a 5-year high school-based RCT that identified Green Dot as an effective bystander program to reduce multiple forms of SVincluding two forms sexual coercion and substance use facilitated sex strongly correlated with CSE/T risk.Given the effectiveness of Green Dot in high schools we propose a rigorous evaluation of a novel Bystander-informed See it Stop it (BiSiSi) program designed to be electronically delivered to middle school staff with thegoal of reducing CSE/T risk in children. Our multi-disciplinary research team has the opportunity to leverageongoing county-level activities addressing substance use and child sexual abuse prevention. 32 Kentuckycounties will be randomized to BiSiSi intervention or attention control conditions; the randomized condition willbe applied to recruited middle schools within counties. Given the strong links between opioid use and CSE/Trisk county selection will reflect those with higher opioid overdose rates (included in HEALing CommunitiesRCT). This recruitment strategy allows an investigation of two potentially complimentary interventions toaddress two highly correlated public health problems: CSE/T and opioid use. Specific Aim 1: To evaluate theeffectiveness of BiSiSi training to change middle school staff 1a) knowledge of CSE/T 1b) attitudes towardsCSE/T (stigma) 1c) willingness and efficacy to intervene 1d) use of bystander actions to thwart CSE/T riskand 1e) use commercial sexual exploitation identification tool (CSE-IT) screening referral and reporting. Aim2: To evaluate the effectiveness of BiSiSi training to increase CSE/T screening and reporting in the short term(from Years 0-2) and begin to reduce CSE/T rates in the longer term (Year 3) by condition with BiSiSiimplementation at the school & county level adjusting for school and county climate. This RCT will beappropriately powered (80% with ~40 staff in each of 64 middle schools in 32 counties with high and loweropioid overdose rates). General estimating equation (GEE) and structural equation modeling will be used toprospectively evaluate how BiSiSi training affects middle school staffs CSE/T knowledge attitudes efficacyand intervention actions to reduce CSAET (Aim 1). Linear mixed models and GEE will be used to evaluate theeffectiveness of BiSiSi to change CSE/T screening and reports measured at the county level. Anticipatedresults: Identification of complementary prevention strategies to reduce child sexual exploitation and trafficking.

public_health_relevance:
Given the promise of bystander programs to reduce youth sexual violence we have used bystander theory toadapt an evidence-based program directed toward the prevention of commercial sexual exploitation andtrafficking (CSE/T) of children (Priority Area 4). A statewide middle-school based randomized controlled trialwill be conducted in 32 Kentucky counties over 4 years with the primary goal of evaluating the effectivenessof our novel Bystander-informed See it Stop it (BiSiSi) program as implemented among middle school staffas interventionists to increase screening and identification of CSE/T in intervention versus attention controlschools in the short term years 0-2) and prevent CSAET in the longer term (year 3)


application_id: 11030486
project_number: 1R61DA061831-01
administering_ic: NIDA
award_notice_date: 2024-09-23
opportunity_number: RFA-DA-24-036
application_type: 1
activity_code: R61
ic: DA
serial_number: 061831
program_official: LEE-WINN, ANGELA EUNJI
project_start_date: 2024-09-30
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZDA1 MXS-E (A1)]
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-30
project_title:
Engaging People Who Use Drugs in Harm Reduction Service Delivery: An Intravention to Reduce Risk of HIV HCV Overdose and Injection-related Infections in Rural Appalachia

project_abstract:
The proposed project will test an innovative peer-driven approach to address unmet harm reduction needs intwo rural Kentucky counties at the epicenter of the opioid/stimulant epidemic with the aim of reducing risk foroverdose (OD) hepatitis C (HCV) skin and soft tissue infections (SSTIs) and HIV. Research has shown thatthese counties and the encompassing rural Appalachian region have high rates of drug-related harms includingODs HCV opioid use disorder methamphetamine use and SSTIs and are at high risk for an HIV outbreakamong people who inject drugs (PWID). In 2020 Kentucky was one of just seven states named in the Endingthe HIV Epidemic initiative based on the percentage of new HIV diagnoses occurring in rural areas. In an effortto reduce drug-related harms Kentucky has opened brick-and-mortar syringe service programs (SSPs) in 65of its 120 counties including those involved in this proposal. Unfortunately this infrastructure remains vastlyunder-utilized. Our ongoing research has shown that only 50% of PWID are using the SSP primarily due tofear of being seen by someone they know concerns around law enforcement or child protective services andanticipated judgment by staff barriers similar to those reported elsewhere in the region. State data haverevealed challenges with client retention particularly in rural communities and substantial recent declines inthe number of SSP clients and visits. Together these data highlight an urgent need to address barriers to SSPservice utilization in rural Appalachia and expand service reach to the growing number of rural PWID withunmet harm reduction needs. To best overcome barriers related to privacy and fear of stigma and judgmentmodels must meet PWID where they are by engaging those whom they trust. For decades scientists havecalled for the expansion of intravention wherein members of communities at risk are engaged inimplementing the interventions intended to improve their communitys health. Engaging PWID who are trustedmembers of the community honors harm reduction principles and is critical to intravention success as they areviewed as more credible are likely to engage those most marginalized and can intervene when and whererisks are highest. Research has established that intraventions are effective yet they have been far under-utilized in rural communities. In response we will partner with local PWID and agency partners to co-developand tailor a peer-driven evidence-based intravention that engages PWID as interventionists to reachindividuals with unmet harm reduction needs in rural Appalachia. The adapted intravention hereafter referredto as ASSIST will address interventionists knowledge gaps related to OD HCV SSTIs and HIV risk reductionand equip them with harm reduction supplies for use and distribution. We will evaluate ASSISTs impact onsubstance use related harms and implementation outcomes using a Type 1 hybrid effectiveness study cost-effectiveness analysis and mathematical modeling. The study will advance harm reduction science and providemuch needed data to inform scale up to rural communities in Appalachia and beyond.

project_terms:
Address;Appalachian Region;Client;Collaborations;Communities;Community Health;Cost Effectiveness Analysis;County;Coupled;Data;Death Rate;Disease Outbreaks;Drug usage;Drug user;Effectiveness;Epidemic;Equipment;Event;Evidence based intervention;Fright;HIV;HIV diagnosis;HIV risk;HIV/HCV;Harm Reduction;Health;Hepatitis C;Human immunodeficiency virus test;Hybrids;Individual;Infection;Infectious Skin Diseases;Infrastructure;Injecting drug user;Injections;Intervention;Judgment;Kentucky;Knowledge;Law Enforcement;Modeling;Names;Needle Sharing;Needle-Exchange Programs;Opioid;Overdose;Penetration;Persons;Pharmaceutical Preparations;Privacy;Process;Quasi-experiment;Reporting;Research;Research Personnel;Risk;Risk Reduction;Rural;Rural Appalachia;Rural Community;Rural Population;Safety;Science;Scientist;Service delivery model;Services;Shapes;Soft Tissue Infections;Sorbus;Sterility;Stimulant;Structure;Testing;Transcend;Trust;Visit;child protective service;cohort;community partners;condoms;cost;cost effectiveness;effectiveness study;effectiveness testing;evidence base;experience;follow-up;high risk;implementation intervention;implementation outcomes;implementation strategy;improved;infection risk;innovation;marginalization;marginalized population;mathematical model;member;methamphetamine use;opioid use disorder;outreach program;overdose death;overdose risk;overdose risk behaviors;peer;response;rural area;rural setting;scale up;service delivery;service utilization;social stigma;substance use;success

public_health_relevance:
NarrativeThe proposed study will test the effectiveness implementation outcomes and cost effectiveness of acommunity-tailored peer-driven intravention to reduce risk for overdose hepatitis C skin and soft tissueinfections and HIV in Appalachian Kentucky counties with extensive unmet harm reduction needs.


application_id: 11027969
project_number: 3UC2FD006890-05S1
project_title: Cigar Reference Products Program
administering_ic: FDA
award_notice_date: 2024-02-10
opportunity_number: RFA-FD-20-002
application_type: 3
activity_code: UC2
ic: FD
serial_number: 006890
suffix: S1
program_official: WAKEFIELD, CHRISTI
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZFD1-KF-1(01)1
contact_pi_person_id: 12031375
contact_pi: CHAMBERS, ORLANDO
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: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/Abstract: Since 1968 the University of Kentucky has provided referencetobacco products as standards for non-clinical investigational purposes by tobacco manufacturerscontract and government laboratories and academic institutions. This project will produce andcharacterize machine made sheet-wrapped cigar tobacco reference products representative oflarge cigars (processed leaf filler non-premium) little cigars (brown cigarettes) and small cigars(cigarillos). These new certified reference products will be manufactured in one manufacturing runeach to ensure product uniformity and will have certified physical and chemical characteristics toallow for proficiency testing instrument calibration employee/student training and for methodvalidation and investigational purposes. A process for the design analysis and approval isincluded to ensure input from stakeholders and that the new cigar reference tobacco productsmeet the specified goals. Quality control and sample testing parameters are defined andsubstantial chemical analyses will be conducted to allow for certification of product characteristicsand constituent levels.The CTRP will advance efforts to collaborate and coordinate studies with stakeholders includingTobacco Centers for Regulatory Science commercial product testing laboratories tobacco productmanufacturers and academic researchers. This proposal outlines significant improvements tocurrent cigar tobacco reference products in terms of product design and certification productdistribution product storage planning for new reference tobacco products establishing researchcapability and providing new services that will benefit the tobacco research community. A web-based interface for ordering reference tobacco products and for the secure transmission andstorage of collaborative data is under development and will be enhanced to include the cigarreference products. The CTRP web-based solution and database will be migrated to a Cloudenvironment to scale resources to meet future demand while reducing operational costs andincreasing the effectiveness of IT processes and personnel. As an academic institution ourproposal will be a service to the entire tobacco research community and is an improvement overcurrent efforts to coordinate and administer inter-laboratory comparison studies on tobaccoreference products and mechanisms to provide various cigar tobacco reference products. Thedevelopment of high-quality cigar tobacco reference products and providing those through theCTRP will strengthen the FDAs effort to develop the science of tobacco regulation and provide amuch needed basic resource for tobacco product research and regulation.

public_health_relevance:
Project NarrativeReference cigar tobacco products are a necessary tool for measuring and reporting harmful andpotentially harmful constituents in tobacco products as required under the Family SmokingPrevention and Tobacco Control Act. Three new machine-made sheet-wrapped certified cigarreference products representative of large cigars (processed leaf filler non-premium) littlecigars (brown cigarettes) and small cigars (cigarillos) will be manufactured in one manufacturingrun each to ensure product uniformity and will have certified characteristics to allow for aproficiency testing program instrument calibration employee/student training method validationand for investigational purposes. The University of Kentucky Center for Tobacco ReferenceProducts (CTRP) will expand our program for tobacco analysis and reference tobacco productsto support collaborative studies improved constituent analysis storage and stability researchand the manufacture and distribution of cigar tobacco reference products with significantproposed improvements and development in all of these areas.


application_id: 11025321
project_number: 3DP2MH136495-01S1
administering_ic: NIMH
award_notice_date: 2024-06-04
opportunity_number: PA-23-189
application_type: 3
activity_code: DP2
ic: MH
serial_number: 136495
suffix: S1
program_official: BURSTEIN, MARCY ELLEN
project_start_date: 2023-09-01
project_end_date: 2025-04-30
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-07-01
project_title:
Innovations in Personalizing Treatment for Eating Disorders Using Idiographic Methods and the Impact of Personalization on Psychological Physical and Sociodemographic Outcomes

project_abstract:
Abstract Eating disorders (ED) are serious psychiatric illnesses associated with various medical and functionalcomplications. It is unknown which specific cognitive-affective mechanisms driving EDs impact thedevelopment of medical and functional complications and whether targeting these mechanisms throughpersonalized treatment leads to better outcomes than existing one-size-fits-all interventions. Furthermore it isunclear how social determinants of health (SDOH) impact the heterogeneity of EDs and how they should bestbe integrated into treatment. The long-term research goal of the diversity supplement candidate Mr. JuanHernandez is to created new innovative efficacious and cost-effective personalized ED treatments for diversecommunities. Consistent with this goal the current Diversity Supplement proposes to use idiographic networkmodeling to examine individual differences in ED symptom presentations and test whether a personalizedintervention approach outperforms existing front-line treatments (i.e. CBT-E). The current proposal builds onthe parent grant (DP2MH136495) and will uniquely contribute to the literature by examining how individualdifferences in EDs are associated with medical and functional complications and SDOH each of which directlyimpact longevity and quality of life. Grounded in existing literature we hypothesize that central cognitive-affective mechanisms will vary across individuals and will be more associated with medical disorders andfunctional outcomes (i.e. health-related quality of life physical functionality and vitality health perceptionsachievement of self-defined goals) than behavioral symptoms. We also hypothesize that more disadvantagedSDOH (e.g. more severe food insecurity more experiences of marginalization) will also be associated withmore medical disorders and worse functional outcomes. As per treatment effects we hypothesize that at post-treatment the personalized treatment condition will be associated with less medical disorders and betterfunctional outcomes compared to the front-line treatment condition. Lastly we hypothesize that at post-treatment the personalized treatment condition will not be as impacted by SDOH as front-line treatmentsacross medical and functional outcomes. This study will be the first to examine (a) individual differences in EDsimpact on medical and functional complications and (b) how to best incorporate SDOH into ED treatment toaddress medical and functional complications. Results will inform important etiological and treatment questionsthat will directly inform efforts to promote longevity and quality of life among those experiencing an ED. Theconceptual quantitative and professional rigor of the training plan will prepare Mr. Hernandez to meet hislong-term goal of conducting clinical ED research at a Research 1 University. With the post-doctoral trainingfrom this supplement Mr. Hernandez will increase diversity of the field and fill a crucial role as an independentclinical science researcher and translational health psychologist.

project_terms:
Achievement;Address;Affective;Aftercare;Automobile Driving;Behavioral Symptoms;Clinical;Clinical Sciences;Cognitive;Communities;Development;Disease;Eating Disorders;Etiology;Fellowship;Goals;Health;Heterogeneity;Individual;Individual Differences;Intervention;Literature;Longevity;Medical;Mental disorders;Methods;Outcome;Perception;Postdoctoral Fellow;Psychologist;Quality of life;Research;Research Personnel;Role;Symptoms;Testing;Training;Universities;comorbidity;cost effective;experience;flexibility;food insecurity;functional outcomes;health related quality of life;innovation;marginalization;network models;parent grant;personalized intervention;personalized medicine;post-doctoral training;psychologic;social disparities;social health determinants;sociodemographics;treatment effect

public_health_relevance:
Project NarrativeExisting eating disorder treatments lack the flexibility to adapt to individuals symptom and environmentalcomplexities. Further it is unknown how individual differences impact associated medical and functionalcomplications. This diversity supplement to DP2MH136495 will lead to personalized eating disorder treatmentthat accounts for social determinants of health medical comorbidities and functional complications whileproviding crucial post-doctoral fellowship training to the diversity supplement awardee.


application_id: 11024117
project_number: 1R01AG090534-01
administering_ic: NIA
award_notice_date: 2025-04-21
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 090534
program_official: NEWMAN, ELIZABETH
project_start_date: 2025-05-01
project_end_date: 2030-01-31
study_section: Special Emphasis Panel[ZRG1 BN-M (91)]
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
budget_start_date: 2025-05-01
project_title:
Blood-Brain Barrier Dysfunction in Alzheimers Disease: New Mechanistic Insights and Therapeutic Strategies

project_abstract:
Amyloid  (A) is a key driver of blood-brain barrier dysfunction in Alzheimers disease (AD). A leaky anddysfunctional barrier in turn contributes to AD pathology and cognitive decline. In addition to A another keydriver of AD pathology is microtubule-associated protein tau (tau). In AD intracellular tau accumulates inneurons contributing to neurodegeneration and cognitive decline. Tau also exists as extracellular tau whichactivates various signaling pathways. Importantly elevated extracellular tau contributes to neurodegenerationand cognitive decline. We found that extracellular tau induces barrier dysfunction and is transported across thebrain capillary endothelium into the vascular lumen. These findings support the conclusion that both A and taucontribute to barrier dysfunction and cognitive decline in AD. However the mechanism underlying tau-inducedbarrier dysfunction is unknown and tau transport has not been described. Thus therapeutic strategies that repairA/tau-induced barrier dysfunction are not available. In this application we address this critical unmet need andpropose to determine the mechanistic link between tau signaling and barrier dysfunction define tau transport atthe blood-brain barrier and develop a strategy to repair A/tau-induced barrier dysfunction. Our objective in thisproposal is to establish a mechanism-based intervention targeting A/tau to treat barrier dysfunction in AD.Based on preliminary data our central hypothesis is that targeting SIRT1/NOX repairs A/tau-mediated barrierdysfunction and slows cognitive decline in APP/tau models. Our rationale is that this proposed research has thepotential to provide a basis for a disease-modifying intervention to treat barrier dysfunction in AD patients. Thehypothesis will be tested by pursuing three specific aims: 1) Identify the mechanism responsible for tau-inducedbarrier dysfunction. 2) Determine tau transport across the blood-brain barrier. 3) Develop a therapeuticintervention to repair Ab/tau-induced barrier dysfunction. In Aim 1 we will identify signaling steps through whichtau induces barrier dysfunction in isolated brain capillaries from wildtype and KO mice and in isolated humanbrain capillaries. In Aim 2 we will define tau transport across the capillary endothelium in vivo and in humanbrain capillaries. In Aim 3 we will block Ab and tau signaling to repair barrier dysfunction and evaluate the benefitof this strategy to slow cognitive decline in two preclinical APP/tau models. The proposed research is innovativebecause it represents a new and substantive departure from the status quo to a disease-modifying combinationtherapy focused on both A and tau aimed at new molecular targets to repair barrier dysfunction and slowcognitive decline. The proposed research is significant because it is expected to create a paradigm shift in ourunderstanding of barrier dysfunction in AD and constitute a crucial step toward developing a mechanism-basedintervention to repair barrier dysfunction in patients.

project_terms:
ABCB1 gene;Address;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid beta-Protein;Blood - brain barrier anatomy;Blood Vessels;Blood brain barrier dysfunction;Blood capillaries;Brain;Carrier Proteins;Cilostazol;Combined Modality Therapy;Cyclic AMP-Dependent Protein Kinases;Data;Disease;Endothelium;Extravasation;FDA approved;Functional disorder;Health;Human;Impaired cognition;Impairment;Intervention;Knockout Mice;Knowledge;Link;Mediating;Microtubule-Associated Proteins;Mission;Modeling;Molecular Target;Mus;NADPH Oxidase;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Nervous System Disorder;Neurons;Outcome;Oxidative Stress;Patients;Personal Satisfaction;Phase II Clinical Trials;Preclinical data;Process;Proteins;Public Health;Research;SIRT1 gene;Signal Pathway;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;Work;aging population;cerebral capillary;extracellular;improved;in vivo;in vivo Model;inhibitor;innovation;insight;metabotropic glutamate receptor type 1;multidrug resistance protein 3;pre-clinical;prevent;protein kinase C beta;repair strategy;repaired;tau Proteins;tau aggregation;treatment strategy

public_health_relevance:
The proposed research is relevant to public health because it is expected to advance our understanding of themechanisms underlying blood-brain barrier dysfunction and potentially establish a new disease-modifyingtreatment strategy that repairs barrier dysfunction to slow cognitive decline in Alzheimers disease. Thus theproposed research is relevant to the missions of the NIH/NINDS and the NIH/NIA that pertain to developingfundamental knowledge that will help reduce the burden of neurological disease and improve health and well-being in our aging population.


application_id: 11021712
project_number: 1R35GM156952-01
project_title: Gene regulatory network plasticity in social behavior
administering_ic: NIGMS
award_notice_date: 2025-01-06
opportunity_number: PAR-23-145
application_type: 1
activity_code: R35
ic: GM
serial_number: 156952
program_official: ADKINS, RONALD
project_start_date: 2025-01-06
project_end_date: 2029-12-31
study_section: Maximizing Investigators' Research Award A Study Section[MRAA]
contact_pi_person_id: 15977809
contact_pi: JONES, BERYL M
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Environmental and developmental variation play large roles in shaping phenotypes yet ourunderstanding of how phenotypic plasticity evolves and is mediated through gene regulatory networks (GRNs)is limited. This knowledge gap hinders our ability to predict how novel or changing environments will affectphenotypes as well as the evolutionary consequences of these changes. To better understand how bothadaptive and aberrant phenotypes emerge from GRN architecture we need tractable models which vary in aphenotype of interest. The proposed research takes an integrative approach to address the gene regulatorymechanisms underlying social behavior in a group of bees with extensive variation in sociality within and betweenspecies. This natural variation enables us to study the mechanistic basis of plasticity across both developmentaland evolutionary timescales. My proposed research combines functional genomics with computational biologyand behavioral profiling to identify gene regulatory plasticity and the consequences of this plasticity in theevolution and development of social traits. I approach these questions from multiple angles optimizing risk andreward and providing training opportunities for students and postdocs in genomics computational biology andbehavior. Objectives of the proposal include: 1) identifying GRN changes associated with evolutionary gains andlosses of social behavior 2) molecular profiling of developmental stages and behavioral phenotypes to determinehow GRNs generate intraspecific plasticity and 3) experimental manipulation of common trans-regulatoryenvironments and use of massively parallel reporter assays to identify context-dependent gene regulatory activityacross species. Together outcomes of these studied objectives would provide fundamental insights into howGRN architecture is modified and utilized during the evolution and development of social traits. More generallythis work will expand our understanding of how phenotypic plasticity emerges from changes in gene regulationan underappreciated contributor to the evolution of novel phenotypes.

project_terms:
Address;Affect;Bees;Behavior;Behavioral;Biological Assay;Biological Models;Computational Biology;Development;Environment;Event;Evolution;Gene Expression Regulation;Genes;Genomics;Knowledge;Mediating;Modeling;Molecular Profiling;Outcome Study;Phenotype;Play;Postdoctoral Fellow;Reporter;Research;Rewards;Risk;Role;Shapes;Social Behavior;Social Development;Students;Variant;Work;behavioral phenotyping;functional genomics;gene regulatory network;insight;interest;network architecture;novel;social;training opportunity;trait

public_health_relevance:
The overall objective of the proposed work is to uncover rewiring of gene regulatory networks (GRNs) duringevolutionary transitions in sociality. By identifying these rewiring events and their associated consequences onthe development of social phenotypes we will provide fundamental insights into how GRN architecture ismodified to facilitate the evolution of novel traits. This work fills a critical knowledge gap in our understanding ofthe interplay between GRNs environmentally-induced plasticity and the development of phenotypes in anemerging model system of social behavior.


application_id: 11021082
project_number: 5F31HL162518-04
project_title: Dynamic Role of Hyaluronan in Ventricular Remodeling
administering_ic: NHLBI
award_notice_date: 2025-01-09
opportunity_number: PA-21-052
application_type: 5
activity_code: F31
ic: HL
serial_number: 162518
program_official: HUANG, LI-SHIN
project_start_date: 2022-02-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1-F10A-K(20)L]
contact_pi_person_id: 15083220
contact_pi: LITTLE, DANIELLE T
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 AbstractThe extracellular matrix (ECM) provides structural and functional support for the myocardium; however heartfailure alters the composition of the ECM. The ECM is composed of a number of proteins lipids and saccharidesyet their function is largely unknown. We found that one of the most abundant components of the ECMhyaluronan (HA) accumulates following myocardial infarction; however the role of HA following during infarct-induced heart failure is not known. Fibroblasts are a major cell type involved in ventricular remodeling. Onceactivated fibroblasts proliferate and produce ECM components such as collagen and HA. These events areassociated with acute scar formation and chronic ventricular remodeling. In this project I will explore the extentto which fibroblast-derived HA impacts the extracellular matrix. Specifically I will study fibroblasts collagensecretion when HA metabolism is manipulated. Additionally I will examine the extent to which fibroblast-derivedHA contributes to acute scar formation post-MI. Finally I will determine the extent to which fibroblast-derivedhyaluronan contributes to chronic ventricular remodeling. We contend that acute increases in HA accumulationare required for scar formation following acute MI; however the persistent excessive production of HA provokesfibrosis beyond the initial scar. Hence we predict that HA has a dynamic role following infarct-induced heartfailure: beneficial early and maladaptive late. Taken together these studies will provide novel insight into the roleof HA in collagen secretion acure scar formation and chronic fibrosis. With this fundamental knowledge wecan in future studies explore therapeutic approaches. Regardless of the specific findings of this research planthis fellowship will serve as an excellent vehicle to enhance my training so I can eventually become anindependent scientist leading my own research laboratory. The combination of the experimental planexperimental tools my sponsor the environment advanced coursework and professional developmentopportunities creates a high likelihood for me to realize my eventual goals and contribute significantly to theliterature in the process.

project_terms:
Acute;Acute myocardial infarction;Adenoviruses;Advocate;Atomic Force Microscopy;Biomechanics;Cardiac;Cardiac Myocytes;Cells;Chronic;Chronic Phase;Cicatrix;Collaborations;Collagen;Data;Deposition;Development;Disease;Echocardiography;Elements;Embryo;Enterobacteria phage P1 Cre recombinase;Environment;Enzymes;Event;Extracellular Matrix;Family;Fellowship;Fibroblasts;Fibrosis;Future;Goals;HAS2 gene;Health;Heart;Heart failure;Hour;Hyaluronan;Hyaluronidase;Immune;In Vitro;Infarction;Inflammatory;Intervention;Ischemia;Knowledge;Laboratory Research;Lipids;Literature;Metabolism;Molecular Weight;Mus;Muscle Cells;Mutant Strains Mice;Myocardial Infarction;Myocardium;Organ;Pathology;Phase;Play;Process;Production;Proliferating;Proteins;Regulation;Research;Role;Rupture;Scientist;Shapes;Techniques;Therapeutic;Tissues;Training;Translating;Ventricular;Ventricular Function;Ventricular Remodeling;acute wound;cell type;disorder risk;gain of function;heart function;histological stains;in vivo evaluation;innovation;insight;loss of function;novel;novel therapeutic intervention;prevent;tool;wound healing

public_health_relevance:
Project NarrativeHyaluronan is a key component of organs and may play a role in wound healing; however the role of hyaluronanin the failing heart is not known. By understanding the role hyaluronan plays in cardiac scar formation and chronicfibrosis we can expose novel therapeutic approaches to optimize these adaptations and minimize disease risk.This project will employ several innovative ideas and techniques to study impact of hyaluronan on fibroblastfunction and ventricular remodeling.


application_id: 11021030
project_number: 5UH3DE032621-03
project_title: Empowering dentists to reduce opioid prescriptions to young people
administering_ic: NIDCR
award_notice_date: 2024-12-12
opportunity_number: RFA-DE-23-010
application_type: 5
activity_code: UH3
ic: DE
serial_number: 032621
program_official: FISCHER, DENA
project_start_date: 2023-01-01
project_end_date: 2028-12-31
study_section: ZDE1-YM(06)
contact_pi_person_id: 15812629
contact_pi: OYLER, DOUGLAS
other_pis: ROJAS RAMIREZ, MARCIA VANESSA
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTDentists are the leading prescriber of opioids to adolescents and young adults (AYAs) even though opioid useafter tooth extraction is not associated with improved pain control or satisfaction. In AYAs an opioid prescriptionafter a dental procedure increases the risk of opioid misuse use disorder and overdose. The long-term goal ofthis project is to develop a framework to reduce opioid prescriptions to AYAs for treatment of acute dental pain.The objective of this proposal is to establish the effectiveness of a multicomponent intervention at reducingdental opioid prescription rates after tooth extraction in AYAs. Our central hypothesis is that a multicomponentintervention is required to produce significant reductions in post-extraction opioid prescriptions to AYAs. Therationale underlying this proposal is that a multicomponent intervention will address provider knowledgemotivation and choice architecture better than a single-component strategy; will engage and educate patients;and will provide a physical item for distribution instead of an opioid prescription. We will test this hypothesis bypursuing four specific aims: in the UG3 period 1) complete requisite preliminary work to test a new approachto manage acute pain following dental treatment and in the UH3 period: 1) establish effectiveness of a noveleducational and drug-dispensing approach using academic detailing patient education and blister-packagednon-opioid analgesics to reduce opioid prescriptions following tooth extraction among AYAs; 2) examine keyimplementation outcomes of the intervention designed to modify dental professional decision-making behaviors;and 3) assess patient-reported pain management analgesic use and drug disposal after tooth extraction. Toaccomplish these aims we propose a stepped wedge cluster randomized trial of community and academic clinicsacross Kentucky using an innovative intervention of one-on-one provider education plus provider distribution ofpatient education materials and standardized blister packs containing acetaminophen and ibuprofen. This studywill be conducted across at least 10 of the largest oral surgery practices in Kentucky enrolling at least 27providers expected to perform tooth extractions on over 40000 AYAs. We will assess effectiveness using aprimary endpoint of the patient-level binary indicator of being prescribed an opioid. Secondary endpointsinclude intervention acceptability appropriateness feasibility and fidelity (UH3 aim 2); and patient-reported painpain interference analgesic use and drug disposal (UH3 aim 3). The proposed research is significant becauseit will provide a framework for wide-scale implementation of interventions to modify dental decision-makingbehaviors towards evidence-based recommendations for acute pain management resulting in a reduction inopioid prescription rates after tooth extraction. The expected outcome is a framework to implement effectiveinterventions to reduce dental opioid prescribing to AYAs. The results will have a positive impact immediatelybecause they will limit unnecessary opioid exposure and long-term because they will help dentistry build aframework for reducing the impact of substance use disorders across the United States.

project_terms:
Academic Detailing;Acetaminophen;Acute;Acute pain management;Address;Adolescent and Young Adult;American;Analgesics;Architecture;Behavior;Bulla;Clinic;Clinical Trials Design;Cluster randomized trial;Community Trial;Country;Data;Decision Making;Dental;Dental Care;Dental Clinics;Dental General Practice;Dentistry;Dentists;Disease;Dose;Drug Monitoring;Drug Prescriptions;Education;Educational Materials;Effectiveness;Electronic Health Record;Enrollment;Environmental Risk Factor;Goals;Ibuprofen;Individual;Intervention;Interview;Kentucky;Knowledge;Measures;Modeling;Morphine;Motivation;National Institute of Dental and Craniofacial Research;Opioid;Oral Surgeon;Oral Surgical Procedures;Outcome;Overdose;Pain;Pain interference;Pain management;Patient Education;Patients;Persons;Pharmaceutical Preparations;Process;Provider;Public Health;Recommendation;Reporting;Research;Risk;Safety;Site;Standardization;Substance Use Disorder;Surveys;Testing;Tooth Extraction;Toothache;United States;Use Effectiveness;Work;academic intervention;clinical decision support;dental agent;effective intervention;effectiveness evaluation;empowerment;evidence based guidelines;experience;health record;high risk;high risk population;implementation evaluation;implementation intervention;implementation outcomes;implementation science;improved;innovation;member;milligram;multi-component intervention;multidisciplinary;non-opioid analgesic;novel;novel strategies;opioid exposure;opioid misuse;opioid use;pill;prescription opioid;prescription opioid misuse;primary endpoint;provider factors;recruit;satisfaction;secondary endpoint;therapy design

public_health_relevance:
NARRATIVEDentists are a leading prescriber of opioids to young people which have a particularly high risk of misusingopioids developing a substance use disorder or overdosing. Efforts to reduce dental opioid prescribingcommonly use single interventions do not specifically target young people and are performed primarily inacademic settings. This large study will test whether a bundled intervention of academic detailing patienteducation and non-opioid blister packs for distribution reduces opioid prescriptions to adolescents and youngadults after tooth extraction.


application_id: 11020971
project_number: 5R21CA280141-02
project_title: Lectikines for Immunotherapy against Ovarian Cancer
administering_ic: NCI
award_notice_date: 2025-01-21
opportunity_number: PAR-22-216
application_type: 5
activity_code: R21
ic: CA
serial_number: 280141
program_official: HARRIS, RAYMOND D
project_start_date: 2024-02-01
project_end_date: 2027-01-31
study_section: ZCA1-RTRB-S(O1)
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
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:
SUMMARYThe goal of this project is to create a novel immunotherapeutic drug candidate against ovarian cancer (OVCA).OVCA is the leading cause of death from gynecological malignancy in the United States with poor survival ratesdue to late diagnosis and chemo-resistant fatal recurrent disease after the first-line debulking surgery andchemotherapies. Immune checkpoint inhibitors have thus far failed to show a significant clinical benefit due tohighly immunosuppressive tumor microenvironment and poor infiltration of T cells. Thus the development ofeffective OVCA immunotherapy requires novel strategies. To address this problem the proposed project willcreate novel immunotherapeutic proteins based on Avaren lectin. It is a small 14-kDa recombinant proteinengineered in the PIs laboratory from a natural actinomycete lectin which selectively recognizes a cluster ofhigh-mannose glycans that are prevalent on the surface of enveloped viruses and malignant cells. A fusionprotein consisting of Avaren lectin and human IgG1 Fc (AvFc) was previously shown to exhibit potent antiviraland antitumor activities without toxicity in in vitro and in vivo animal models. Based on growing evidenceindicating that high-mannose overaccumulation also occurs on the surface of OVCA cells we hypothesize thatAvaren lectin can be utilized in novel OVCA-targeting strategies. Our preliminary data show that AvFc efficientlybinds to OVCA but not to adjacent normal tissues. AvFc elicited potent antibody-dependent cell-mediatedcytotoxicity (ADCC) against OVCA cell lines. Furthermore AvFc treatment exhibited moderate yet statisticallysignificant efficacy extending the survival of animals in a syngeneic orthotopic murine OVCA model using theID8 cell line. Building on these data in this project we will create immunostimulatory variants of Avaren lectinthat can transform OVCA into more immunologically hot tumors thereby exhibiting potent immunotherapeuticefficacy. Specifically we will engineer translational fusion proteins consisting of Avaren lectin / AvFc and anantitumor cytokine (lectikines). In Aim 1 we will generate lectikines by fusing a variant of IL-2 devoid of CD25binding (IL-2v) or IL-15 to AvFc which will be produced in Nicotiana benthamiana plants using a transientoverexpression system. After thorough purification we will assess their molecular properties OVCA cell-bindingaffinity and cytokine functions in a battery of biochemical biophysical and cell-based assays. In Aim 2 we willevaluate the therapeutic effects of lectikines in comparison with AvFc in a murine ID8 OVCA model. Diseaseprogression will be monitored through abdomen circumference body weight and live animal bioluminescenceimaging. Immunophenotyping of peritoneal cells will be performed by flow cytometry. We anticipate that lectikineswill elicit significant efficacy through increased immune activation in the tumor microenvironment. Successfulcompletion of this pilot project will establish an initial proof-of-concept and generate a compelling data set forfurther investigation and development of a first-in-class OVCA immunotherapy.

project_terms:
Abdomen;Actinobacteria class;Address;Affinity;Animal Model;Animals;Anti-viral Agents;Antineoplastic Agents;B16F10;Binding;Biochemical;Biological;Biological Assay;Biological Products;Biophysics;Body Weight;C57BL/6 Mouse;Cancer Model;Cancer cell line;Cause of Death;Cell Line;Cell surface;Cells;Chemoresistance;Chimeric Proteins;Clinical;Data;Data Set;Development;Diagnosis;Disease Progression;Engineering;Enzyme-Linked Immunosorbent Assay;Euthanasia;Exclusion;Exhibits;Flow Cytometry;Foundations;Goals;HIV;High Pressure Liquid Chromatography;Human;IL2RA gene;IgG1;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunohistochemistry;Immunologics;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Implant;In Vitro;Infiltration;Interleukin-15;Interleukin-2;Investigation;Laboratories;Lectin;Malignant Breast Neoplasm;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mannose;Measurement;Melanoma;Modeling;Molecular;Monitor;Mus;Nicotiana;Non-Small-Cell Lung Carcinoma;Normal Cell;Normal tissue morphology;Operative Surgical Procedures;Ovary;Patients;Peritoneal;Peritoneal lavage;Pilot Projects;Plant Viruses;Plants;Polysaccharides;Primary Neoplasm;Property;Protein Engineering;Proteins;Recombinant Fusion Proteins;Recombinant Proteins;Recurrent disease;Series;Site;Skin Cancer;Spleen;Surface;Surface Plasmon Resonance;Survival Rate;System;T cell infiltration;Therapeutic Effect;Tissues;Toxic effect;Tumor Debulking;United States;Variant;Viral;Viral Physiology;Virus;Western Blotting;Xenograft Model;analog;antibody-dependent cell cytotoxicity;antitumor effect;antiviral immunity;bioluminescence imaging;biophysical properties;cancer cell;cancer immunotherapy;cancer therapy;chemotherapy;cytokine;design;drug candidate;experience;experimental study;expression vector;human model;immune activation;immunogenicity;improved;in vitro Assay;in vivo;manufacture;monocyte;neoplastic cell;novel;novel strategies;ovarian neoplasm;overexpression;preclinical development;recruit;targeted agent;therapeutic evaluation;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
NARRATIVEThis project will generate novel immunotherapeutic drug candidates against ovarian cancer based on lectikineswhich are recombinant fusion proteins consisting of the tumor glycobiomarker-targeting lectin Avaren and anantitumor cytokine. We will design and produce several lectikine constructs and evaluate them in in vitro assaysand in a mouse ovarian cancer model. Successful completion of this pilot project will establish an importantproof-of-concept data package justifying further preclinical development of our first-in-class immunotherapeuticcandidate for ovarian cancer.


application_id: 11020935
project_number: 5F31HL170972-02
administering_ic: NHLBI
award_notice_date: 2024-12-05
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: HL
serial_number: 170972
program_official: HUANG, LI-SHIN
project_start_date: 2024-01-01
project_end_date: 2026-12-31
study_section: ZDK1-GRB-2(M1)
contact_pi_person_id: 78710593
contact_pi: KIPP, ZACHARY 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
budget_start_date: 2025-01-01
project_title:
Bilirubin Catabolism induces Plasminogen-Activator Inhibitor 1 (PAI-1) worsening Metabolic Dysfunction

project_abstract:
Summary:Urobilin is formed in the intestine as a biproduct of conjugated bilirubin catabolism. Currently the physiologicalfunction of urobilin is unknown. Human association studies have indicated a positive correlation to obesity andcardiovascular diseases (CVD). Since obesity is a major risk factor for the development of CVD we hypothesizedthat urobilin levels might change with the altered metabolic state and induce adiposity. To determine the role ofurobilin in lean mice we treated C57/bl6 mice on a normal-chow diet with urobilin for 4 weeks. We found thaturobilin had no effect on body weight but significantly increased adiposity in the inguinal white adipose tissue(iWAT) depot compared to the vehicle-treated mice. To determine how urobilin changes the transcriptome profilein the iWAT we preformed RNA-sequencing which showed that urobilin increases the expression of Serpine1mRNA. Serpine1 is translated into the protein plasminogen activator inhibitor-1 (PAI-1). PAI-1 is secreted intocirculation promoting a prothrombotic environment and is thought to increase the risk of CVD. The goal of thisresearch proposal is to determine whether urobilin induces CVD via PAI-1 and if this mechanism is a link betweenCVD and obesity. We will investigate if lowering plasma urobilin is a possible therapeutic for the treatment andprevention of CVD. To study this in Aim 1 we will use PAI-1 knockout (KO) mice and littermate controls treatedwith urobilin or vehicle while on a high-fat or calorie-match low-fat diets. We expect the PAI-1KO mice will beprotected from urobilin induced CVD. In Aim 2 we will use diet-induced obese (DIO) mice treated with a liver-specific GalNac-Ugt1a1-RNAi or GalNac-scramble control to suppress hepatic Ugt1a1 which is responsible forinitiating the conjugation of bilirubin that leads to elevated urobilin production. We show preliminary data that theRNAi technology suppresses Ugt1a1 94.7% and that this leads to a significant (p<0.01) decrease in plasmaurobilin and an increase in plasma unconjugated bilirubin. We expect that the suppression of Ugt1a1 will protectthe mice from the development of CVD by lowering urobilin levels increasing unconjugated bilirubin preventingadiposity and high PAI-1 plasma levels. This is the first proposed mechanism of urobilin in promoting thedevelopment of CVD which we will extensively study to better understand how to reverse its deleterious effects.This fellowship will provided critical training in research techniques scientific training and professionaldevelopment to give me the tools to become a successful independent scientist.

project_terms:
Adipose tissue;Affect;Antioxidants;Arterial Fatty Streak;Bilirubin;Binding;Blood Pressure;Blood Vessels;Body Weight;Calories;Cardiovascular Diseases;Cardiovascular system;Catabolism;Cause of Death;Cessation of life;Cholesterol;Circulation;Coagulation Process;Data;Development;Diet;Environment;Enzymes;Excretory function;Fat-Restricted Diet;Fatty acid glycerol esters;Fellowship;Fibrosis;Financial Hardship;Foundations;Future;Generations;Genetic Polymorphism;Gilbert Disease;Glucuronic Acids;Goals;Health Care Systems;Heart Diseases;Heart failure;Heme;Hepatic;High Fat Diet;Hormonal;Human;Intestines;Knock-out;Knockout Mice;Lead;Link;Liver;Measures;Mediator;Messenger RNA;Metabolic;Metabolic Diseases;Metabolic dysfunction;Mus;Nuclear Receptors;Obese Mice;Obesity;PPAR alpha;Pathway interactions;Patients;Physiological;Plasma;Plasminogen Activator Inhibitor 1;Portal System;Prevention;Production;Proteins;RNA Interference;Research;Research Proposals;Research Technics;Risk;Risk Factors;Role;Scientist;Serum;Structure;Technology;Testing;Therapeutic;Thinness;Training;Translating;Travel;UGT1A1 gene;United States;Water;Woman;Work;absorption;bile duct;cardioprotection;cardiovascular disorder prevention;cardiovascular disorder risk;career;comorbidity;coronary fibrosis;diet-induced obesity;feeding;glucose tolerance;gut microbiota;improved;men;mouse development;new therapeutic target;novel marker;novel therapeutics;obese patients;prevent;promoter;therapeutic target;tool;transcriptome;transcriptome sequencing

public_health_relevance:
Project Narrative:The work proposed in this fellowship has the potential to uncover a possible link between obesityand the development of cardiovascular disease. This research could lead to the discovery of anovel biomarker and a possible therapeutic target for the prevention and treatment ofcardiovascular disease.


application_id: 11019787
project_number: 5R01HL168085-02
administering_ic: NHLBI
award_notice_date: 2025-02-25
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 168085
program_official: LIU, SONGTAO
project_start_date: 2024-02-01
project_end_date: 2028-01-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 8487070
contact_pi: WANG, DONGFANG
other_pis: YOGANATHAN, AJIT P
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
budget_start_date: 2025-02-01
project_title:
Development of a Percutaneous Double Lumen Cannula-Based Cavopulmonary Assist System Toward Clinical Application

project_abstract:
The standard palliative surgery for a single ventricle defect is a total cavopulmonary connection (TCPC) whichseparates the pulmonary and systemic circulations. This Fontan circulation eventually fails with high long-termmortality. A failing Fontan includes cavopulmonary failure (CPF) and/or ventricular failure. No cavopulmonaryassist (CPA) device is available for CPF. Our ultimate goal is to develop a percutaneous CPA system for totalambulatory support of CPF patients. Our enabling technology is a CPA dual lumen cannula (DLC) with pairedmembrane umbrellas. Via ony 1 venous cannulation this DLC connects the TCPC to an external pump withoutmajor surgery. This system provided total CPA and reversed CPF hemodynamics/renal dysfunction in ourlethal CPF sheep model enabling 96 hr survival. To move our CPA DLC toward clinical application thefollowing specific aims were developed: Specific Aim 1: To design optimize and fabricate a new CPADLC for least thrombogenic/ hemolytic potential and smooth installation/deployment. Two membraneumbrellas ensure efficient/reliable performance. Slipknots ensure easy DLC installation/umbrella deployment.Validated computational fluid dynamics will be used for design optimization. The CPA DLC body will be madeof ultrathin reinforced polyurethane (PU) with a PU membrane sleeve infusion lumen. The two membraneumbrellas will be molded onto DLC. Specific Aim 2: [To assess the anatomic fittingness of the CPA DLCin patient specific TCPC silicone models and evaluate the potential of reversing pathophysiology inCPF patients using our established mathematical model validated with CPF patients comprehensivehemodynamic data]. Patient specific silicone TCPC models will be made from MRIs in our Fontan database.A mock loop with these models will assess the CPA DLC for: 1) ability to fit/function well; 2) flow stasis/highshear stress areas. Our patient specific Fontan simulation platform will quantify CPA flow rates that mitigateliver congestion. Specific Aim 3: To evaluate final CPA DLC prototype in a [patient specific TCPC mockloop] for performance reliability and 30 day durability. This mock loop with 37% glycerin will test CPADLC for: 1) flow efficiency/reliability at 360 [axial] rotation/8 cm dislocation and 2) 30 day durability at 4 L/minflow. Specific Aim 4: To evaluate the CPA DLC prototype for in vivo performance reliability and ease ofinstallation/deployment in a CPF sheep model. Ease of installation/deployment and performance/reliabilitywill be assessed in 6 hr studies (n=15). A 2-week preclinical study (n=15) will confirm full reversal of CPFhemodynamics/end-organ dysfunction and will assess biocompatibility.

project_terms:
3-Dimensional;Acute;Anatomy;Area;Blood;Cannulas;Cannulations;Catheters;Circulation;Common Ventricle;Data;Databases;Development;Dislocations;Eligibility Determination;Ensure;Failure;Functional disorder;Glycerol;Goals;Grant;Heart;Heart Transplantation;Hemolysis;Hypoxia;Implantable Pump;In Vitro;Inferior vena cava structure;Infusion procedures;Kentucky;Liquid substance;Live Birth;Liver;Magnetic Resonance Imaging;Massachusetts;Medical Device;Membrane;Modeling;Molds;Operative Surgical Procedures;Organ;Palliative Surgery;Patient Simulation;Patients;Performance;Polyurethanes;Pulmonary artery structure;Pump;Reconstructive Surgical Procedures;Recovery;Rotation;Self-Help Devices;Sheep;Silicones;Single ventricle congenital heart disease;Superior vena cava structure;System;Technology;Testing;Thrombosis;Universities;Venous;Ventricular;Work;bench testing;biomaterial compatibility;clinical application;clinical efficacy;clinically relevant;design;flexibility;hemodynamics;improved outcome;in vivo;kidney dysfunction;mathematical model;mortality;novel;pre-clinical;preclinical study;pressure;prevent;prototype;pulmonary;shear stress;sheep model;simulation;thrombogenesis;ventricular assist device

public_health_relevance:
We are proposing to further develop a percutaneous cavopulmonary assist system toward clinical application.The enabling technology is a cavopulmonary assist dual lumen cannula with paired membrane umbrellas. Ourcavopulmonary assist system will provide total ambulatory support to cavopulmonary failure patients bridgingthese patients with failing Fontan circulation to recovery reconstructive surgery and heart transplantation toimprove outcomes.


application_id: 11019567
project_number: 3R01DK131786-03S1
project_title: Administrative Supplements for Research on Sexual and Gender Minority (SGM) Populations
administering_ic: NIDDK
award_notice_date: 2024-07-30
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: DK
serial_number: 131786
suffix: S1
program_official: LOH, KATRINA SHUEH WEN
project_start_date: 2022-07-01
project_end_date: 2027-04-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
In this Administrative Supplements for Research on Sexual and Gender Minority Populations our aim is to fill asignificant gap in Turner syndrome (TS) research by addressing how the missing sex chromosome impactsliver health in this unique female population. Patients with TS frequently present with obesity and liver damageincluding non-alcoholic fatty liver disease (NAFLD). However the underlying mechanisms are unclear.Leveraging our expertise in NAFLD study this application focuses on investigating the role of an X-linkedgene KDM6a/UTX in TS-associated NAFLD. KDM6a/UTX a gene that codes for H3K27 demethylases isdownregulated in TS patients as well as in TS mouse livers. It plays a critical role in the histone demethylationof genes crucial for heart development and is also associated with the development of hyperinsulinemiametabolic abnormalities or acetaminophen overdose-induced hepatotoxicity. Based on these findings wehypothesize that KDM6a/UTX may play a role in the development of Turner syndrome-related NAFLD. Thishypothesis will be tested by both in vitro and in vivo studies involving the utilization of primary mousehepatocytes and Turner syndrome mouse models. The successful completion of these studies will establishwhether KDM6a is a key player in regulating hepatocyte lipid metabolism and fatty liver disease in TurnerSyndrome mouse models. This will lay a critical foundation for future translational studies contributing to thewell-being of Turner Syndrome patients.

project_terms:
3-Dimensional;ATAC-seq;Address;Adenoviruses;Administrative Supplement;Affect;Alanine Transaminase;Animals;Area;Aspartate Transaminase;Biliary;Birth;Body System;Categories;Cell Culture Techniques;Cells;Chromosome abnormality;Cirrhosis;Code;Development;Diet;Elements;Enzymes;Estrogens;Exhibits;Face;Fatty Acids;Female;Foundations;Future;Genes;Health;Healthcare;Heart Diseases;Hepatocyte;Hepatotoxicity;Histology;Histones;Hormone replacement therapy;Hyperinsulinism;Hyperplasia;In Vitro;Individual;Infertility;Knowledge;Laboratories;Link;Liver;Liver Cirrhosis;Liver Dysfunction;Liver diseases;Metabolic;Modeling;Molecular;Mus;Obesity;Organ;Organoids;Outcome;Patients;Personal Satisfaction;Phenotype;Play;Population;Reporting;Research;Risk;Role;Sex Chromosomes;Somatotropin;Steatohepatitis;Supplementation;Symptoms;Syndrome;Techniques;Testing;Triglycerides;Turner's Syndrome;Woman;X Chromosome;acetaminophen overdose;cardiogenesis;comparison control;demethylation;differential expression;fatty liver disease;gender minority group;genotypic sex;hearing impairment;in vivo;kidney malformation;lipid metabolism;liver injury;medical complication;mouse model;non-alcoholic fatty liver disease;regenerative;sexual minority group;small hairpin RNA;tool;transcriptome sequencing;translational study;uptake;vector

public_health_relevance:
Turner syndrome a condition exclusive to females occurs when one of the X chromosomes (sexchromosomes) is absent or partially missing affecting multiple organs. The aim of this administrativesupplemental application is to fill a significant gap in tuner syndrome research by addressing how the missingsex chromosome impacts liver health in this unique female population. Knowledge gained from our studiesmay lay a critical foundation for future translational studies contributing to the well-being of Turner Syndromepatients.


application_id: 11018469
project_number: 3R43AG080890-01S1
administering_ic: NIA
award_notice_date: 2024-04-22
opportunity_number: PAR-22-073
application_type: 3
activity_code: R43
ic: AG
serial_number: 080890
suffix: S1
program_official: MARTIN, ZANE
project_start_date: 2023-02-15
project_end_date: 2024-09-30
contact_pi_person_id: 1971555
contact_pi: ZHOU, JIANHUA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 801721601
primary_uei: G942LFRXSK87
duns_number: 801721601
uei: G942LFRXSK87
fips: US
organization_id: 10017951
organization_name: INFLAMED, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402411864
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Treatment with hrVCP of ApoE4 genetic predisposition to AD by controlling complement mediated neuroinflammation

project_abstract:
Project Summary/AbstractVaccinia virus complement control protein (VCP) has been shown to have structural and functional similarityto human complement control proteins. VCP modulates the human and rodent complement system. Duringthe past two decades we have studied VCP extensively in a number of preclinical inflammatory diseasemodels including Alzheimers disease (AD) and spinal cord injury (SCI) and demonstrated that controllingcomplement mediated inflammation by VCP has significantly improved outcomes leading to our hypothesisthat VCP can be potentially used for therapeutic treatments of these diseases. AD is one of the mostdevastating diseases amongst the aging population in the world and the 6th leading cause of death in theUS. It is well known that amyloid proteins and plaques are associated with activation of severalproinflammatory mediators especially complement components. Interestingly ApoE genotypes thatsignificantly facilitate A- deposit are strongly involved in regulation of classical complement cascade.These pro-inflammatory mediators can cause damage on their own as well as working in synergy with eachother ultimately leading to neurodegeneration. Over time the damaging role of complement componentsoverpowers their beneficial effects as the disease progresses. As a result complement pathways havebecome potential targets for developing treatments of diseases such as AD. To provide a proof of conceptwe investigated the role of complement pathways regulated by VCP in AD mice model. In this model VCPwas shown to be effective in preventing memory loss. To further develop VCP as a potential treatment forAD in this SBIR phase I study we will aim at characterizing high qualify humanized recombinant VCP(hrVCP) and at the assessment of candidate hrVCP in animal models in a more clinical relevant manner byan independent CRO company with two specific aims: 1) To subject hrVCP to a full battery of in-houseanalytical characterization and stability profiling; ; Specific Aim 2: To validate our previous findings bytesting efficacy of hrVCP in APP/PS1 AD models with collaboration of an independent CRO laboratory. Ourmilestone goals include development of active and stable hrVCP pre-formulation in Saline production ofmore hrVCP if resources allow and validation of efficacy data in AD models from a laboratory other thanour own. If we are successful PK/safety assessments and other preclinical studies of purified hrVCPprotein will be the goal of Phase II studies along with even more rigorous safety studies including in vitrocardiotoxicity hepatotoxicity and bone marrow toxicity studies in stem cells derived tissue cells. We expectthat the SBIR phase1 studies will lead to development of hrVCP for a commercial scale therapeuticapproach to target the progression of neuroinflammation and neurodegeneration anticipated in AD patients.

project_terms:
APP-PS1;Achievement;Aducanumab;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid Proteins;Amyloid beta-Protein;Amyloid deposition;Animal Disease Models;Animal Model;Animals;Apolipoprotein E;Award;Binding;Bone Marrow;Brain;Carcinogens;Cardiotoxicity;Cause of Death;Cells;Characteristics;Clinical Research;Clinical Trials;Collaborations;Complement;Complement Activation;Contractor;Data;Dementia;Deposition;Development;Disease;Effectiveness;Endotoxins;Event;FDA approved;Formulation;Funding;Genetic Predisposition to Disease;Genotype;Goals;Government;Grant;Heavy Metals;Hepatotoxicity;Human;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Injections;Insurance;Intervention;Laboratories;Legal patent;Mediating;Memory Loss;Modeling;Mus;Mutagens;Nerve Degeneration;Nose;Outcome;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physicians;Population;Poxviridae;Privatization;Production;Proteins;Publishing;Qualifying;Regulation;Resources;Rodent;Role;Safety;Saline;Senile Plaques;Small Business Innovation Research Grant;Social Impacts;Spinal cord injury;Sterility;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Toxic effect;Toxin;Traumatic Brain Injury;Vaccinia Virus Study;Vaccinia virus;Vaccinia virus complement-control protein;Validation;aging population;apolipoprotein E-4;clinically relevant;complement C3 precursor;complement pathway;complement system;cost;disease model;disorder control;economic impact;efficacy evaluation;efficacy testing;efficacy validation;extracellular;genetic regulatory protein;improved;improved outcome;manufacture;mouse model;neuroinflammation;phase 1 study;phase 2 study;pre-clinical;preclinical study;prevent;safety assessment;safety study;stem cell derived tissues;synergism

public_health_relevance:
Narrative:In our preliminary studies we have shown promising results to treat Alzheimers disease(AD) in animal models by inhibiting complement pathways with humanized recombinantVaccinia Virus Complement Control Protein (hrVCP). This project will carry outcharacterizing a large scale of high quality hrVCP in pre-formulation saline solution thatwill be then tested in AD animal models for validation of our earlier results by anindependent CRO laboratory so that we will be able to seek additional funds fromgovernments and private investors pre-clinical and then clinical studies in animals andhumans. If successful it will contribute to an intervention for AD.


application_id: 11018276
project_number: 1P20GM156679-01
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8037
contact_pi_person_id: 12197125
contact_pi: WEN, YUAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-12-01
project_title:
Muscle-derived extracellular vesicles and their interactions with adipocytes in human metabolic dysfunction

project_abstract:
ABSTRACT- PROJECT 5There is growing recognition of the significant changes in extracellular vesicle (EV) biology in the pathogenesisof obesity and diabetes. Although evidence points to deviations in EV biogenesis and abundance in circulationthe mechanisms by which EVs are regulated are poorly understood. Research has mostly focused on thetissues of origin for circulating EVs but almost nothing is known about tissue-specific plasma membraneadaptations that either increase or decrease vesicle uptake. The proposed studies will investigate the role ofmembrane receptivity to circulating EVs in the pathophysiology of obesity and metabolic disorders. The projectleader and mentors have already performed studies in this area and found an exciting EV communication axisfrom skeletal muscle to adipose tissue that is conserved in mice and humans. This led us to postulate thatadipose tissue may become resistant to EV endocytosis in people with prediabetes and this endocytosis-resistance contributes to progression to diabetes. Changes in EV-uptake in adipose tissue may not be aprimary dysfunction in adipose but rather may be a maladaptive tissue crosstalk response in prediabeticskeletal muscle. To test these hypotheses we propose to recruit participants with and without prediabetes andsubject them to a single bout of whole-body resistance exercise to simulate EV secretion. Biopsies will beobtained from subcutaneous adipose and vastus lateralis for transcriptomics analyses and primary cellcultures. Aim 1: Determine whether there is a baseline variance in EV receptivity in human adipose tissue andadipocyte cultures. EV uptake will be assessed 1) in vivo using adipose tissue mature miR-1 levels as a proxyand 2) in vitro using non-stimulated myotube derived EVs that have been labeled with tetraspanin fluorescentreporter. Transcriptomics analysis will be used to analyze gene expression in both adipose tissue andadipocyte cultures. Aim 2: Assess the impact of exercise-induced muscle-derived EVs on adipose tissue andEV uptake in adipocyte cultures. Aim 3: Determine whether pre-diabetes impacts adipose tissue EV receptivityat baseline and following exercise. This proposal will provide the first evidence for this muscle-adipose EVcommunication and membrane resistance as a contributing factor in metabolic dysfunction and prediabetes.

project_terms:
Acute;Adipocytes;Adipose tissue;Adult;Area;Automobile Driving;Biogenesis;Biology;Biopsy;Body mass index;CD81 gene;Cell Culture Techniques;Cell membrane;Cells;Centers of Research Excellence;Circulation;Communication;Data;Defect;Diabetes Mellitus;Diabetes prevention;Electric Stimulation;Endocytosis;Etiology;Exercise;Exhibits;Fluorescence;Functional disorder;Future;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genetic;Human;In Vitro;Individual;Kentucky;Label;Link;Membrane;Mentors;Metabolic;Metabolic Diseases;Metabolic dysfunction;Mus;Muscle;Muscle Cells;Muscle Fibers;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Pathogenesis;Pathway interactions;Patient Recruitments;Persons;Physiology;Population;Prediabetes syndrome;Primary Cell Cultures;Proxy;Recombinants;Regulation;Reporter;Research;Research Personnel;Resistance;Risk Factors;Role;Signal Transduction;Skeletal Muscle;Testing;Tissue Model;Tissues;Universities;Variant;Vesicle;adipose derived stem cell;diabetes risk;effective intervention;effective therapy;exosome;experimental study;extracellular vesicles;improved;in vivo;resistance exercise;response;subcutaneous;transcriptome;transcriptomics;uptake;vastus lateralis


application_id: 11018275
project_number: 1P20GM156679-01
project_title: Fructose breakdown uniquely controls global metabolism
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8036
contact_pi_person_id: 10251386
contact_pi: SOFTIC, SAMIR
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:
ABSTRACT- PROJECT 4The overconsumption of sugar-sweetened beverages is a well-established risk factor for the development ofobesity insulin resistance and type 2 diabetes (T2D). A nutrient-induced decline in mitochondrial function isthought to be the underlying driver of these metabolic complications. Conversely an improvement inmitochondrial function could prevent the development of insulin resistance and progression to T2D. We showthat mice consuming 30% fructose (HFD+F) but not 30% glucose (HFD+G) drinks on an HFD developmitochondrial damage. These effects are dependent on fructose metabolism via ketohexokinase (KHK) the rate-limiting enzyme of fructose metabolism. Thus our preliminary experiments confirmed that KHK knockdownrestored mitochondrial fragmentation increased complex I and complex II protein abundance and enhancedCPT1 mediated fatty acid oxidation (FAO). These effects are in part mediated via acetylation a post-translational protein modification. Indeed acetylation of CPT1 at lysine (K) 508 lowered CPT1a protein anddecreased mitochondrial FAO. Similarly overexpression (OE) of KHK in cultured hepatocytes increased globalprotein acetylation while it decreased CPT1 protein. Lastly all HFDs that promote obesity contain sugar whilefat oxidation and weight loss are induced by sugar-fee (ketogenic) HFDs. Based on these novel findings wehypothesize that fructose metabolism via KHK drives global protein acetylation triggering ER stress andmitochondrial fragmentation while acetylation of mitochondrial complex I and II proteins directly impairs electrontransport chain activity and mitochondrial function. This hypothesis will be tested in three specific aims. Aim 1will elucidate if KHK mediated protein acetylation impairs mitochondrial remodeling. We will determine (i) if AAV-mediated OE of SIRT2 a major cytoplasmic deacetylase can lower acetylation and ER stress in HFD+F-fedmice; (ii) elucidate whether SIRT2 OE is sufficient to restore mitochondrial fission/fusion defects; and (iiiif the inverse correlation between KHK and SIRT2 proteins observed in our murine model persists in) probehumansubjects leveraging liver biopsies from our bariatric surgery biorepository. Aim 2 seeks to understand howfructose metabolism via KHK lowers mitochondrial function. This will involve (i) quantifying mitochondrialcomplex activity using Oroboros O2K Respirometer in HFD+F-fed mice treated with KHK or scramble siRNA; ( )iiusing immunoprecipitation and immunoblot techniques we will ascertain if complex I (NDUFA2) and complex II(SDHA) proteins are acetylated in KHK dependent manner; and ( ) utilizing CRISPR Cas9 we will introducegain/loss of function mutations in NDUFA2 and SDHB to elucidate the impact of acetylation mimicking (KQ)iiiand acetylation null (KR) mutations on their respective activities. Aim 3 will determine if a modest amount offructose within a solid HFD can affect the development of obesity and mitochondrial dysfunction. We will (i)measure mitochondrial function and hepatic acetylome in male and female mice on custom diets treated withKHK or control siRNA and (hepatic insulin sensitivity inii) perform hyperinsulinemic euglycemic clamps to determine if KHK KD can improvemice fed our custom diets.

project_terms:
Acetylation;Acute;Affect;Attention;Body Weight decreased;CRISPR/Cas technology;Centers of Research Excellence;Chronic;Citric Acid Cycle;Complex;Comprehension;Consumption;Custom;Cytoplasm;Data;Deacetylase;Defect;Deposition;Development;Diabetes prevention;Diet;Dietary Sugars;Electron Transport;Energy Intake;Enzymes;Exhibits;Fatty Liver;Fatty acid glycerol esters;Fees;Female;Fructose;Glucose;Glucose Clamp;Goals;Hepatic;Hepatocyte;High Fat Diet;Hyperinsulinism;Immunoprecipitation;Impairment;Insulin Resistance;Intake;Kentucky;Ketohexokinase;Knowledge;Link;Lipids;Liver;Lysine;Measures;Mediating;Metabolic;Metabolic dysfunction;Metabolism;Mitochondria;Molecular;Mus;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity Epidemic;Pathway interactions;Phosphorylation;Point Mutation;Post-Translational Protein Processing;Prevalence;Process;Production;Protein Acetylation;Proteins;Reactive Oxygen Species;Research;Risk Factors;Small Interfering RNA;Solid;Techniques;Testing;Universities;Western Blotting;bariatric surgery;biobank;burden of illness;dietary;endoplasmic reticulum stress;experimental study;fatty acid oxidation;fatty liver disease;fructose-1-phosphate;human subject;improved;insulin sensitivity;ketogentic;knock-down;lipid biosynthesis;liver biopsy;loss of function mutation;male;mitochondrial dysfunction;mouse model;novel;obesity development;obesogenic diet;overexpression;oxidation;prevent;repaired;sugar;sweetened beverage


application_id: 11018273
project_number: 1P20GM156679-01
project_title: Monoclonal antibodies as a therapeutic to prevent Type 2 Diabetes
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8034
contact_pi_person_id: 15354015
contact_pi: MISHRA, ILA
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:
ABSTRACT- PROJECT 2Type 2 diabetes (T2DM) impacts a staggering 462 million individuals globally with approximately 70% ofprediabetic patients transitioning to T2DM. Understanding the driving factors behind this progression is crucialnecessitating the development of therapeutics to prevent the onset of T2DM. Genetic studies conducted onindividuals with Neonatal Progeroid Syndrome (NPS) unveiled a novel hormone called asprosin characterizedby its glucogenic and orexigenic functions. Recent investigations have uncovered a third critical role forasprosinits detrimental impact on insulin secretion from pancreatic  cell line. Asprosin therefore emerges asa pivotal factor linking the three core components of prediabetes to the flourishing progression of T2DM:heightened hepatic glucose production compromised  cell function and increased energy accretion.We recently identified Protein Tyrosine Phosphatase type  (Ptprd) as the receptor that asprosin engages for itsorexigenic function. While Ptprd is also expressed in the  cells of humans and mice the functional relevance ofit is currently unknown. We hypothesize that asprosin directly affects  cell function via the Ptprd receptor andneutralizing asprosin/Ptprd signaling can prevent T2DM by acting as a single remedy for treatment of threemaladies:  cell dysfunction hyperphagia and hyperglycemia. While the effects of asprosin neutralization on cell function remains to be seen we have previously shown through a series of experiments in mice thatpharmacologic inhibition of asprosin using mouse anti-asprosin monoclonal antibodies (mAb) neutralizesasprosins glucogenic and orexigenic function. The mice treated with the anti-asprosin mAb display reducedhepatic glucose production and reduced appetite. This evidence paves the way for further development ofresearch grade mouse mAb towards a clinical grade fully human mAb an investigational new drug applicationand subsequent human trials for prevention of T2DM a defining physical ailment of our time.We will test the role of pancreatic  cells asprosin/Ptprd signaling in development of T2DM and explore thepotential of anti-asprosin monoclonal antibodies as a preventive therapeutic in the following 2 aims: (1)Determine the role of asprosin/Ptprd signaling in regulation of  cell function and (2) Asprosin neutralization asa therapeutic strategy for prevention of T2DM in mice. By the conclusion of this award period we anticipate notonly discovering a novel function of asprosin-Ptprd signaling but also having a leading fully-human anti-asprosinmonoclonal antibody with a well-established efficacy pharmacokinetics and toxicity profile. This achievement ispoised to significantly advance T2DM prevention drug development strategies.

project_terms:
Achievement;Acids;Adverse effects;Affect;Antibodies;Antibody Response;Antibody Therapy;Appetite Stimulants;Attenuated;Automobile Driving;Award;Beta Cell;C-Peptide;Cell Line;Cell Physiology;Cell Survival;Cells;Centers of Research Excellence;Chronic;Clinical;Clinical Research;Data;Desire for food;Development;Diabetes prevention;Diabetic mouse;Diet;Drug Kinetics;Failure;Fat-Restricted Diet;Functional disorder;Functional impairment;Genetic;Genetic study;Gluconeogenesis;Glucose;Goals;Hepatic;High Fat Diet;Hormones;Human;Human Anti-Mouse Antibody;Hyperglycemia;Hyperphagia;Immune system;Impairment;Individual;Inflammation;Insulin;Insulin Resistance;Investigation;Investigational New Drug Application;Kentucky;Knock-out;Life;Link;Liver;LoxP-flanked allele;Measures;Monoclonal Antibodies;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathogenicity;Pathologic;Patients;Peptides;Phage Display;Phase;Phenotype;Phosphorylation;Prediabetes syndrome;Prevention strategy;Prevention trial;Preventive;Process;Protein Tyrosine Phosphatase;Proteins;Publications;Regulation;Reporting;Research;Role;Series;Signal Pathway;Signal Transduction;Structure of beta Cell of islet;Testing;Therapeutic;Time;Toxic effect;United States National Institutes of Health;Universities;Wiedemann-Rautenstrauch syndrome;adipokines;analog;antagonist;antibody libraries;diabetic patient;drug development;experimental study;gain of function;glucose production;glucose tolerance;human monoclonal antibodies;impaired glucose tolerance;improved;in vivo;increased appetite;insulin secretion;insulin signaling;islet;loss of function;neutralizing monoclonal antibodies;novel;pharmacologic;prevent;preventive intervention;receptor;research and development;response;small molecule;spatiotemporal;stem;targeted treatment;therapeutic development


application_id: 11018271
project_number: 1P20GM156679-01
project_title: Diabetes Prevention Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8032
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP 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:
ABSTRACT- DIABETES PREVENTION PHENOTYPING COREThe Diabetes Prevention Phenotyping Core (DPPC) within the University of Kentucky Diabetes PreventionCOBRE (UK-DPC) is a specialized human and rodent experimental facility that will offer critical infrastructureand technical support to empower junior faculty members and the broader University of Kentucky diabetesprevention research community for project success. The DPPC will supply comprehensive design and supportfor diabetes prevention research projects by offering seasoned expertise in experimental design executionand results interpretation for addressing research questions in whole organisms and biological samples fromboth human subjects and rodents. The DPPC will also pilot and establish new techniques in diabetesprevention research to facilitate the adoption of new technologies. The DPPC will be unique on campusbecause of its commitment to offering services techniques and specialized equipment that are not currentlyavailable within the institution. These include dedicated personnel and space for human and rodent metabolicclamp measurements human tissue biopsies clinical coordination pancreatic islet isolation from rodents andtraining in basic methods of rodent metabolic characterization and clinical research concepts. Thesecapabilities will foster technical and conceptual independence of junior investigators and grow our base ofresearchers answering important questions in diabetes prevention through state-of-the art approaches coupledwith technological innovation.The support services offered by the DPPC are tailored to address the specific requirements of the proposedresearch project leaders (RPL) scientific projects and to offer support for expected projects of future RPL andpilot project leader (PPL) studies in diabetes prevention. These services have been strategically aligned toseamlessly integrate with and complement the research activities in UK-DPC laboratories and beyond. TheDPPC will also serve as a pivotal recruitment tool for junior faculty candidates and RPLs as the first cohort ofRPLs and PPLs transition to independent funding. The DPPC will encourage junior investigators to enhancetheir studies in pre-clinical models with complementary human subjects' research by lowering the barrier ofentry into translational research study design and methodologies. We expect the long-term impact of the DPPCwill be to substantially enhance the competitiveness of applications for extramural funding while establishingthe University of Kentucky as a technological leader in diabetes prevention research.

project_terms:
Address;Adoption;Animal Model;Biochemical;Biological;Biological Assay;Biopsy;Centers of Research Excellence;Clinical;Clinical Research;Closure by clamp;Collaborations;Communities;Complement;Comprehension;Consult;Consultations;Coupled;Data;Dedications;Development;Diabetes Mellitus;Diabetes prevention;Disease;Ensure;Equipment;Experimental Designs;Extramural Activities;Faculty;Fatty acid glycerol esters;Fostering;Foundations;Funding;Future;Glucose Clamp;Glucose tolerance test;Goals;Human;Human Resources;Human Subject Research;Infrastructure;Institution;Islets of Langerhans;Kentucky;Laboratories;Leadership;Lipids;Lipoproteins;Liver;Measurement;Mentorship;Metabolic;Methodology;Methods;Muscle;Outcome;Phase;Phenotype;Pilot Projects;Plasma;Pre-Clinical Model;Prevention Research;Procedures;Process;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Research Project Grants;Research Training;Resources;Rodent;Rodent Model;Sampling;Seasons;Services;Standardization;Technical Expertise;Techniques;Technology;Training;Translational Research;Translations;Universities;Validation;Whole Organism;base;clinical translation;cohort;design;empowerment;experimental study;human subject;human tissue;innovation;member;multidisciplinary;new technology;novel;preclinical study;primary outcome;recruit;success;technological innovation;tool;training opportunity


application_id: 11018270
project_number: 1P20GM156679-01
project_title: Diabetes Prevention Data Solutions Core
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8031
contact_pi_person_id: 10776717
contact_pi: ZHANG, XIAOHUA DOUGLAS
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:
ABSTRACT  DIABETES PREVENTION DATA SOLUTIONS CORE The Data Solutions Core (DSC) within the University of Kentucky Diabetes Prevention COBRE (UK-DPC) is positioned at the forefront of using advanced data analytics to enhance our understanding of diabetes risk factors optimize prevention strategies and contribute to the broader research goals of UK-DPC investigators University of Kentucky researchers and others in the COBRE community interested in diabetes prevention. The DSC team will consult on experimental design including statistical power considerations and randomization and apply sophisticated statistical techniques and machine learning algorithms to identify novel biomarkers and predictive indicators that inform the development of targeted interventions for diabetes prevention. Collaboration is central to the core's mission fostering interdisciplinary partnerships among researchers clinicians and data scientists at University of Kentucky. As such the core will serve as a hub for data sharing that will facilitate seamless communication and collaboration within UK-DPC. Privacy and ethical considerations are paramount and the DSC will adhere to rigorous standards to ensure participant confidentiality and data security. The proposed infrastructure is designed to be scalable accommodating the evolving needs of the diabetes prevention research community. The DSC will support the appropriate use of commercially available software novel adaptations of that software and the design of fundamentally new methods. This combination of strategies coupled with the expertise of the DSC team in outcomes particular to diabetes studies will fulfill project-specific needs and thus identify modifiable risk factors and effective preventive measures for diabetes. At the same time the team will be generating innovative tools for the global community in diabetes prevention data analysis. Integration with emerging technologies such as high- throughput RNA sequencing kinome antibody arrays and continuous monitoring tools will enhance data interpretation and provide a comprehensive understanding of the dynamic interplay between metabolism lifestyle factors and diabetes prevention. This analytical resource will be unique on campus due to the published expertise of the team in the outcomes and tool development unique to diabetes prevention studies. The DSC will be a catalyst for advancing rigorous and reproducible diabetes prevention research implementing the Data Management and Sharing Plan bridging gaps between disparate data sources fostering collaboration and driving innovation. By harnessing the power of data-driven insights the lasting impact of the DSC will be the identification of targeted and scalable preventive strategies ultimately mitigating the impact of diabetes on public health.

project_terms:
Animal Model;Antibodies;Automobile Driving;Bioinformatics;Biological Models;Centers of Research Excellence;Clinical Trials;Collaborations;Communication;Communities;Complement;Computer software;Computerized Medical Record;Computing Methodologies;Consult;Consultations;Continuous Glucose Monitor;Controlled Clinical Trials;Coupled;Data;Data Analyses;Data Analytics;Data Scientist;Data Security;Data Sources;Dedications;Development;Diabetes Mellitus;Diabetes prevention;Disparate;Doctor of Philosophy;Emerging Technologies;Ensure;Ethics;Experimental Designs;Faculty;Familiarity;Fostering;Foundations;Funding;Future;Goals;High-Throughput RNA Sequencing;Infrastructure;Intervention;Kentucky;Leadership;Liquid substance;Metabolism;Methods;Mission;Modeling;Outcome;Outcomes Research;Participant;Phase;Phosphoproteins;Pilot Projects;Positioning Attribute;Predictive Value;Prevention Research;Prevention strategy;Preventive measure;Privacy;Public Health;Publications;Publishing;Randomized;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Risk Factors;Scientist;Services;Techniques;Testing;Time;Training;Translating;Universities;Work;World Health;analytical method;animal data;catalyst;continuous monitoring;data hub;data management;data sharing;design;diabetes risk;improved;innovation;insight;interest;lifestyle factors;machine learning algorithm;member;method development;modifiable risk;novel;novel marker;skills;success;tool;tool development;transcriptome sequencing


application_id: 11018269
project_number: 1P20GM156679-01
project_title: University of Kentucky Diabetes Prevention COBRE (UK-DPC)
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8030
contact_pi_person_id: 7926891
contact_pi: FISHER, SIMON J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT- ADMINISTRATIVE COREThe rapid rise in prediabetes prevalence has put 33% of U.S. adults (96 million people) at very high risk ofdeveloping overt diabetes. Kentucky is a leading state for prediabetes: 38% of our residents are estimated tohave prediabetes. Five to 10% of adults with prediabetes are diagnosed with diabetes each year indicatingthat Kentucky is on the precipice of disturbing increases in our already high diabetes rate. These statisticshighlight the critical need for fundamentally new strategies that will delay or even halt the transition fromprediabetes to diabetes throughout Kentucky and our nation. The University of Kentucky proposes toestablish a Center of Biomedical Research Excellence (COBRE) focused on Diabetes Prevention (UK-DPC). This proposed transdisciplinary Center leverages support from institutional entities including theUniversity-wide Diabetes Research Priority Area the Barnstable Brown Diabetes Center and our establishedresearch base in diabetes and diabetes complications. The UK-DPC will be overseen by an Administrative(Admin) Core a unique resource intentionally structured to coordinate and facilitate diabetes preventionresearch at the University of Kentucky. The overall objective of the Admin Core is to support the developmentof skilled early-stage investigators and foster their independent research careers in diabetes prevention. Thisobjective will be met through the primary goal of intensive mentoring teams for junior faculty Research ProjectLeaders (RPLs) with diabetes prevention research interests. The Admin Core will also award theme-relatedpilot grants targeted to junior faculty with high potential as future RPLs. Finally the Admin Core will enrich alljunior investigators projects through organization and oversight of theme-specific infrastructure provided by theDiabetes Prevention Data Solutions and Diabetes Prevention Phenotyping Cores which will also be sharedacross the campus. To achieve these goals the Admin Core will (1) implement the overall plan of the UK-DPC;(2) coordinate the scientific cores projects advisory committees and mentoring activities; and (3) fulfill allevaluation responsibilities of the COBRE award with the ultimate outcome of developing a critical mass ofinvestigators who compete effectively for independent external research funding in diabetes prevention. Theimpact of the UK-DPC Admin Core will be a lasting infrastructure that supports scientific mentoring andleadership along with sustainable core facilities that facilitate diabetes prevention research. Together theseefforts will generate a cadre of junior faculty scientists with independent research careers in diabetesprevention and position the University Kentucky as a national leader in this research area.

project_terms:
18 year old;Adult;Advisory Committees;Area;Award;Centers of Research Excellence;Communication;Complications of Diabetes Mellitus;Core Facility;Data;Dedications;Development;Development Plans;Diabetes Mellitus;Diabetes prevention;Diagnosis;Disease;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Health;Infrastructure;Institution;Interdisciplinary Study;Kentucky;Leadership;Mentors;National Institute of General Medical Sciences;Outcome;Persons;Phenotype;Positioning Attribute;Prediabetes syndrome;Prevalence;Prevention Research;Research;Research Personnel;Research Priority;Research Project Grants;Resources;Risk;Scientist;Structure;Training;Universities;base;career;career development;faculty mentor;faculty research;high risk;interdisciplinary collaboration;interest;member;multidisciplinary;prevent;programs;recruit;skill acquisition;statistics;stem;supportive environment;synergism


application_id: 11018268
project_number: 1P20GM156679-01
project_title: University of Kentucky Diabetes Prevention COBRE
administering_ic: NIGMS
award_notice_date: 2025-08-30
opportunity_number: PAR-22-250
application_type: 1
activity_code: P20
ic: GM
serial_number: 156679
program_official: BASKIR, RUBIN SAM
project_start_date: 2025-09-01
project_end_date: 2030-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
contact_pi_person_id: 7926891
contact_pi: FISHER, SIMON J
other_pis: NIKOLAJCZYK, BARBARA
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:
ABSTRACT- OVERALLPrediabetes puts ~96 million US adults at very high risk of developing overt diabetes. Kentucky is a leading state for prediabetes with 38% of our residents affected by this harbinger disease compared to 33% prevalence of prediabetes throughout the U.S. Under current standards of care 5-10% of adults with prediabetes transition to diabetes annually indicating that Kentucky is on the brink of epidemic increases in our already high diabetes burden (13% of KY residents compared to 11% of U.S. resident have diabetes). These statistics highlight the critical need for developing fundamentally new strategies for diabetes prevention that will delay or stop the transition from prediabetes to diabetes throughout Kentucky and our nation. The University of Kentucky (UK) proposes to establish a Center of Biomedical Research Excellence (COBRE) focused on Diabetes Prevention (UK-DPC). The UK-DPC will leverage support from institutional entities including the UK-wide Diabetes Research Priority Area and the Barnstable Brown Diabetes Center to achieve two overarching goals: (1) to strengthen the foundation of diabetes prevention research by expanding and modernizing diabetes prevention-focused infrastructure across the campus; (2) to couple new infrastructurewith personalized mentor teams and a pilot grant program to develop a world-class cohort of junior researchers with expertise in cutting-edge concepts technologies and analyses of diabetes prevention strategies.Completion of these two objectives will position our junior researchers for success in securing independent NIH funding and in establishing diabetes prevention as an area of research excellence at UK. Both UK-DPC objectives are unique within the UK campus and complement the missions of existing entities that focus on equipment investments student training and diabetes complications symposia. To achieve our goals the UKDPC proposes to establish three new cores. The Diabetes Prevention Data Solutions Core led by diabetes investigators with expertise in biostatistics bioinformatics and machine learning will enhance rigor of experimental design and expand the interpretive value of outcomes in this thematic area. This core will also train diabetes prevention researchers in the skill of analytical consulting. The Diabetes Prevention PhenotypingCore will provide expertise in state-of-the-art human and animal phenotyping to characterize prediabetes in pre-clinical and clinical models. The Phenotyping Core will also spearhead the implementation of cutting-edge technologies in diabetes prevention research to lower the burden of introducing new methods to UK-DPCsupportedprojects. The Administrative Core will provide oversight organization outcome tracking and reporting. The impact of a cohesive UK-DPC is an increase in the number of junior faculty who are successful in addressing critical research questions in diabetes prevention. New infrastructure including core capabilities and the intentional fostering of a collaborative culture of mentor/junior faculty/core teams will complement existing strengths to establish UK as a national leader in diabetes prevention research.

project_terms:
Abbreviations;Address;Adult;Affect;Amputation;Animals;Appalachian Region;Area;Basic Science;Bioinformatics;Biometry;Blindness;CDC2 gene;Caring;Catchment Area;Cause of Death;Centers of Research Excellence;Clinical;Clinical Research;Clinical Sciences;Clinical and Translational Science Awards;Complement;Complications of Diabetes Mellitus;Country;Creativeness;Data;Dedications;Development;Diabetes Mellitus;Diabetes prevention;Discipline;Disease;Eligibility Determination;Ensure;Environment;Epidemic;Experimental Designs;Face;Faculty;Faculty Recruitment;Fostering;Foundations;Funding;Future;Goals;Grant;Health;Health Care;Health Sciences;Heart Diseases;Human;Individual;Infrastructure;Institution;Kentucky;Kidney Failure;Machine Learning;Medicine;Mentors;Metabolic syndrome;Methods;Mission;Modeling;Outcome;Phase;Phenotype;Positioning Attribute;Prediabetes syndrome;Prevalence;Prevention Research;Prevention strategy;Principal Investigator;Program Research Project Grants;Reporting;Reproducibility;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Seasons;Secure;Stroke;Teacher Professional Development;Technology;Training;United States National Institutes of Health;Universities;career development;cohort;college;diabetes risk;equipment acquisition;experience;high risk;improved;innovation;novel;peer coaching;pre-clinical;pre-clinical research;programs;response;skills;statistics;student training;success;symposium;synergism;tool

public_health_relevance:
PROJECT NARRATIVE - OVERALLThe University of Kentucky Diabetes Prevention Center of Biomedical Research Excellence (UK-DPC) will serveas an integrated and synergistic research support across multiple disciplines. The center will support juniorfaculty career development/mentoring and advance impactful pre-clinical and clinical research/tools. Cutting-edge research cores will stimulate transdisciplinary between project leaders and leading researchers from bothwithin and outside UK.


application_id: 11017837
project_number: 5R01DK124774-05
administering_ic: NIDDK
award_notice_date: 2025-02-25
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 124774
program_official: SILVA, CORINNE M
project_start_date: 2021-04-01
project_end_date: 2027-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-02-01
project_title:
Circadian Regulation of Metabolic Risk in Mice and Women: Role of Estrogen and Time-Restricted Feeding

project_abstract:
Abstract TextProject Summary Men and women differ in their susceptibility to obesity-related disorders and estrogen is a primary protective factor in women. Premenopausal women have a lower incidence of cardiometabolic disease compared to age- matched men. After menopause when circulating estrogens decline a womans risk for metabolic syndrome and heart disease increases dramatically. The circadian system is also a critical regulator of metabolism and obesity. Circadian rhythms are ~24-hour cycles of behavior and physiology that are generated by a network of molecular clocks located in nearly every tissue in the body. These clocks are entrained by cues such as food and light and are typically synchronized with environmental light-dark cycles. Studies of shift workers who have disordered exposure to food and light show that disruption of the circadian system increases risk of obesity heart disease metabolic syndrome and type 2 diabetes. Our overall objectives are to elucidate the estrogen-related circadian mechanisms that regulate metabolism and to test interventions that target the circadian system and benefit women who are estrogen deficient. Most studies to date have investigated circadian regulation of obesity and diabetes in males. High-fat diet feeding in male mice profoundly disrupts daily rhythms and this circadian disruption regulates diet-induced obesity. In contrast very little is known about the interplay between circadian rhythms and metabolism in females. The objective of this proposal is to investigate the interaction between estrogen signaling time-restricted feeding and circadian rhythms in regulating obesity and its comorbidities in mice and women. We will test the central hypothesis that daily metabolic rhythms are regulated by estrogen signaling and are therapeutic targets to treat obesity and prediabetes in postmenopausal women. In Aim 1 experiments will elucidate the molecular mechanisms by which estradiol protects daily metabolic rhythms from disruption by high-fat feeding in female mice. These mechanisms will be studied using global estrogen receptor (ER) knockout mice and by targeting ER expression in hepatocytes. Then we will determine whether time-restricted feeding inhibits diet-induced obesity insulin resistance and glucose intolerance in female ER knockout mice. In Aim 2 experiments will test the hypothesis that time-restricted feeding improves metabolic risk factors in postmenopausal women. Using a two-arm randomized controlled clinical trial design metabolically-unhealthy postmenopausal women will be randomized to either a 16-week time-restricted feeding intervention or no intervention control and we will measure metabolic and anthropometric outcomes and circadian rest-activity patterns by actigraphy with change in insulin sensitivity and body weight as primary outcomes. Together these experiments will elucidate the interplay between estrogens daily rhythms and interventions that target circadian rhythms to alleviate metabolic dysfunction.

project_terms:
Age;Agonist;Behavior;Biological;Body Weight;Body Weight Changes;Cardiometabolic Disease;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical;Clinical Trials Design;Complex;Control Groups;Cost of Illness;Cues;Darkness;Data;Diabetes Mellitus;Disease;ESR1 gene;Eating;Eating Behavior;Estradiol;Estrogen Receptor 2;Estrogen Receptors;Estrogen Therapy;Estrogen decline;Estrogen deficiency;Estrogens;Excision;Exposure to;Fasting;Fatty acid glycerol esters;Feeding behaviors;Female;Food;Functional disorder;GTP-Binding Proteins;Glucose Intolerance;Health;Heart Diseases;Hepatocyte;High Fat Diet;Hour;Incidence;Insulin Resistance;Intervention;Knockout Mice;Life;Light;Liver;Malignant Neoplasms;Measures;Metabolic;Metabolic dysfunction;Metabolic syndrome;Metabolism;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Ovariectomy;Overweight;Pattern;Phase;Physiology;Postmenopause;Pre-Clinical Model;Prediabetes syndrome;Predisposition;Premenopause;Randomized;Randomized Controlled Clinical Trials;Research;Resistance;Rest;Risk;Risk Factors;Risk Reduction;Role;Sex Differences;Signal Transduction;Stroke;System;Testing;Text;Therapeutic;Time-restricted feeding;Tissues;United States;Woman;actigraphy;arm;cancer risk;cardiometabolism;circadian;circadian biology;circadian pacemaker;circadian regulation;comorbidity;diet-induced obesity;estrophilin;experimental study;feeding;heart disease risk;high risk;improved;insulin sensitivity;male;men;molecular clock;mouse model;obesity risk;primary outcome;protective factors;receptor expression;therapeutic target;time use

public_health_relevance:
Project NarrativePostmenopausal women who have very low levels of circulating estrogens are at high risk of life-threatening obesity-related disorders such as metabolic syndrome. Many studies have shown that estrogen is the factor that protects women from metabolic risk. This project will investigate new directions in estrogen and circadian biology research in mouse models and therapeutic feeding behaviors for at-risk postmenopausal women.


application_id: 11017836
project_number: 5R01AG070952-03
project_title: Dynamic GABA and Glutamate Neurotransmission in Alzheimers Disease and Aging
administering_ic: NIA
award_notice_date: 2025-03-04
opportunity_number: PAR-19-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 070952
program_official: DIBATTISTA, AMANDA
project_start_date: 2021-02-15
project_end_date: 2027-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTAlzheimers disease (AD) progression and normal aging are complex and often heterogeneous processesinvolving functional changes to neuronal and glial elements that are not just related to neuronal cell loss [1-4143]. Prior in vitro and in vivo data support that aberrant regulation of glutamate neuronal systems can be acontributor to neuronal degeneration in aging and likely a contributor to the age-dependent development of AD[1 4 6-8]. We think that because there is a dearth of treatment and monitoring options our study will help in thefuture development of therapeutics and non-invasive spectroscopic monitoring techniques for AD. Recently wehave successfully adapted our enzyme-based microelectrode arrays (MEAs) which are designed to preciselymeasure tonic and phasic neurotransmitter release in discrete brain structures in awake animals for use in agedrodents and AD mouse models [54-56 79 112]. A major knowledge gap in AD and aging involves changes inthe excitatory/inhibitory balance between glutamate (Glu) and GABA release and regulation [9-15]. We believethat the use of our new recording technology will improve our understanding of the glutamate/GABA interplay inan AD model and in normal aging. Our recent studies using this superior technology now allows themeasurements of tonic and phasic glutamate levels found that rats >18 months of age have normal or elevatedbasal Glu levels compared to younger rats. Thus some animals have elevated glutamate while others do not.As outlined in NIH Notice NOT-AG-18-051 & related announcement PAR-19-070 issues surrounding age andits role in dementia are critical in furthering our understanding of the metabolic and pathological changes thataffect signaling in neuronal circuits and networks. We will use young and aged normal and the APPNLh/NLh xPS1P264L/P264L knock-in mouse (APP/PS1 KI) that does not overexpress APP or PS1 or use artificial promotersmaking it an ideal system for the study of how aging affects the development of AD-related neuropathology [86-90]. We will use our novel methods to simultaneously record GABA and glutamate signaling in either the CA1region of the hippocampus or Frontal Cortex. We will first behaviorally characterize all animals so that we candetermine potential correlations between the behavioral performance of mice and glutamate and GABA releaseand/or regulation in the hippocampus (Morris water maze test) and frontal cortex (spatial memory variant ofMorris water maze test) [115] and performed as per [116]. Finally mice that are studied will undergo apathological examination to evaluate neurodegeneration by evaluating reactive gliosis may be present by lookingat Iba1 and GFAP. Collectively these studies will allow us to compare the effects of normal aging in male andfemale to the effects seen from a mouse model of AD on the balance of glutamate and GABA signaling and itsrelationship(s) to cognitive function in both male and female animals towards the development of noveltherapeutics to possibly treat the development and progression of AD.

project_terms:
Address;Affect;Age;Age Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Animals;Behavioral;Brain;Cell Death;Complex;Data;Dementia;Development;Disease Progression;Elements;Enzymes;Equilibrium;FDA approved;Female;Fostering;Future;Glial Fibrillary Acidic Protein;Gliosis;Glutamates;Goals;Hippocampus;Impaired cognition;Impairment;In Vitro;Individual;Knock-in Mouse;Knowledge;Measurement;Measures;Memantine;Memory;Metabolic;Methodology;Methods;Microelectrodes;Monitor;Mus;Mutation;Nerve Degeneration;Neurons;Noise;Pathologic;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Phase;Population;Prefrontal Cortex;Process;Property;Rattus;Regulation;Role;Signal Transduction;Structure;System;Techniques;Technology;Testing;Time;United States National Institutes of Health;Variant;age related;age related changes;age-associated memory impairment;aged;aged rodent;awake;cognitive function;design;excitotoxicity;familial Alzheimer disease;frontal lobe;gamma-Aminobutyric Acid;glutamatergic signaling;improved;in vivo;male;morris water maze;mouse model;neuron loss;neuronal circuitry;neuropathology;neurotransmission;neurotransmitter release;new therapeutic target;normal aging;novel;novel therapeutics;old mice;promoter;spatial memory;therapeutic development

public_health_relevance:
PROJECTIVE NARRATIVERecent data support that changes in the functional properties of glutamate and GABA neurotransmission in thehippocampus and frontal cortex in the CNS contribute to Alzheimers disease (AD) and age-related declines incognition and memory. A further understanding of the balance between glutamate levels and glutamate andGABA neurotransmission in vivo are needed from the frontal cortex and hippocampus in AD models and innormal aging. These studies will aid in the identification of targets and consistent comparable non-invasivespectroscopic monitoring techniques for existing FDA approved drugs as well as possibly new targets for drugsto treat AD to address the growing population with dementia.


application_id: 11017715
project_number: 5R01AI172873-03
project_title: Neutrophil Heterogeneity and Immunopathogenesis of COVID-19 ARDS
administering_ic: NIAID
award_notice_date: 2024-12-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 172873
program_official: JOFFE, AARON MICHAEL
project_start_date: 2023-01-01
project_end_date: 2027-12-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: HUANG, JIAPENG ;URIARTE, SILVIA M
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:
Project SummaryCoronavirus disease 2019 (COVID-19) is a potentially life-threatening disease caused by the novel viralpathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the 10%-20% of COVID-19patients hospitalized approximately 1/3 develop acute respiratory distress syndrome (ARDS). COVID-19-induced ARDS results from a combination of virally induced lung injury and the rapid influx of immune cells thatrelease inflammatory mediators leading to a hyper-activated state known as cytokine storm. Understanding thepathophysiology of COVID-19 ARDS is critical to finding effective therapeutic interventions. Accumulatingevidence indicates critical roles for neutrophils in both ARDS and immunothrombosis in COVID-19. Multi-omicsstudies identified dramatic neutrophil heterogeneity in COVID-19 including emergence of a large number oflow density neutrophils (LDN). We reported a novel population of LDN present in both the circulation and lungsof severe COVID-19 patients which expresses intermediate levels of CD16 (CD16Int LDN). CD16Int LDNspontaneously form neutrophil extracellular traps (NETs) activate platelets in vivo and in vitro and haveheightened degranulation. Our preliminary data show that LDN subsets from severe COVID-19 patients arefunctionally distinct from mature normal density neutrophils (NDN). Based on these findings we postulatethat differential functional responses of heterogeneous neutrophil populations collaborate to inducesystemic and pulmonary inflammation leading to ARDS in COVID-19 patients. Three specific Aims areproposed to further dissect the underlying mechanisms. Aim 1 will comprehensively characterize neutrophilsubsets from severe/critical COVID-19 patients using proteomics and transcriptomics approaches. Theinformation gained from those studies will be used to refine our CyTOF antibody panel and prospectivelymeasure dynamic changes of neutrophil subsets over the disease course in COVID-19 patients. Aim 2 willdetermine neutrophil subset functional changes during disease progression and their contributions todysregulated inflammatory response and coagulopathy in severe/critical COVID-19 patients. Neutrophildegranulation NET formation phagocytosis chemotaxis T cell suppressive activity and cytokine/chemokinerelease will be examined. We will also determine if LDN subsets and NDN or their derived products promotecoagulopathy in COVID-19 patients. Aim 3 will determine the relative contributions of neutrophil host defensesystems to development of acute lung injury. We will also use a hACE2 Tg mouse model to determine theroles of neutrophil respiratory burst granule exocytosis and NET formation to SARS-CoV-2-induced acutelung inflammation. Successful completion of this proposal will provide novel insights into COVID-19-inducedARDS pathophysiology by defining the functional roles of different neutrophil subsets and by establishingwhich host defense systems of neutrophils as a therapeutic target for inhibiting inflammatory lung injury andimmunothrombosis in COVID-19.

project_terms:
2019-nCoV;Acute;Acute Lung Injury;Acute Respiratory Distress Syndrome;Age;Antibodies;Bilateral;Blood;Blood Coagulation Disorders;Blood Platelets;Bronchoalveolar Lavage Fluid;COVID-19;COVID-19 patient;COVID-19 vaccine;COVID-19/ARDS;Cells;Chemotaxis;Circulation;Clinical;Collaborations;Cytometry;Cytoplasmic Granules;Data;Development;Disease;Disease Progression;Economics;Exocytosis;FCGR3B gene;Fibrin fragment D;Functional disorder;Gene Expression;Hemorrhage;Heterogeneity;Hospitalization;Host Defense;Immune;In Vitro;Individual;Inflammation Mediators;Inflammatory;Inflammatory Response;Intensive Care Units;Interleukin-6;Life;Lung;Lymphocyte;Measures;Myeloid-derived suppressor cells;Neutrophil Infiltration;Outcome;Patient Transfer;Patients;Pattern;Personal Satisfaction;Phagocytosis;Plasma;Platelet Activation;Pneumonia;Population;Proteome;Proteomics;Psyche structure;Pulmonary Inflammation;Reactive Oxygen Species;Reporting;Respiratory Burst;Role;Severity of illness;Surface;System;T-Lymphocyte;TNF gene;Therapeutic Intervention;Variant;Viral;antimicrobial;chemokine;cytokine;cytokine release syndrome;density;effective therapy;emerging virus;extracellular;immune activation;immunothrombosis;in vivo;inhibitor;insight;lung injury;mouse model;multiple omics;neutrophil;novel;novel marker;novel therapeutic intervention;pandemic disease;pathogenic virus;pharmacologic;post SARS-CoV-2 infection;prospective;response;severe COVID-19;sex;systemic inflammatory response;therapeutic target;therapeutically effective;tissue injury;transcriptome sequencing;transcriptomic profiling;transcriptomics

public_health_relevance:
Project NarrativeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has resulted inongoing pandemic tragic loss of life and dire economic consequences. COVID-19 patients with severeand critical disease also develop pulmonary inflammation and abnormal bleeding problems. We proposeto study the mechanisms underlying these problems and develop a novel therapeutic approach; this willhelp us achieve rapid progress toward overcoming the challenges of COVID-19.


application_id: 11017385
project_number: 2P40OD019794-11
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2025-02-24
opportunity_number: RFA-OD-23-001
application_type: 2
activity_code: P40
ic: OD
serial_number: 019794
project_start_date: 2015-03-01
project_end_date: 2030-02-28
study_section: Special Emphasis Panel[ZRG1 BTC-Y (55)]
subproject_number: 7888
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
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:
APPLIED RESEARCH COMPONENT - PROJECT SUMMARYThis component addresses the significance and need to generate new assays and approaches for diseasemonitoring within the AGSC and beyond and the need to generate and centralize information for diagnosingand treating axolotl diseases. Next generation 16S rRNA sequencing will be performed to increase breadth ofpathogen monitoring and generate baseline microbial data in support of microbiome research both of whichwill better ensure the health and reproducibility of AGSC axolotl lines. Additionally an axolotl disease manualwill be developed to provide a reference that axolotl labs can use to monitor pathogens and diagnose commonaxolotl diseases. The manual will include protocols assays and treatments curated from the literature anddeveloped in house. Accomplishment of this sub aim will provide an essential resource for characterizinglesions in diseased and genetically modified axolotls that serve as models of human disease.

project_terms:
16S ribosomal RNA sequencing;Address;Ambystoma;Amphibia;Applied Research;Autopsy;Biological Assay;Clinical;Data;Diagnosis;Disasters;Disease;Ensure;Gene Modified;Genetic;Health;Lesion;Life;Literature;Manuals;Methods;Monitor;Pathogen detection;Pathogenicity;Protocols documentation;Publishing;Quarantine;Reproducibility;Research Personnel;Resources;Review Literature;Source;Testing;Vendor;Veterinarians;Viral;animal facility;common treatment;disease diagnosis;human disease;human model;microbial;microbiome;microbiome research;next generation;pathogen;peer;sex;web site


application_id: 11017384
project_number: 2P40OD019794-11
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2025-02-24
opportunity_number: RFA-OD-23-001
application_type: 2
activity_code: P40
ic: OD
serial_number: 019794
project_start_date: 2015-03-01
project_end_date: 2030-02-28
study_section: Special Emphasis Panel[ZRG1 BTC-Y (55)]
subproject_number: 7887
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
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:
CURATION AND INFORMATICS COMPONENT - PROJECT SUMMARYThis component introduces the need to improve AGSC data management practices and efficiencies. AGSCoperations will be made more efficient under a new data management plan that will enable multiple types ofdata to be recorded and retrieved electronically and remotely. A new website will be created to provide curatedinformation about AGSC stocks protocols for standardized husbandry procedures protocols for pathogenmonitoring developmental and life history information to aid experimental planning execution and reportingprotocols for laboratory educational activities and information to identify the best axolotl models for humandisease. Web content will be redundantly linked to facilitate searching within the website and externally linkedto outside gene orthology gene ontology disease animal model and literature databases. The AGSC websitewill use surveys to obtain customer feedback about AGSC products and services and a discussion forum willfacilitate community sharing of knowledge and data. Through these mechanisms the new website will increasethe visibility of axolotl stocks and establish the AGSC as a critical source of information for advancing axolotlresearch and educational efforts.

project_terms:
Address;Adopted;Ambystoma;Animal Model;Animals;Biological;Communities;Computer software;Data;Databases;Development;Disease;Education;Educational Activities;Feedback;Genes;Genetic;Genetic Models;Home Page;Informatics;Information Resources;Internet;Knowledge;Laboratories;Link;Literature;Modeling;Monitor;Ontology;Positioning Attribute;Practice Management;Procedures;Protocols documentation;PubMed;Records;Reporting;Research;Resources;Services;Source;Standardization;Surveys;Time;Xenopus;animal resource;data management;data sharing;experience;handheld mobile device;human disease;improved;interest;life history;marine;model organism;multiple data types;operation;pathogen;web site;wireless


application_id: 11017383
project_number: 2P40OD019794-11
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2025-02-24
opportunity_number: RFA-OD-23-001
application_type: 2
activity_code: P40
ic: OD
serial_number: 019794
project_start_date: 2015-03-01
project_end_date: 2030-02-28
study_section: Special Emphasis Panel[ZRG1 BTC-Y (55)]
subproject_number: 7886
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
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:
RESOURCE COMPONENT - PROJECT SUMMARYThis component provides details about AGSC operations. During the 2025-2030 funding period the AGSC willcontinue to generate and import high quality axolotl stocks and innovate new husbandry methods servicesand protocols. The AGSC will offer a formal workshop to provide training in axolotl husbandry and embryomicroinjection at UK and AGSC staff will develop and present educational activities in local K-12 schools.A financial plan is described that will ensure long-term sustainability of axolotl stocks and move the AGSCeach year towards greater self-sufficiency. Also plans are presented to share methods protocols and data.The AGSC is a proven axolotl resource provider and will continue to ensure distribution and long-termsustainability of axolotl stocks to NIH investigators.

project_terms:
Adolescent;Adult;Ambystoma;Animals;Awareness;Biological Assay;Biomedical Research;Breeding;Collection;Communication;Communities;Data;Data Management Resources;Development;Disease;Education;Educational Activities;Educational workshop;Embryo;Ensure;Funding;Genetic;Laboratories;Methods;Microinjections;Monitor;Newsletter;Population;Protocols documentation;Provider;Publications;Reporting;Reproducibility;Research;Research Personnel;Resources;Schools;Science;Series;Services;System;Training;United States National Institutes of Health;Work;cost;genotypic sex;improved;innovation;meetings;operation;outreach;pathogen;timeline;web site


application_id: 11017382
project_number: 2P40OD019794-11
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2025-02-24
opportunity_number: RFA-OD-23-001
application_type: 2
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2030-02-28
study_section: Special Emphasis Panel[ZRG1 BTC-Y (55)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
OVERALL COMPONENT - PROJECT SUMMARYThe Ambystoma Genetic Stock Center (AGSC) at the University of Kentucky (UK) is the only federally fundedresource center that distributes laboratory axolotls (Ambystoma mexicanum) a salamander that provides livingmaterials in support of biomedical research nationally and internationally. Most notably axolotls are uniqueamong vertebrates in being able to regenerate numerous tissues and body parts including limbs and brain.Since 2020 31 different axolotl-associated projects have been awarded by NIH with support coming frommultiple institutes (NICHD NHLBI NIDDK NIGMS NINDS OD NEI and NCI). NIH support is catalyzingadvances in biomedical research through its support of the axolotl and the AGSC increasing the likelihood thatinvestigators will use axolotl models in the future.During the 2025-2030 funding period the AGSC will continue to generate and import high quality axolotlstocks and innovate new husbandry methods services and protocols. AGSC operations will be made moreefficient under a new data management plan that will enable multiple types of data to be recorded andretrieved electronically and remotely. A new website will be created to provide curated information about AGSCstocks protocols for standardized husbandry procedures protocols for pathogen monitoring developmentaland life history information to aid experimental planning execution and reporting protocols for laboratoryeducational activities and information to identify the best axolotl models for human disease. Web content willbe redundantly linked to facilitate searching within the website and externally linked to outside gene orthologygene ontology disease animal model and literature databases. The AGSC website will use surveys to obtaincustomer feedback about AGSC products and services and a discussion forum will facilitate communitysharing of knowledge and data. Through these mechanisms the new website will increase the visibility ofaxolotl stocks and establish the AGSC as a critical source of information for advancing axolotl research andeducational efforts. In regards to outreach the AGSC will offer a formal workshop to provide training in axolotlhusbandry and embryo microinjection at UK and AGSC staff will develop and present educational activities inlocal K-12 schools. In regards to applied research 16S rRNA sequencing will be performed to increasebreadth of pathogen monitoring and generate baseline microbial data in support of microbiome research bothof which will better ensure the health and reproducibility of AGSC axolotl lines. Finally an axolotl diseasemanual will be developed to provide a reference that axolotl labs can use to monitor pathogens and diagnosecommon axolotl diseases. The manual will include protocols assays and treatments curated from theliterature and developed in house. Overall the project will increase the AGSCs impact in biomedical researchand education ensuring the distribution and long-term sustainability of axolotl resources to NIH-fundedinvestigators.

project_terms:
16S ribosomal RNA sequencing;Address;Adolescent;Adult;Aging;Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Animals;Applied Research;Autopsy;Award;Awareness;Biological Assay;Biomedical Research;Body part;Brain;Breeding;Clinical;Communication;Communities;Data;Data Management Resources;Databases;Development;Diagnosis;Disasters;Disease;Education;Educational Activities;Educational workshop;Embryo;Embryonic Development;Ensure;Feedback;Funding;Future;Gene Modified;Genes;Genetic;Genetic Models;Health;Home Page;Human;Information Resources;International;Internet;Kentucky;Knowledge;Laboratories;Lesion;Life;Limb structure;Link;Literature;Manuals;Methods;Microinjections;Modeling;Monitor;National Heart Lung and Blood Institute;National Institute of Child Health and Human Development;National Institute of Diabetes and Digestive and Kidney Diseases;National Institute of General Medical Sciences;National Institute of Neurological Disorders and Stroke;Natural regeneration;Ontology;Pathogen detection;Pathogenicity;Population;Postembryonic;Procedures;Protocols documentation;PubMed;Publishing;Quarantine;Reporting;Reproducibility;Research;Research Personnel;Resources;Review Literature;Salamander;Schools;Science;Services;Source;Standardization;Surveys;System;Testing;Time;Tissues;Training;Trauma;United States National Institutes of Health;Universities;Vendor;Vertebrates;Veterinarians;Viral;animal facility;animal resource;clinically significant;common treatment;data management;disease diagnosis;experience;human disease;human model;improved;innovation;interest;life history;meetings;microbial;microbiome;microbiome research;model organism;multiple data types;operation;organ regeneration;outreach;pathogen;peer;sex;tissue regeneration;tissue repair;web site

public_health_relevance:
PROJECT NARRATIVEThis project seeks support for the Ambystoma Genetic Stock Center an animal resourcecenter that uniquely supplies axolotl salamanders for studies of organ regeneration tissuerepair and post-embryonic development. Understanding the cellular and genetic mechanismsthat axolotls use to regenerate tissues could have clinical significance for treating humantrauma disease and aging.


application_id: 11016710
project_number: 1C06OD037831-01
administering_ic: OD
award_notice_date: 2024-09-13
opportunity_number: PAR-23-306
application_type: 1
activity_code: C06
ic: OD
serial_number: 037831
program_official: CHEN, YONG
project_start_date: 2024-09-15
project_end_date: 2028-08-31
study_section: Scientific and Technical Review Board on Biomedical and Behavioral Research Facilities[STOD]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-15
project_title:
University of Kentucky Center for Clinical and Translational Science Enterprise Data Center Expansion

project_abstract:
PROJECT SUMMARY/ABSTRACTThe University of Kentucky (UK) proposes to significantly advance its secure research data infrastructurecapacity within the Enterprise Data Center (EDC) an integral component of the Kentucky Center for Clinicaland Translational Science (CCTS). The CCTS currently supports more than $34.1 million in annual direct costgrant funding to support biomedical and population health projects with significant needs for secure researchdata infrastructure including HIPAA-compliant data management and storage. Unprecedented advances inresearch computing and data capabilities are revolutionizing biomedical research and transforming discoveriesin these research domains. New computationally and data-driven research approaches such as artificialintelligence machine learning omics data mining and analytics as well as computationally based simulationsand modeling are enabling bold new directions in biomedical research and drawing in entirely new biomedicalinvestigators whose studies are increasingly computationally based. Critical research data needs at UK residein prominent NIH-supported centers including the Markey Cancer Center the Alzheimers Disease ResearchCenter within the Sanders-Brown Center on Aging and the Center on Drug and Alcohol Research as well aswithin a wide array of individual NIH-funded researchers. Burgeoning needs have placed critical demands onthe EDC to accommodate increased numbers of users greater amounts of high-speed data storage andgreater demand for high performance computing infrastructure. The proposed facilities expansion will expandthe 352 sq. ft. EDC UKs only HIPAA-secure data center (HITRUST Certification) by merging two vacantadjacent rooms to create a secure 1155 sq. ft. data center and ADA-compliant entry corridor and providerequisite cooling electrical distribution and communication infrastructure to support the purchase andinstallation of 28 additional racks of high-density high-performance computing equipment through universityresources. The goal of the proposed 1231 sq. ft. facilities renovation is to address a critical shortage of securebiomedical research data center space at UK by more than tripling EDC capacity to accommodateexponentially rising biomedical research volume and associated data infrastructure. The proposed expansionis consistent with overarching UK priorities to support rapid advances in clinical and translation discoverythrough enhanced capacity for secure HIPAA-compliant data infrastructure and to continue to meet rapidlyexpanding demand presented by NIH-funded researchers involved in data-intensive biomedical and populationhealth research. The proposed facilities expansion project is closely aligned with NIH priorities for datamanagement and sharing and embeds clear national impact by meeting those priorities.

project_terms:
Address;Aging;Alzheimer's Disease;Artificial Intelligence;Biomedical Research;Cancer Center;Certification;Clinical;Clinical Sciences;Communication;Data;Data Analytics;Data Storage and Retrieval;Direct Costs;Equipment;Funding;Goals;Grant;Health Insurance Portability and Accountability Act;High Performance Computing;Individual;Infrastructure;Kentucky;Machine Learning;Pharmaceutical Preparations;Research;Research Personnel;Secure;Speed;Translational Research;Translations;United States National Institutes of Health;Universities;University resources;alcohol research;clinical center;data centers;data infrastructure;data management;data mining;data sharing;density;facility renovation;meetings;models and simulation;population health;square foot


application_id: 11015770
project_number: 5F31DA057812-02
administering_ic: NIDA
award_notice_date: 2024-12-13
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: DA
serial_number: 057812
program_official: FALCON-MORALES, EDGARDO
project_start_date: 2024-01-12
project_end_date: 2025-12-20
study_section: Special Emphasis Panel[ZRG1-F03B-L(20)L]
contact_pi_person_id: 78480172
contact_pi: PRANTZALOS, EMILY
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: 2025-01-12
project_title:
Role of Dynamic Signaling of NRG3-ErbB4 in the Prefrontal Cortex in Mediating Nicotine Withdrawal Phenotypes

project_abstract:
PROJECT SUMMARY/ABSTRACTWhile several pharmacotherapies are currently available for nicotine dependence smoking cessation is only 7.5%successful. Recent advances in the study of genetic contributions to nicotine dependence represent a promising avenuefor the development of novel smoking cessation therapies. Our lab has shown that variations in the gene for Neuregulin3 (NRG3) and its cognate receptor ErbB4 are linked to smoking cessation outcomes and may be responsible in part foraffective nicotine withdrawal (WD) phenotypes. Therefore the overarching goal of this fellowship-training proposal is tosystematically investigate the region-specific functional role of the Neuregulin Signaling Pathway during nicotine use andWD. To accomplish this we are evaluating two central aims: 1) Determine the PFC-specific contributions of ErbB4 tonicotine WD related behavioral phenotypes and the mechanism by which they occur and 2) Characterize expressionpatterns of NRG3-ErbB4 signaling within the prefrontal cortex and identify the molecular alterations induced duringchronic nicotine and WD. Our approach is significant because it utilizes a novel genetic mouse model of nicotinedependence in a multidimensional approach to provide insight into the underlying mechanisms that define the NRG3signaling pathway and its role in nicotine dependence. Research undertaken in this fellowship will be performed at theUniversity of Kentucky College of Pharmacy under the purview of the Graduate Program in Pharmaceutical Sciences amultidisciplinary program designed to prepare motivated individuals for academic industrial or government careers inpharmaceutical and biomedical research. My mentor Dr. Jill Turner has helped develop a training plan for my graduatecareer that consists of professional development and didactic training in techniques that will develop my understandingand expertise in the field. The outlined training plan will help me to develop expertise in the field ofneuropharmacology/genetics of addiction expand upon my experimental techniques refine my experimental design anddata analysis skills and continue to work on my presentation and networking skills. The training gained during my graduatecareer under the guidance of Dr. Turner will provide me with a broad exposure to the neurobiology of substance usedisorders; in addition to my research work these experiences will help me in my future goals of developing novel precisiontherapeutics for nicotine dependence and other co-morbid psychiatric disorders. The combination of my dedicatedmentor that will assist in the development and progression of my training with innovative research venues to conduct andshare my research will warrant my success as a well-trained graduate student.

project_terms:
Acoustics;Affective;Anxiety;Behavior;Behavioral;Biomedical Research;Chronic;Darkness;Data Analyses;Dedications;Development;Dimensions;Drosophila acetylcholine receptor alpha-subunit;EGF gene;ErbB4 gene;Exhibits;Experimental Designs;Exposure to;Fellowship;Functional disorder;Future;Genes;Genetic;Genetic Transcription;Genetic study;Goals;Government;Hippocampus;Individual;Industrialization;Injections;Interruption;Kentucky;Knowledge;Ligands;Light;Link;Location;Mediating;Mental disorders;Mentors;Molecular;Mus;NRG3 gene;Neuregulins;Neurobiology;Neuropharmacology;Nicotine;Nicotine Dependence;Nicotine Withdrawal;Nicotinic Receptors;Outcome;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Pharmacy facility;Phenotype;Phosphotransferases;Precision therapeutics;Prefrontal Cortex;Receptor Protein-Tyrosine Kinases;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Science;Signal Pathway;Signal Transduction;Site;Smoker;Startle Reaction;Substance Use Disorder;Techniques;Testing;Therapeutic;Time;Tobacco smoking behavior;Training;Universities;Variant;Western Blotting;Withdrawal;Work;addiction;animal tissue;anxiety-like behavior;behavioral outcome;behavioral phenotyping;behavioral response;career;college;design;exhibitions;experience;experimental study;extracellular;field study;graduate student;improved;innovation;insight;interdisciplinary approach;kinase inhibitor;knock-down;mRNA Expression;member;mouse model;multidisciplinary;neural;neuroadaptation;new therapeutic target;nicotine treatment;nicotine use;novel;pharmacologic;preventable death;programs;protein expression;psychiatric comorbidity;receptor;skills;smoking cessation;success

public_health_relevance:
PROJECT NARRATIVETobacco smoking is a leading cause of preventable death in the US though most smokers who would liketo quit are unable to do so with current available therapeutics. The molecular mechanisms underlying thefailed successes of smokers attempting to quit remain a critical gap in our knowledge. This proposal aimsto elucidate the roles of a novel signaling pathway (NRG3-ErbB4) during nicotine use and withdrawal inhopes of developing better therapeutics for nicotine dependence by specifically targeting affectivedisruption thereby improving smoking cessation and outcomes.


application_id: 11014059
project_number: 5R01ES027778-07
project_title: Mechanism for arsenic induced carcinogenesis
administering_ic: NIEHS
award_notice_date: 2024-12-05
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: ES
serial_number: 027778
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-08-01
project_end_date: 2028-11-30
study_section: Environmental Determinants of Disease Study Section [EDD]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Arsenic exposure is a worldwide environmental health problem causing multiple chronic diseases includingcancer. Cancer results from mutations in and epigenetic modifications of oncogenes and tumor suppressorgenes. The molecular mechanisms driving arsenic (iAs)-induced carcinogenesis are likely a complex interplayof multiple factors contributing to yet unidentified genetic changes responsible for tumorigenesis. Onemechanism is the epigenetic effect of miRNA dysregulation. iAs-exposure induces chromosomal instability(CIN) and CIN contributes to carcinogenesis. We focused on mechanism and effects of overexpression of hsa-miR-186 on CIN in the previous funding period. miR-186 is an intronic miRNA and is overexpressed in iAs-induced squamous cell carcinoma (SCC). The parent gene encodes an alternative mRNA splicing factor thatis disrupted by iAs-exposure. miR-186 overexpression in human keratinocytes suppresses two mitoticregulators and gives rise to aneuploidy a hallmark of cancer. This investigation led to establishment of a newhuman keratinocyte model for iAs-induced carcinogenesis using Ker-CT cells that is more amenable tokaryotype analysis necessary to analyze CIN for leads into carcinogenic mutations. We identified 5 additionalmiRNAs that are overexpressed in iAs-induced SCC and also in human keratinocytes (HaCaT) chronicallyexposed to low dose iAs. These miRNAs are predicted to target multiple proteins also targeted by knownoncogenic miRNAs. This continuation application focuses on miRNAs dysregulated in iAs-induced SCC andproposes to identify additional miR-186 targets contributing to CIN and to characterize the impact of theadditional 5 overexpressed miRNAs on carcinogenesis. The hypothesis underlying these studies is thatdysregulation of RNA metabolism contributes to iAs-induced carcinogenesis by modulating gene expressionand inducing CIN. The specific aims are: 1) Determine the mechanism of hsa-miR-186 overexpressioninducing aneuploidy and CIN in new Ker-CT model; 2) Characterize the new Ker-CT model of iAs-induced skincarcinogenesis; 3) Investigate role in cellular transformation of miRNAs common to SCC and arsenite-exposedHaCaT cells. Mutations in cancer genes in cells transformed by miR-186 overexpression and arsenicexposure will be characterized providing information to fill a knowledge gap. Demonstrating that these miRNAsoverexpressed in human iAs-induced SCC share targets with known oncogenic miRNAs will establish anepigenetic mechanism and be a major step forward in our understanding of the mechanism of iAs-inducedcarcinogenesis thus filling a critical knowledge gap in our understanding. The principles learned will provide atranslational framework for understanding the molecular mechanisms operative in iAs-induced carcinogenesisin other tissues and cell types. Identification of mutations in or epigenetic silencing of cancer genes inducedby iAs exposure will be a major step forward in our understanding of the mechanism of iAs-inducedcarcinogenesis.

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

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


application_id: 11014043
project_number: 5R21ES036036-02
project_title: R21-UKY East Palestine Train Derailment Health Tracking Study
administering_ic: NIEHS
award_notice_date: 2024-12-30
opportunity_number: RFA-ES-23-004
application_type: 5
activity_code: R21
ic: ES
serial_number: 036036
program_official: QUINN, ASHLINN KO
project_start_date: 2024-01-23
project_end_date: 2026-03-31
study_section: ZES1-LWJ-D(TS)
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
RESEARCH SUMMARYOn February 3 2023 a freight train derailed and caught fire in the town of East Palestine Ohio. Of the derailedrail cars ~20 of them were carrying hazardous materials which were released into the air soil and water. Offurther concern a controlled release/burning of the remaining toxic chemicals was performed promptingofficials to order an immediate mandatory evacuation of all residents. The evacuation order was lifted after theU.S. Environmental Protection Agency released a statement that air quality was safe. However residentsremain concerned about safety while others have reported symptoms including headaches and difficultybreathing as well as odors in the home and in the community. At present a systematic evaluation of theexperiences exposures and health symptoms (including stress outcomes) of the residents of East Palestineand the surrounding area related to the train derailment disaster has not been conducted. Although multipleentities  including federal and state agencies and academic research teams  have been collectingenvironmental and health data community members are being bombarded with information and scientific datathat is not being communicated effectively. Moreover the community does not have a structured mechanism toprovide their insight or recommendations for research. Thus there is a clear need for a researcher networkand mechanisms to engage the community and facilitate dissemination of research findings. This proposal willtake the critical foundational steps toward launching longitudinal investigations of exposures and healthimpacts and ensuring effective and targeted communication of results to residents in the East Palestinecommunity and surrounding populations. Given our longstanding community-engaged environmental healthscience research studies in nearby communities we are strategically poised to accomplish the followingspecific aims. Aim 1: Examine experiences/concerns health symptoms psychosocial/traumatic stressemotional well-being trust networks and environmental health literacy of residents of East Palestine and thesurrounding area related to the train derailment disaster as well as changes in these measures over time; andAim 2: Enhance communication among the scientific research community federal state and local agenciesand the East Palestine community. This time-sensitive and highly relevant study provides the first opportunityfor community members to identify their research priorities based on their experiences/concerns and includes ahealth tracking study (via an online survey) to fully characterize and collect longitudinal measures of healthsymptoms stress and well-being of East Palestine residents. To inform best practices for future disasterresponse research we will evaluate the impact of community-researcher interactions on building both trust andenvironmental health literacy over time. The proposed study will also establish a researcher network toenhance study methodology and inform research dissemination strategies.

project_terms:
Acrylates;Address;Air;Area;Back;Breathing;Chemicals;Communication;Communication Tools;Communities;County;Data;Data Reporting;Disasters;Ensure;Environmental Health;Evaluation;Explosion;Exposure to;Eye;Fire - disasters;Focus Groups;Frustration;Future;Hazardous Substances;Headache;Health;Home;Inhalation;Institutional Review Boards;Investigation;Learning;Lifting;Measures;Methodological Studies;Newsletter;Odors;Ohio;Outcome;Participant;Patient Recruitments;Personal Satisfaction;Poison;Population;Process;Railroads;Recommendation;Reporting;Research;Research Activity;Research Personnel;Research Priority;Risk;Safety;Series;Skin;Soil;Specificity;Stress;Structure;Surveys;Symptoms;Time;Training;Trust;United States Environmental Protection Agency;Universities;Update;Vinyl Chloride;Water;Well in self;community engagement;community partners;controlled release;data sharing;dissemination strategy;experience;health data;health literacy;health science research;insight;irritation;meetings;member;prevent;psychosocial;repository;research data dissemination;research study;respiratory;response;social;traumatic stress;web site

public_health_relevance:
Narrative: A community-academic team will respond to the East Palestine derailment with a healthtracking survey and strategies to engage the community in identifying their communication needs andenvironmental health research directions.


application_id: 11013934
project_number: 5R01AI168475-04
administering_ic: NIAID
award_notice_date: 2025-05-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 168475
program_official: CONNOLLY, KRISTIE LEE
project_start_date: 2022-02-25
project_end_date: 2028-01-31
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 10797120
contact_pi: FRIEBOES, HERMANN
other_pis: LEWIS, AMANDA L.
congressional_district: 03
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-02-01
project_title:
3D-bioprinting  of sustained- and phased-release antibiotic and probiotic scaffolds to treat bacterial vaginosis

project_abstract:
PROJECT SUMMARYBacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that affects ~29% of reproductive age womenand is linked with higher risks of adverse pregnancy outcomes postsurgical infections and sexually transmittedinfections. While lactobacilli typically dominate the healthy vagina BV is characterized by low lactobacilli levelsand an overgrowth of diverse anaerobic bacteria most often including Gardnerella and Prevotella. Current oralor topical antibiotic treatments alleviate symptoms in 80% of women at least temporarily. However most womenwill experience a recurrence of BV within one-year post-treatment. A recent clinical study showed that a vaginalprobiotic treatment regimen (with Lactobacillus crispatus) used following a vaginal course of antibiotics(metronidazole) significantly improved long-term treatment efficacy. Unfortunately current topically-appliedformulations require repeated administrations (once to twice daily) which can hinder female convenience andadherence to treatment particularly when undergoing multiple weeks of treatment (required to administer bothantibiotic and probiotics).In this project we will use 3D printing and computational modeling iteratively enabled by functional investigationof prototype scaffolds in vitro and in vivo to design long-acting products that sustain therapeutic delivery whileenabling phased-delivery of antibiotics and probiotics to the female reproductive tract. Our team brings togetherfemale reproductive tract-specific expertise in delivery vehicle design computational modeling and preclinicalBV models. The ultimate goal is to use 3D-bioprinting to incorporate different device compartments whichsequentially release antibiotics that target anaerobic overgrowth followed by live probiotics that restore balanceback in favor of vaginal lactobacilli. In Aim 1 we will design and characterize 3D-printed silicone scaffolds thatsustain antibiotic-only delivery. Aim 2 will design and evaluate 3D-printed silicone and gelatin alginatecomposites that sequentially release antibiotics followed by probiotics providing a 1-2 punch strategy to kill BVbacteria and provide a healthy Lactobacillus alternative. Each aim will focus first on a materials-basedcharacterization of Met-containing silicone (1A) or Met-silicone probiotic-gelatin alginate composites (2A).Measurements from in vitro release experiments will be used to develop and test computational models thatpredict the delivery of antibiotic (1B) or dual agents (2B) in a virtual female reproductive tract and ultimately ina mouse co-infection model. We will evaluate Met-silicone (1C) and Met-silicone probiotic-gelatin alginatecomposites (2C) for cytotoxicity to the vaginal epithelium and ability to stimulate soluble proinflammatorymediators and downstream histopathology. In our mouse model we will measure levels of viable Gardnerellaand Prevotella recovered from vaginal and uterine tissues following treatment with blank or active agent-containing 3D-printed scaffolds. If successful this project will support the development of multipurpose platformsto prevent and treat BV as well as other female reproductive tract applications.

project_terms:
3-Dimensional;3D Print;Adherence;Adverse event;Affect;Aftercare;Alginates;Anaerobic Bacteria;Antibiotic Therapy;Antibiotics;Appearance;Atopobium vaginae;Back;Bacteria;Bacterial Vaginosis;Biological Assay;Biomedical Engineering;Calibration;Cell Line;Cells;Clinical;Clinical Research;Clinical Trials;Complex;Computer Models;Data;Development;Devices;Epithelial Cells;Epithelium;Equilibrium;Experimental Models;Female;Formulation;Gardnerella;Gardnerella vaginalis;Gelatin;Goals;Growth;HIV;Health;Histopathology;Human;In Vitro;Infection;Infertility;Inflammation Mediators;Investigation;Kinetics;Lactobacillus;Link;Measurement;Measures;Medicine;Metronidazole;Microbe;Modeling;Mucous body substance;Mus;Oral;Outcome;Pelvic Inflammatory Disease;Phase;Pre-Clinical Model;Prevotella;Printing;Probiotics;Process;Proliferating;Property;Reapplication;Records;Recurrence;Regimen;Retreatment;Serum;Sexually Transmitted Diseases;Silicones;Symptoms;Syndrome;Testing;Therapeutic;Therapeutic Agents;Tissues;Topical Antibiotic;Topical application;Treatment Efficacy;Treatment Protocols;Treatment outcome;Uterus;Vagina;Vaginal delivery procedure;Woman;Work;adverse pregnancy outcome;aged;anti-fungal agents;bioprinting;co-infection;cytotoxicity;delivery vehicle;design;dysbiosis;engineering design;experience;experimental study;fabrication;female reproductive tract;gut health;high risk;improved;improved outcome;in vitro Model;in vitro testing;in vivo;infected women;mathematical model;microbial;microbicide;mouse model;multidisciplinary;novel;pathogen;pre-clinical;predictive modeling;prevent;probiotic therapy;prototype;reduce symptoms;reproductive age;scaffold;vaginal lactobacilli;vaginal microbiome;virtual

public_health_relevance:
NARRATIVEBacterial vaginosis (BV) is a dysbiotic condition of the vaginal microbiome that affects ~29% of reproductive agewomen and is linked with higher risks of adverse pregnancy outcomes postsurgical infections and sexuallytransmitted infections. Current topically-applied medicines require frequent repeated administrations which canhinder convenience and adherence to treatment particularly when undergoing multiple weeks of treatment. Inthis project we will use 3D-printing and computational modeling iteratively enabled by functional investigation ofprototype scaffolds to design long-acting products that sustain phased-delivery of antibiotics and probiotics torestore and maintain vaginal health.


