# projects

application_id: 11109593
project_number: 5R01NS120882-04
project_title: Neuronal IL-1R1 Signaling in Mild Closed Head Injury
administering_ic: NINDS
award_notice_date: 2025-06-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 120882
program_official: AWWAD, HIBAH OMAR
project_start_date: 2022-07-01
project_end_date: 2027-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: NORRIS, CHRISTOPHER MARK
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe cytokine interleukin-1 (IL-1) is well known to mediate detrimental inflammatory processes in peripheraltissues. IL-1 is elevated in age and in neurodegenerative disease. As a result IL-1 has become a major focusof anti-inflammatory strategies to treat neuroinflammation following acute injury and in chronicneurodegenerative disease. Surprisingly there is scant evidence that neurons are damaged through the directactions of IL-1. To the contrary a neuron-specific non-canonical IL-1 receptor (IL-1R1) pathway thatpromotes rather than erodes neuronal viability has been identified. Despite this paradigm-shifting observationthe non-canonical pathway has received little attention. Much remains unknown about how neuronal IL-1R1signaling contributes to the brain's inflammatory milieu synaptic physiology and cognitive function andrecover from injury and progression of neurodegeneration. This knowledge gap could undermine potentialneuroprotective approaches that target suppression of IL-1 as part of the mechanism-of-action.To address this knowledge gap we will use novel mouse models exhibiting neuron-specific modulation of IL-1signaling (i.e. IL-1R1-floxed mice to look at neuron-specific knockdown and IL-1R1-restore mice to look at theneuron-specific expression of IL-1R1). Our overarching hypothesis is that neuronal IL-1R1 signaling isinherently protective.We will test this hypothesis in the following Specific Aims: SA1 Define the role of the neuronal IL-1R1 pathway in the inflammatory response to a CHI in mice. SA2 Define the neuronal IL-1R1 pathway in homeostatic synaptic plasticity after a CHI in mice. SA3 Determine the temporal role of neuronal IL-1R1 in the cognitive recovery following a CHI.If our hypothesis is affirmed we will provide knowledge of a new neuroprotective approach and enable thedevelopment of new formulations of existing anti-inflammatory interventions that preserve the neuroprotectivefunctions of IL-1. The development of novel IL-1R1 therapies would include agents that only suppress theinflammatory IL-1R1 pathway or only activate the neuroprotective IL-1R1 pathway.

project_terms:
Acute;Address;Age;Animal Disease Models;Anti-Inflammatory Agents;Attention;Autoimmune Diseases;Axon;Behavior;Behavioral Assay;Brain;Cells;Chronic;Closed head injuries;Complex;Data;Development;Electrophysiology (science);Exhibits;FDA approved;Formulation;Functional disorder;Gene Expression Profile;Genes;Goals;Inflammation;Inflammatory;Inflammatory Response;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Intervention;Knockout Mice;Knowledge;LoxP-flanked allele;Maintenance;Mediating;Memory;Modeling;Mus;Nature;Nerve Degeneration;Nervous System Disorder;Nervous System Trauma;Neurodegenerative Disorders;Neuroglia;Neurons;Pathway interactions;Peripheral;Phase;Phenotype;Physiology;Process;Receptor Signaling;Recovery;RiboTag;Role;Signal Transduction;Synapses;Synaptic plasticity;System;Testing;Therapeutic;Tissues;Traumatic Brain Injury;cell type;cognitive function;cognitive recovery;cytokine;experimental study;genetic approach;inducible Cre;inflammatory milieu;interleukin-1 receptor accessory protein;knock-down;mouse model;nerve injury;neuroinflammation;neuroprotection;neuroregulation;novel;preservation;response;synaptic function

public_health_relevance:
PROJECT NARRATIVEThis study would have critical implications for the pathophysiology of numerous CNS conditions and helpreconcile mixed results with anti-IL-1 therapeutics and inform new IL-1 modulation strategies. Moreoverdefining the role of neuronal IL-1R1 signaling would provide a new neuroprotective approach as well asenable the development of new formulations of existing IL-1 targeted interventions to preserve theneuroprotective functions of IL-1.


application_id: 11109484
project_number: 5R01AI178106-03
project_title: Impact of inflammatory lipids on Yersinia pestis infection
administering_ic: NIAID
award_notice_date: 2025-06-26
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 178106
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2023-07-14
project_end_date: 2027-06-30
study_section: Bacterial-Host Interactions Study Section [BHI]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Yersinia pestis causes the acute human disease commonly referred to as plague. A hallmark manifestation ofthis disease is delayed inflammation despite active bacterial replication. Y. pestis modulates inflammation byactively inhibiting the expression of pro-inflammatory cytokines via the action of a group of proteins called Yopeffectors that are directly injected into host cells by a bacterial type three secretion system (T3SS). Becauseestablishment of this non-inflammatory environment is key for Y. pestis to colonize the host understanding howY. pestis modulates the host inflammatory response during early stages of infection will provide crucial insightsinto both the pathogenesis of the bacterium and potential strategies to improve therapy. Lipid mediators suchas members of the eicosanoid family are essential to initiate the cascade of signaling events that regulatesinflammation. Therefore disruption of the synthesis of pro-inflammatory eicosanoids can effectively stifle a rapidimmune response. Despite their importance in initiating inflammation the role of lipid mediators in the context ofplague has not been previously investigated. Recently we discovered a dysregulation in eicosanoid synthesisduring pneumonic plague highlighted by the inhibition in the synthesis of the pro-inflammatory lipid leukotrieneB4 (LTB4). Furthermore using Y. pestis mutants we uncovered a novel mechanism for the recognition of theT3SS by neutrophils that triggers LTB4 synthesis which is normally inhibited by the Yop effectors. Togetherthese discoveries support a conceptually innovative hypothesis that Y. pestis actively manipulates the synthesisof lipid mediators to disrupt the proper inflammatory cascade that would normally recruit circulating leukocytesto control infection. In Aim 1 we will test this hypothesis using animal models to define the contribution ofeicosanoids to the host response during plague and determine how disruption of LTB4 synthesis benefits Y.pestis. In Aim 2 we will use Y. pestis as a tool to define the molecular mechanisms responsible for T3SS-dependent LTB4 synthesis by neutrophils. Because lipid mediators of inflammation have been overlooked in thecontext of Y. pestis immune evasion completion of these studies will significantly transform our conceptualunderstanding of the early immune events during pneumonic plague.

project_terms:
Acute;Animal Model;Bacteria;Bacterial Infections;Biology;Cells;Chemotactic Factors;Data;Disease;Eicosanoids;Environment;Event;Family;Goals;Immune;Immune Evasion;Immune response;Infection;Infection Control;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Innate Immune System;Kinetics;Leukocytes;Leukotriene B4;Lipids;Lipoxygenase;Lung;Macrophage;Mediating;Molecular;Mus;Neutrophil Infiltration;Pathogenesis;Pathway interactions;Plague;Pneumonic Plague;Predisposition;Production;Proliferating;Prostaglandin-Endoperoxide Synthase;Proteins;Role;Signal Transduction;Site;System;Testing;Therapeutic Intervention;Time;Tissues;Type III Secretion System Pathway;Virulence;Virulence Factors;Yersinia pestis;chemokine;cytokine;defined contribution;host colonization;human disease;immunoregulation;improved;in vivo evaluation;innovation;insight;leukocyte mediator;lipid mediator;mast cell;member;mutant;neutrophil;novel;pathogen;recruit;response;tool

public_health_relevance:
PROJECT NARRATIVEInflammation is controlled by a cascade of signaling events which are initiated by the secretion of lipid mediatorsby leukocytes to recruit and activate additional immune cells to sites of infection. Our goal is to define how Y.pestis dysregulation of host lipid mediator synthesis contributes to the establishment of plague. Because theinhibition of inflammation is key to Y. pestis virulence defining the role of host lipid mediators during plague isessential for us to understand the pathogenesis of this bacterium and provide new insights to improve currentplague therapy.


application_id: 11108037
project_number: 1R01CA300706-01
project_title: Identification of NNMT as a New Target to Treat Triple-negative Breast Cancer
administering_ic: NCI
award_notice_date: 2025-04-07
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 300706
program_official: GREENBERG, WILLIAM A
project_start_date: 2025-04-07
project_end_date: 2030-03-31
study_section: Mechanisms of Cancer Therapeutics C Study Section [MCTC]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: HUANG, RONG
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryTriple-negative breast cancer (TNBC) is the most aggressive disease noted for the development of recurrencedistant metastases and short survival times particularly and tragically in young women. Mounting evidencesindicate that TNBC cells underwent a metabolic rewiring to scavenge the upsurge of reactive oxygen species(ROS) encountered during metastasis in order to survive and outspread. The overarching goal of this proposalto identify the metabolic dysregulation and signaling pathways governing metastasis in TNBC and to developnovel intervention to prevent this deadly disease. Recently we found that a robust induction of nicotinamide N-methyltransferase (NNMT) is concomitant with ROS upsurge when TNBC cells detached from matrix and grownin anchorage-independent manner. NNMT-KO inhibits anchorage-independent growth in vitro and suppressestumor growth and metastasis in vivo. Further mechanistic analyses indicate that NNMT-KO induces soaring ROSand promotes ferroptosis by decreasing the levels of NAD(P)+ and glutathione (GSH). We hypothesize thatNNMT is a salient molecule to promote NAM uptake and NAD(P)+ synthesis in TNBC cells under anchorage-independent growth thereby alleviating rising ROS and protecting them from ferroptosis. Thus NNMTrepresents an appealing therapeutic target to inhibit TNBC survival and metastasis. In line with this idea ournewly developed NNMT specific bisubstrate inhibitor presents a proof-of-concept as they potently suppressedTNBC growth both in vitro and in vivo. Guided by strong preliminary data we will test this hypothesis by pursuingthree specific aims: 1) to define how NNMT promotes anchorage-independent growth and protects ferroptosisin TNBC; 2) to evaluate the potency specificity and mechanism of NNMT bisubstrate inhibitor in TNBC; and 3)to determine NNMTs function and explore therapeutic potential of NNMT inhibitor in pre-clinical mouse models.We will utilize a wide variety of innovative complementary and systematic methods to vigorously validate thecentral hypothesis and achieve the goals of this study. This is multiple PI project combines the Zhou laboratorysstrength in TNBC research with the Huang laboratorys expertise in drug discovery and medicinal chemistry. Ourproposal is innovative and significant because NNMT represents the Achilles heel of TNBC cells; targeting thiskey molecule with specific inhibitor offers an immense potential for treating metastatic TNBC in the near future.

project_terms:
Affect;Anchorage-Independent Growth;Antioxidants;Binding;Biological Assay;Biometry;Brain;Breast Cancer Cell;Cancer Cell Growth;Cells;Cessation of life;Code;Data;Deacetylation;Development;Disease;Disease Progression;Distant Metastasis;Enzymes;Future;Glutathione;Goals;Growth;In Vitro;Intervention;Invaded;Iron;Knock-out;Laboratories;Lipid Peroxidation;Lung;Malignant Breast Neoplasm;Mammary gland;Mediating;Metabolic;Metabolism;Methods;Methyltransferase;Mouse Mammary Tumor Virus;Mus;NADP;Neoplasm Metastasis;Nicotinamide N-Methyltransferase;Nicotinamide adenine dinucleotide;Oxidation-Reduction;Pathologic;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Positioning Attribute;Pre-Clinical Model;Prognosis;Property;Protein Methyltransferases;Reactive Oxygen Species;Recurrence;Regulation;Repression;Signal Pathway;Signal Transduction;Site;Specificity;Structure;Suspensions;Testing;Therapeutic;Treatment Efficacy;Treatment Protocols;Vertebral column;Xenograft procedure;anti-cancer research;breast cancer survival;cancer subtypes;cellular targeting;chemoproteomics;drug discovery;druggable target;effective intervention;improved;in vivo;inhibitor;innovation;mouse model;neoplastic cell;novel;novel therapeutic intervention;palliative;patient derived xenograft model;pharmacokinetics and pharmacodynamics;polyoma middle tumor antigen;pre-clinical;prevent;programs;promoter;research and development;structural biology;success;supportive environment;therapeutic target;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor growth;uptake;young woman

public_health_relevance:
Project NarrativeNicotinamide N-methyltransferase (NNMT) a prime enzyme that promotes the synthesis of cellular antioxidantsis essential to scavenge soaring ROS and protect TNBC cells from ferroptosis under anchorage-independentgrowth. This study will not only delineate the function and regulation of NNMT in TNBC but also determine thetherapeutic efficacy of specific NNMT bisubstrate inhibitor for treating this disease in preclinical models.


application_id: 11105800
project_number: 5F31DC020639-04
project_title: Mechanisms of Tip Link Tensioning in Mammalian Auditory Hair Cells
administering_ic: NIDCD
award_notice_date: 2025-06-12
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: DC
serial_number: 020639
program_official: SCHURMAN, JACLYN REBECCA
project_start_date: 2022-07-31
project_end_date: 2026-07-30
study_section: ZDC1-SRB-Y(56)
contact_pi_person_id: 78133926
contact_pi: DRAGICH, ABIGAIL
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMammalian auditory hair cells detect sound through deflections of stereocilia that are organized in precisestaircase-like bundles and interconnected by extracellular tip links. Sound-induced deflections modulate thetension of tip links and convey these forces to mechano-electrical transduction (MET) channels located atthe tips of the shorter rows of stereocilia. Even at rest there is a certain amount of tension on the tip linkswhich ensures detection of the softest sounds and results in some resting amount of MET currentcontinuously entering the cell. We and other groups demonstrated that this resting MET current regulatesthe height of transducing stereocilia thereby providing a plausible mechanism for long-term maintenance ofthe shape of stereocilia bundle. Furthermore my recent study revealed that MET-dependent retraction ofstereocilia in mammalian auditory hair cells increases the tension within MET machinery which could onlyoccur if in contrast to the classical models the upper end of the tip link is not freely moved by myosinmotors but instead somehow locked to the stereocilia core (Dragich et. al. in review). The proposed projectwill explore a potential molecular mechanism of this phenomenon. We hypothesize that G-InteractingProtein C-terminus-3 (GIPC3) is involved in locking the upper end of the tip link to the stereocilia actin core.Several mutations in GIPC3 have been linked to hearing loss in humans but the exact function of thisprotein in the mammalian cochlea is yet unknown. Data from our collaborator (Dr. Craig Vander Kooi) showthat GIPC3 interacts with myosin VI (MYO6) and the upper tip link density (UTLD) proteins cadherin-23(CDH23) and potentially myosin VIIa (MYO7a). My preliminary data also show that GIPC3 deficiency resultsin the loss of resting MET current and slipping adaptation of the MET responses in cochlear outer haircells of mice carrying the p.W301X mutation in Gipc3 recapitulating a known human deafness. In thisproject we will use this Gipc3W301X mouse strain as well as a Gipc3 knockout strain to determine: (a) therole of GIPC3 in regulating the tension within the MET machinery and adaptation in mammalian auditoryhair cells; (b) the role of GIPC3 in UTLD assembly and maintenance; and (c) the potential for restoringwildtype MET responses in Gipc3-deficient mice. This project will not only identify the specific role of GIPC3in mammalian auditory hair cells but also elucidate the mechanisms behind the maintenance of stereociliabundle structure and tensioning of the MET machinery. Approaching this project using electrophysiologyadvanced electron microscopy and cell biology techniques will help me to develop a unique set of scientificskills in preparation for a career as a future principal investigator in basic auditory research.

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

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


application_id: 11104947
project_number: 3R01DA057605-01S3
project_title: Enhancing opioid surveillance in RADOR-KY using social media
administering_ic: NIDA
award_notice_date: 2024-09-05
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: DA
serial_number: 057605
suffix: S3
program_official: KURAMOTO-CRAWFORD, SATOKO JANET
project_start_date: 2022-09-30
project_end_date: 2025-09-29
contact_pi_person_id: 12111311
contact_pi: SLAVOVA, SVETLA STEFANOVA
other_pis: TALBERT, JEFFERY C
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT:The opioid epidemic continues to plague the United States. Unreliable and slow data systemspose a continuing challenge to the public health response. There is a paucity of real-time datathat can be used to detect or forecast increases in opioid overdoses and coordinate timelycommunity resource mobilization efforts. Household surveys underestimate use and usedisorder rates mortality data has a time lag that makes evaluating policy impact difficult andnew illicit drugs are identified too slowly. Creating valid sensitive real-time data systems is thusa critical priority. Kentucky has suffered greatly during the opioid epidemic. In response theRapid Actionable Data for Opioid Response in Kentucky (RADOR-KY; 1-R01 DA057605-01)system enhances surveillance capacity with machine learning models designed to forecastfuture trends. The system currently uses data from 11 sources and integrates them forforecasting county-level risk of opioid overdose. The proposed administrative supplement ofRADOR-KY will evaluate the added value of real-time social media data to improve opioidoverdose surveillance and forecasting. Recent studies have shown that social media can signalopioid trends. Mentions of opioids on Reddit and language markers of distress on Twitter/Xcorrelate with regional opioid-related overdose deaths. It is unclear if these signals are capturedby current RADOR-KY data streams or if they provide independent information that could beuseful for improving performance of the system. Evaluating whether social media data canimprove the RADOR-KY prediction models is thus a major public health priority for Kentuckyand to the extent it can be shown effective could be applied nationwide. In this supplement wepropose to work with Stanford University to (1) analyze the utility of counting direct social mediamentions of opioids for forecasting overdoses across Reddit and Twitter/X (2) analyze the utilityof indirect population sentiment signals for forecasting overdoses and (3) analyze the value ofconsidering additional social media context around opioid use (e.g. addiction vs. recovery). Thiswork will measure the potential value of social media data for opioid surveillance and estimateits incremental value to RADOR-KY.

project_terms:
Address;Administrative Supplement;Affect;Algorithms;Anxiety;Area;Artificial Intelligence;COVID-19 pandemic;Communities;Country;County;Data;Data Linkages;Data Sources;Disease;Distress;Emotions;Epidemic;Funding;Future;Grant;Happiness;Health Resources;Healthcare Systems;Household;Illicit Drugs;Informatics;Information Systems;Intervention;Kentucky;Language;Link;Machine Learning;Measures;Mental Depression;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Natural Language Processing;Opioid;Overdose;Parents;Performance;Pharmaceutical Preparations;Policies;Population;Predictive Analytics;Predictive Value;Productivity;Public Health;Recovery;Reporting;Research;Resolution;Resource Allocation;Resources;Risk;Signal Transduction;Social Values;Source;Statistical Models;Surveys;System;Testing;Time;Twitter;United States;Universities;Visual;Visualization software;Work;addiction;computerized data processing;data ingestion;data streams;experience;high risk;improved;insight;large language model;machine learning model;meetings;mobile application;model design;mortality;mortality statistics;opioid epidemic;opioid mortality;opioid overdose;opioid use;opioid use disorder;overdose death;overdose prevention;overdose risk;parent grant;pharmacovigilance;population based;predictive modeling;psychologic;public health priorities;real time model;response;social;social media;surveillance strategy;trend;web app

public_health_relevance:
Project NarrativeRADOR-KY (Rapid Actionable Data for Opioid Response in Kentucky) is a statewidepopulation-based surveillance system with a key feature of forecasting opioid-related overdosemortality and morbidity so that public health resources can be deployed timely to the areas andpopulations that need them most to save lives. The system currently integrates 11 sources ofdata but these do not include social media. This supplement proposes to investigate the valueof two sources of (in principle real-time) social media data (Reddit Twitter/X) to improve theperformance of forecasting algorithms potentially providing a model for real-time opioidoverdose epidemic surveillance.


application_id: 11103963
project_number: 3P30CA177558-12S2
project_title: Assessing Markey Cancer Center's Alignment with National Standards for Survivorship Care
administering_ic: NCI
award_notice_date: 2024-09-04
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S2
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: ZCA1(M1)
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-24-032. This administrative supplement application pertains to the National Cancer Institute (NCI) P30Cancer Center Support Grant that supports the Markey Cancer Center (MCC) a university-based matrix cancercenter at the University of Kentucky (UK). The mission of MCC is to reduce cancer burden through researchprevention treatment education and community engagement with a focus on Kentucky and its most vulnerablepopulations. As the only NCI-designated Comprehensive Cancer Center in the state MCC is vital to Kentuckythe state which leads the nation in all-site cancer incidence and mortality. MCC aims to translate scientificdiscoveries into innovative and personalized diagnostic and treatment advances that improve the lives of cancersurvivors. Consistent with MCCs goal to provide exceptional patient-centered outcome-driven cancer care thatexceeds expectations of cancer survivors and caregivers alike MCC employs advanced practice providers whodeliver survivorship care. NOT-CA-24-032 provides a perfect opportunity to examine the quality of MCCsurvivorship care and take initial steps toward improvement and expansion. The specific aims of theadministrative supplement are: 1) Describe the degree to which MCC survivorship care meets the NationalStandards for Survivorship Care; 2) Identify MCC cancer survivor and caregiver-reported barriers and facilitatorsto accessing MCC survivorship care and explore differences based on survivors treatment phase disease stageand geographic residence; and 3) Ascertain promising implementation strategies to improve the quality reachadoption and effectiveness of MCC survivorship care. To accomplish these specific aims a concurrent mixed-methods study that is guided by the Practical Robust Implementation and Sustainability Model and includesmultiple stakeholders (specifically MCC providers administrators advisory group members survivors andcaregivers) as participants will be conducted during the 1-year award period. With unique research strengthsand a firm commitment to quality cancer care MCC is well-poised to generate robust data that will improve thesurvivorship care it provides.

project_terms:
Administrative Supplement;Administrator;Adoption;Award;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Survivor;Caregivers;Caring;Catchment Area;Comprehensive Cancer Center;County;Data;Disease;Education;Effectiveness;Geography;Goals;Health Services Accessibility;Incidence;Kentucky;Methods;Mission;National Cancer Institute;Outcome;Participant;Phase;Practical Robust Implementation and Sustainability Model;Prevention;Provider;Quality of Care;Reporting;Research;Survivors;Translating;Universities;Vulnerable Populations;cancer care;cancer site;cancer survivorship care;community engagement;expectation;implementation strategy;improved;innovation;interest;member;mortality;patient oriented;personalized care;personalized diagnostics;personalized medicine;residence;response;survivorship

public_health_relevance:
PROJECT NARRATIVE Markey Cancer Center is the only NCI-designated Comprehensive Cancer Center in the state ofKentucky and its catchment area includes all 120 counties in Kentucky. The mission of Markey CancerCenter is to reduce cancer burden which necessitates translating scientific discoveries into innovativepersonalized care and providing the highest quality care to cancer survivors. This administrative supplementaims to assess alignment between survivorship care at Markey Cancer Center and the National Standardsfor Cancer Survivorship Care identify determinants of survivorship care access for survivors and theircaregivers and identify implementation strategies to improve quality effectiveness adoption and reach ofsurvivorship care at Markey.


application_id: 11101983
project_number: 1S10OD038345-01
project_title: Expansion of Physiology Core: The Vevo F2 High Resolution Preclinical Ultrasound System
administering_ic: OD
award_notice_date: 2025-04-24
opportunity_number: PAR-22-080
application_type: 1
activity_code: S10
ic: OD
serial_number: 038345
program_official: SPECTOR, JEFFREY O
project_start_date: 2025-05-01
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1 ISB-S (30)]
contact_pi_person_id: 10287199
contact_pi: NONG, YIBING
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 Abstract: This SIG Grant details the critical need for a VisualSonics Vevo F2 preclinical ultrasoundSystem to expand the capacity of the Physiology Core at the University of Louisville. The Core is the only corefacility on Campus to support the ultrasound imaging needs of the fast-growing User base which includesmore than thirty investigators from five NIH-funded centers in the field of cardiovascular health cancerhepatic and metabolic disease environmental toxicology exercise science immunology and oral health. Thejustification for a second ultrasound instrument is clear: 1) The ever-increasing and diverse needs from Majorand Minor Users far exceed the capacity of our initial single instrument. Ultrasound imaging wait time for anew study is extended beyond acceptable measures. 2) The capacity limits the Cores ability to develop newintegrated physiology approaches a unique feature of the Core to meet the needs of investigators for theircompetitive grant applications and cutting-edge research projects. 3) No systems from other vendors have thecombination of applications spatiotemporal resolution and the open architecture that the Vevo F2 provides.The Users more than $18million (majorly NIH-funded) portfolios of grants have benefited from the Coresexisting Vevo 3100 system. As the Vevo 3100 entered end-of-sale stage the Vevo F2 is now the only option toexpand the Cores capacity with the established high level imaging standard. The requested instrument will behoused in an existing core with two-plus decades of experience on preclinical ultrasound. The existing Coreleadership space ongoing financial support and technical expertise guarantees effective use andmaintenance of the requested instrument from day-one of its installations. The requested instrument will notonly effectively expand the most needed capacity to meet the demand of ultrasound imaging; but also allow theCore to develop and provide advanced integrated physiology approaches such as cardiac pacing stressechocardiography echocardiography-pressure volume loop myocardial contrast echocardiography + pressurevolume loop and whole-view coronary artery function measurement package to the Cores User base; inaddition provide the opportunity of bioengineering research for future-oriented imaging technologydevelopment. The over-arching theme among the Major Users are the continued need for precise sensitivedetermination of changes in cardiac structure and function for vascular function for quantifiable vasculaturemeasurements for live tissue blood flow/perfusion and for tissue stiffness/fibrosis measurements. Over thenext several years procurement of this Vevo F2 system will allow the Physiology Core to scale to meet theever-growing investigators demand in NIH funded cross-functional biomedical research projects that arefocused primarily on the most significant public health concerns.

project_terms:
Applications Grants;Architecture;Biomedical Engineering;Biomedical Research;Blood Vessels;Blood flow;Cardiac;Contrast Echocardiography;Core Facility;Coronary artery;Echocardiography;Exercise;Fibrosis;Financial Support;Funding;Future;Grant;Image;Imaging technology;Immunology;Leadership;Liver diseases;Maintenance;Malignant Neoplasms;Measurement;Measures;Metabolic Diseases;Minor;Myocardial;Oral health;Perfusion;Physiology;Public Health;Research;Research Personnel;Research Project Grants;Resolution;Sales;Science;Stress Echocardiography;Structure;System;Technical Expertise;Tissues;Ultrasonography;United States National Institutes of Health;Universities;Vendor;Wait Time;base;cardiac pacing;cardiovascular health;environmental toxicology;experience;instrument;pre-clinical;pressure;spatiotemporal;technology development;ultrasound

public_health_relevance:
Project Narrative: The investigators represented in this proposal are engaged in understanding the molecularregulation of cardiovascular disease diabetes cancer liver disease environmental toxicology immunologyaging and oral health. To maintain and grow their clinically translatable work these investigators need topurchase a second ultrasound systems to meet their imaging demands.


application_id: 11101240
project_number: 5F30AG079506-03
administering_ic: NIA
award_notice_date: 2025-04-24
opportunity_number: PA-21-050
application_type: 5
activity_code: F30
ic: AG
serial_number: 079506
program_official: ROVESCALLI, ALESSANDRA C
project_start_date: 2023-05-10
project_end_date: 2025-11-09
study_section: Special Emphasis Panel[ZRG1-F01A-V(20)]
contact_pi_person_id: 78025226
contact_pi: LIBECAP, TJ
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-10
project_title:
Investigating Enlarged Perivascular Spaces as a Neuroimaging Biomarker of Cerebral Small Vessel Disease

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

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

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


application_id: 11101099
project_number: 5T03OH008437-20
project_title: Occupational Safety and Health Program Improvement
administering_ic: NIOSH
award_notice_date: 2025-07-02
opportunity_number: PAR-15-352
application_type: 5
activity_code: T03
ic: OH
serial_number: 008437
program_official: O'NEILL, EDUARDO
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: ZOH1-DVN(02)1
contact_pi_person_id: 15422252
contact_pi: BYRD, TRACI
other_pis: Not Applicable
congressional_district: 01
department: OTHER HEALTH PROFESSIONS
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
With over forty years of experience in educating Occupational Safety and Health (OSH)students the purpose of this proposal is to strengthen the learning environment to prepare thenext generation of leaders in OSH practice. This will be accomplished by preparing graduatestudents who are well-trained to enter the workforce ready to respond to both established risksas well as new challenges brought on by the changing nature of work. The primary focus will be:1. Opportunities for interaction between faculty internship instructors and on-site intern supervisors to sustain and advance employer-intern-university relationships.2. Develop and host workshops and seminars to address advances in OSH practice.3. Faculty professional development to respond to the changing nature of work.4. Support for graduate students in the form of tuition fees and travel.5. Improve program curriculum to modernize offerings.6. Increase program's capacity for use of virtual/digital applications in placement-related activities communication academic offerings and profession-related applications.The OSH department had 289 students in the program during the fall 2019 semester whichincluded 39 in the graduate program and 250 in the undergraduate program.

public_health_relevance:
The Department of Occupational Safety and Health at Murray State University suppliesdiversified education and training for occupational safety and health professionals to meet thelocal regional and national demand. Curricula programs and training within the departmentare designed to meet the professional preparation of students as well as the manpowercontinuing education training and advisory needs of the region and state.


application_id: 11099966
project_number: 5R35HL155649-05
project_title: Determinants of Aorta Heterogeneity
administering_ic: NHLBI
award_notice_date: 2025-07-28
opportunity_number: RFA-HL-20-011
application_type: 5
activity_code: R35
ic: HL
serial_number: 155649
program_official: CHARETTE, MARC F
project_start_date: 2021-06-01
project_end_date: 2028-05-31
study_section: ZHL1-CSR-I(O2)
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractAortopathies including aneurysms dissection and rupture represent a key challenge in HLBSresearch. In the past twenty years of our continuously funded research on aortopathies wehave contributed to many mechanistic insights into the aortopathy research including a newconcept: There are regional characteristics of the aorta in regard to diverse embryonic originsand functions of cells. The overall hypothesis of this R35 program is that heterogeneity ofcellular origins imparts functional variances along the length of the aorta including diversity ofextracellular matrix stability which in turn contributes to regional specificity of aortopathies.Regional specificity of aortopathies is present in many mouse models that we have validatedand characterized. Our initial single cell transcriptomic and proteomic data have also implicatednew potential contributors to heterogeneity of the normal aortic biology and aortopathies. Threemajor themes are proposed in this program: (1) What are the structural and molecularmechanisms that contribute to biological and pathophysiological heterogeneity along the lengthof the aorta? (2) Are cellular and extracellular heterogeneity a basis for regional specificity ofaortopathies? (3) How do signaling pathways extracellular matrix and crosstalk betweenresident aortic cells coordinate to promote the heterogeneity of aortopathies? We have robusttools including a spectrum of reagents multiple classic and new mouse modelsultrasonography MRI intravital microscopy proteomics and single cell RNA sequencingtechniques. In addition to aortopathy research the PI has more than 30-year expertise in thefields of lipoprotein metabolism inflammation and atherosclerosis research. Aortopathies arenot a sole aortic disease but is associated with a wide range of diseases or syndromes thatmay affect skin lung kidney brain bone and other organs. The proposed research programwill benefit from the flexibility to pursue potential contributions of other tissues and organs toaortopathies and vice versa the influences of aortopathies on other tissues and organs. ThisR35 mechanism will also benefit the PIs strength in basic research enhance his interaction withthe translational research in the clinical arena and train the next generation of scientists.

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

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


application_id: 11099739
project_number: 5R01HL164398-04
project_title: Targeting GLP-1 receptor as a new chronotherapy against nondipping blood pressure in diabetes
administering_ic: NHLBI
award_notice_date: 2025-07-03
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 164398
program_official: OH, YOUNGSUK
project_start_date: 2022-06-15
project_end_date: 2027-05-31
study_section: Integrative Vascular Physiology and Pathology Study Section[IVPP]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYType 2 diabetes is one of the most prevalent and costly chronic diseases worldwide. Hypertension andnondipping blood pressure (BP) are prevalent comorbidities of type 2 diabetes and significant risk factors fordetrimental cardiovascular outcomes. While up to 75% of diabetic patients are nondippers no effective therapytargets nondipping BP in diabetes. Glucagon-like-peptide-1 receptor agonists (GLP-1RA) are a class ofrecently FDA-approved anti-diabetic drugs that provide exciting new means for the critical but challenging taskof managing cardiovascular risk in diabetic patients. The use of GLP-1RAs increased rapidly due to theirrecently recognized cardiovascular benefits including lowering BP in addition to effectively reducing HbA1Cand body weight. However whether GLP-1RA influences nondipping BP in diabetes is scarcely studied andthe mechanisms via which GLP-1RA lowers BP remain to be defined. Our preliminary data demonstrate for thefirst time that a short-acting GLP-1RA exenatide (Ex) when injected i.p. into type 2 diabetic db/db mice at thebeginning of the inactive phase (ZT0 light on time) effectively restored nondipping BP to normal dipping BP.In contrast when administered at the beginning of the active dark phase (ZT12 light off time) Ex worsenednondipping BP to reversed dipping (most harmful disruption). Our preliminary data also show for the first timethat GLP-1 receptor (GLP-1R) mRNA varies with the time of day and is regulated by clock gene BMAL1.Interestingly we also found that Ex administrated at ZT0 or ZT12 restored or inverted food intake rhythm indb/db mice in parallel with its effects on BP. Together with our recent publication that demonstrated time-restricted feeding effectively prevents and treats nondipping BP via the sympathetic nervous system (SNS) indiabetic db/db mice and literature evidence that the vagus nerve links food intake to modulation of BP wehypothesize that GLP-1RA administered at ZT0 inhibits food intake vagus nerve and SNS via the GLP-1receptor and its cross-talk with clock BMAL1 thus protecting BP circadian rhythm in type 2 diabetes. Twospecific aims are Aim 1. Investigate GLP-1RA as a novel chronomedicine to protect BP circadian rhythm viainhibiting food intake in type 2 diabetes. Aim 2. Define the mechanism by which GLP-1RA protects BPcircadian rhythm in type 2 diabetes. To achieve these goals we will determine the effects of short-acting GLP-1RA Ex and long-acting GLP-1RA liraglutide administered at ZT0 or ZT12 on the circadian rhythms ofmetabolism food intake clock genes SNS and BP in diabetic db/db db/db-Per2Luc Bmal1-iKO Glp1r-KObrain-specific Glp1r-KO and vagal neuron-specific Glp1r-KO mice under various feeding regimens. Theproposed studies will provide novel pre-clinical evidence suggesting GLP-1RA serves as a novelchronomedicine targeting the nondipping BP in type 2 diabetes thus improving prognoses and outcomes ofdiabetic patients. Furthermore results from the proposed studies will shed new light on how GLP-1RAs lowerBP thus laying a foundation for optimizing GLP-1RA therapy for diabetic patients.

project_terms:
ARNTL gene;Agonist;Animals;Anti-diabetic Drugs;Bilateral;Blood Pressure;Body Weight;Brain;Cardiovascular system;Chronic Disease;Chronotherapy;Circadian Rhythms;Clinical Trials;Darkness;Data;Diabetes Mellitus;Diabetic mouse;Duodenum;Eating;FDA approved;Fatty acid glycerol esters;Female;Foundations;Future;GLP-I receptor;Genes;Glycosylated hemoglobin A;Goals;High Fat Diet;Hippocampus;Hypertension;Hypothalamic structure;Knock-out;Knockout Mice;Knowledge;Light;Link;Literature;Mediating;Messenger RNA;Metabolism;Mus;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Phase;Prognosis;Publications;Regimen;Rest;Risk Factors;Role;Scheme;Sympathetic Nervous System;Time;Time-restricted feeding;Type 2 diabetic;Vagotomy;Vagus nerve structure;blood pressure reduction;cardiovascular risk factor;comorbidity;cost;db/db mouse;diabetic;diabetic patient;effective therapy;exenatide;feeding;gut-brain axis;improved;liraglutide;male;novel;pre-clinical;prevent;protective effect;sex;sexual dimorphism;targeted treatment

public_health_relevance:
PROJECT NARRATIVENormal blood pressure has a regular circadian rhythm which is disrupted in up to 75% of diabetic patients andassociates with detrimental cardiovascular outcomes. Using a glucagon-like-peptide-1 receptor agonist (GLP-1RA) an FDA approved anti-diabetic drug we found that it protects blood pressure circadian rhythm in diabeticmice only when administered during their resting time. This proposal will investigate mechanisms of thisprotective effect in diabetic mice for the future potential of GLP-1RA as a chronomedicine that correctsdisrupted blood pressure circadian rhythm in diabetic patients.


application_id: 11099147
project_number: 3R01GM150200-02S2
project_title: Study of PTPRF-Mediated Regulation of Wnt Signaling- Supplement
administering_ic: NIGMS
award_notice_date: 2024-09-04
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: GM
serial_number: 150200
suffix: S2
program_official: SALAZAR, DESIREE LYNN
project_start_date: 2023-06-01
project_end_date: 2027-03-31
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;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;knock-down;novel;novel therapeutic intervention;receptor;self-renewal;single-cell RNA sequencing;stem cell fate;stem cell function;stem cell proliferation;stem cells;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: 11098865
project_number: 3R01AA029798-04S1
project_title: Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
administering_ic: NIAAA
award_notice_date: 2024-06-11
opportunity_number: PA-20-185
application_type: 3
activity_code: R01
ic: AA
serial_number: 029798
suffix: S1
program_official: JUNG, KATHY
project_start_date: 2021-09-22
project_end_date: 2026-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
2.5% of United States population is affected by alcohol-associated liver disease (ALD) which represents theeighth most common cause of mortality. Despite significant progress in the field the complex mechanismsdriving the onset and progression of ALD are still not fully understood. cAMP is a second messenger that playsa critical role in regulating multiple cellular functions via its effectors (e.g. protein kinase A). Amplitude andduration of cAMP signaling is fine-tuned by phosphodiesterases (PDEs) via cAMP hydrolysis and degradation.Our work has shown that ethanol increases expression of hepatic PDE4 in experimental ALD as well as inalcohol-associated hepatitis (AH) patients livers. However their role in ALD pathogenesis is not clear. Westarted elucidating the role of PDE4s in ALD by demonstrating that Pde4b plays a critical role in ethanol-mediated impairment of fatty acid -oxidation and steatosis. We also showed that inhibition of PDE4 activityattenuates liver injury in in vivo and in vitro models of ALD. However underlying mechanisms of ethanolmediated induction of PDE4 enzymes have not been determined. Moreover how PDE4 inhibition exerts itsbeneficial effect on dysregulated lipid metabolism and hepatocytes survival is not fully understood. Ourpreliminary studies using animal and cell models of ALD identified novel pathways of ethanol and PDE4-mediated regulation of hepatic lipid metabolism and cell injury which have never been examined before. Basedon our previous work and preliminary data our central hypothesis is that ethanol via cytochrome p450(CYP2E1) mediated increase in hypoxia inducible factor 1 (HIF1) induces hepatic PDE4 whichcontributes to dysregulation of hepatic lipid metabolism and injury.The specific objectives of these mechanistic studies are to:Aim 1: Determine the underlying mechanisms of PDE4 upregulation by ethanol in hepatocytes.Aim 2: Determine mechanisms underlying ethanol/PDE4-mediated de novo lipogenesis and hepaticsteatosis.Aim 3: Determine the role of MKP1 in ethanol/PDE4-mediated toxicity in hepatocytes.The ultimate goal of this application is to identify not only the mechanisms of PDE4 upregulation but also therole of PDE4s in the development of ALD. Importantly we predict that these preclinical studies will providestrong rationale using PDE4 specific inhibitors in the treatment of ALD. Importantly there are potent PDE4inhibitors that are already FDA-approved for the treatment of other inflammatory disease processes and theseinhibitors could potentially be repurposed for ALD.

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

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


application_id: 11098405
project_number: 5T03OH010637-12
project_title: The Environmental and Occupational Health Science Program at Western Kentucky University
administering_ic: NIOSH
award_notice_date: 2025-07-02
opportunity_number: RFA-OH-22-003
application_type: 5
activity_code: T03
ic: OH
serial_number: 010637
program_official: O'NEILL, EDUARDO
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: ZOH1-DVN(03)
contact_pi_person_id: 14375391
contact_pi: TAYLOR, RITCHIE DON
other_pis: Not Applicable
congressional_district: 02
department: PUBLIC HEALTH & PREV MEDICINE
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 PUBLIC HEALTH
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Western Kentucky University offers undergraduate (B.S.) and graduate (M.S.) Environmental andOccupational Health Science (EOHS) Programs that are driven by the shortage of trained occupational safetyand health (OSH) and environmental health and safety (EHS) professionals in underserved regions ofKentucky that will advance worker safety and health. These programs have dedicated regional supportthrough the EOHS Advisory Board industries agencies first responders municipalities schools collegesuniversities and communities. The success rate of graduates from each program the inclusion ofunderrepresented trainees as well as the accreditation of the graduate program by the National EnvironmentalHealth Science and Protection Accreditation Council has established the credibility of the institution to offereach curriculum. Both the undergraduate and graduate EOHS Programs are supported by the NationalInstitute for Occupational Safety and Health (NIOSH) through a Training Project Grant (TPG). A critical need inthe region is to create a more diverse EOHS workforce especially in underserved rural areas. Continuance ofthe WKU NIOSH TPG will assist in meeting this need and provide opportunities for innovative educationalstrategies relevant to contemporary work exposures including the COVID-19 pandemic and the recent tornadodisaster in Kentucky. The EOHS Bachelor of Science (B.S.) and Master of Science (M.S.) degree programs at WKU arecomprehensive Science Technology Engineering and Mathematics (STEM) programs built on education inbasic and applied sciences and specialized training in anticipation recognition evaluation and control ofworkplace factors that may affect the health well-being and productivity of workers and the public. The overalleducational objective is a multidisciplinary approach that provides students a comprehensive understanding ofthe chemical biological physical and social factors or stressors in the occupational and natural environmentsthat impact public health outcomes. Specifically the NIOSH TPG will provide tuition scholarships and stipends training opportunities throughNIOSH ERCs webinars conferences and development and delivery of a series of workshops to train six (6)undergraduate students and seven (7) graduate students at minimum each project annum. Continued supportof the WKU EOHS Programs will ensure opportunities and training that will promote expertise in the OSHEHS and associated fields in rural and underserved communities in Kentucky and throughout the region.

public_health_relevance:
Public Health Relevance Statement To meet the public health needs of our regional communities the EOHS programs Bachelor of Scienceand Master of Science prepare students with a foundation in basic and applied sciences including biologychemistry mathematics physics geology and public health. The interdisciplinary application of training in theEOHS programs has led to the development of skills that trainees utilize in a variety of public health settings.Students graduating from the EOHS programs regularly pursue advanced degrees and have becomeoccupational safety and health specialists environmental health and safety specialists industrial hygienists orwork in closely related fields with emphases on human health protection and advancement in diverse worksitesand in underserved communities across Kentucky and beyond.


application_id: 11097778
project_number: 3R01AA028735-06S1
administering_ic: NIAAA
award_notice_date: 2024-06-11
opportunity_number: PA-17-297
application_type: 3
activity_code: R01
ic: AA
serial_number: 028735
suffix: S1
program_official: LIN, LI
project_start_date: 2021-11-01
project_end_date: 2026-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

project_abstract:
PROJECT SUMMARYApproximately ~7% of alcohol-consuming individuals engage in chronic heavy drinking (CHD) which isassociated with increased susceptibility to infections as well as impaired wound healing and tissue repairresulting in poor post-operative outcomes. Evidence suggests that many of these defects are mediated byexcessive inflammatory responses originating from myeloid cells notably circulating monocytes and tissue-resident macrophages. These data were primarily generated from in vitro studies where monocytes from healthydonors or cell lines are treated high doses of ethanol. However the mechanisms underlying the effects of CHDcannot be fully understood by in vitro studies because immune cells carry out their functions in a multicellularenvironment in which alcohol has widespread effects. Due to a lack of studies utilizing reliable in vivo modelsour understanding of the mechanisms underlying aberrant inflammatory responses in the context of CHDremains incomplete. To address these knowledge gaps we propose to leverage a rhesus macaque model ofvoluntary ethanol self-administration that accurately mirrors human physiology and recapitulates complex humandrinking behavior. Using this model our lab has recently demonstrated that CHD results in transcriptional andepigenetic rewiring of circulating monocytes and splenic macrophages resulting in aberrant responses to LPSstimulation. However the functional implications of this reprogramming and the epigenetic mechanismscontrolling it remain unknown. Importantly because monocytes are short-lived circulating cells under constantrepopulation from the bone marrow these observations suggest perturbations of the hematopoietic niche.Preliminary single-cell analyses of hematopoietic progenitors point to a shift in differentiation potential towardsmore mature myeloid progenitors with alcohol. However a link between this observation in progenitor cells andtheir differentiated states in blood and tissue remains unclear. In this application we propose to test thehypothesis that chronic alcohol consumption reprograms the epigenetic landscape of monocyteprogenitors in the bone marrow giving rise to circulating monocytes poised towards a hyper-inflammatory response. We will first examine the impact of CHD on functional reprogramming of circulatingmonocytes implementing assays to test their ability to migrate phagocytose and generate proper metabolicresponses. We will next examine the effect of stimulation on the monocyte epigenetic landscape throughassessment of chromatin accessibility and abundance of specific histone modifications. Finally we will determinethe effect of CHD on the differentiation potential transcriptome activation and epigenetic rewiring of bonemarrow myeloid progenitors and integrate these data with those obtained from peripheral blood monocytes.Completion of this proposal will provide novel insight into the impact of CHD on myelopoiesis and mechanismsby which it compromised immunity and host defense as well as design interventions to mitigate these adverseevents and improve immunological outcomes.

project_terms:
ATAC-seq;Abstinence;Address;Adverse event;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Animals;Area;Bacterial Infections;Biological Assay;Biological Response Modifiers;Biology;Blood;Blood specimen;Bone Marrow;Cardiovascular Diseases;Categories;Cell Line;Cells;Chromatin;Chronic;Chronic Disease;Communicable Diseases;Complex;Data;Defect;Development;Dose;Environment;Epigenetic Process;Ethanol;Etiology;Event;Failure;Female;Gene Expression;Genetic Transcription;Goals;Health;Heavy Drinking;Hematopoietic;Hematopoietic stem cells;Heterogeneity;Homeostasis;Host Defense;Housing;Human;Immune;Immune Tolerance;Immunity;Immunocompetence;Immunologics;Immunology procedure;Impaired wound healing;In Vitro;Individual;Infection;Inflammation Mediators;Inflammatory;Inflammatory Response;Intercistronic Region;Intervention;Knowledge;Link;Macaca;Macaca mulatta;Macrophage;Mediating;Metabolic;Metabolism;Modeling;Myeloid Cells;Myeloid Progenitor Cells;Myelopoiesis;Natural Immunity;Outcome;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phenotype;Physiology;Population;Postoperative Period;Predisposition;Promoter Regions;Reporting;Research;Respiratory Tract Infections;Risk;Sampling;Self Administration;Testing;Tissues;Virus Diseases;alcohol availability;alcohol effect;antimicrobial;cancer type;chronic alcohol ingestion;comparison control;cytokine;data integration;drinking behavior;epigenome;experimental study;fitness;histone modification;immune activation;improved;in vivo;in vivo Model;insight;male;migration;monocyte;next generation sequencing;nonhuman primate;novel;pathogen;peripheral blood;progenitor;programs;response;single cell analysis;single-cell RNA sequencing;stem cells;therapy design;tissue repair;transcriptome;transcriptomics;wound healing

public_health_relevance:
PROJECT NARRATIVE/RELEVANCEApproximately 7% of alcohol users engage in chronic heavy drinking (CHD) which is associated with increasedrisk of bacterial and viral infections as well as decreased tissue repair ability. These observations suggest afailure of innate immune cells to perform their functions. The proposed research aims to identify CHD-mediatedfunctional transcriptomic and epigenetic alterations in monocytes and their progenitors in the bone marrow withthe goal of better understanding the etiology of reduced immune fitness.


application_id: 11097184
project_number: 5R21AI182568-02
administering_ic: NIAID
award_notice_date: 2025-04-25
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 182568
program_official: BOWDEN, NADINE
project_start_date: 2024-06-01
project_end_date: 2027-04-30
study_section: Transmission of Vector-Borne and Zoonotic Diseases Study Section [TVZ]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_title:
Impacts of Borrelia burgdorferi Gac protein on infectivity and regulation of virulence protein expression

project_abstract:
ABSTRACTWe recently found that the Gac DNA-binding protein of Borrelia burgdorferi the Lyme disease bacteriumfunctions as a transcriptional repressor of the essential ospC gene. RNA-sequencing (RNA-Seq) analyses of agac mutant revealed that Gac impacts levels of transcripts of several other virulence-associated proteinsincluding the alternative sigma factors RpoN and RpoS. Prior studies demonstrated that RpoN is required forexpression of RpoS and both are required for mammalian infection. The planned studies will furtherinvestigate the functions of Gac in the Lyme disease spirochete including its impacts on mammalian and tickinfection and molecular characterization of Gac's impacts on rpoN expression. Results of these studies willprovide important insights on regulatory mechanisms that control virulence of the Lyme disease spirochete andhelp identify key components for development of improved specific antibacterials.

project_terms:
Anti-Bacterial Agents;Applications Grants;Bacteria;Bacteria sigma factor KatF protein;Bacterial Adhesins;Binding Sites;Biochemical;Borrelia;Borrelia burgdorferi;C-terminal;DNA;DNA Binding Domain;DNA Gyrase;DNA-Binding Proteins;Development;Enzymes;Exhibits;Genes;Infection;Initiator Codon;Investigation;Life;Lyme Disease;Mammals;Membrane Proteins;Messenger RNA;Molecular;Mus;Names;Open Reading Frames;Operon;OspC protein;Process;Production;Protein Binding Domain;Proteins;Regulation;Reporter;Ribosomes;Role;Series;Sigma Factor;Site;Structure;Surface;Tertiary Protein Structure;Ticks;Time;Transcript;Transcription Repressor;Transcriptional Regulation;Vertebrates;Virulence;curative treatments;genetic analysis;improved;insight;mutant;novel;pathogenic microbe;promoter;protein expression;transcriptome sequencing;transmission process;vector

public_health_relevance:
NARRATIVEThe Lyme disease spirochete Borrelia burgdorferi produces a unique DNA-binding protein named Gac. Ourbiochemical and genetic analyses indicate that Gac regulates expression of several genes that encode proteinsthat are essential for mammalian infection including the alternative sigma factors RpoN and RpoS. Our studieswill define the role of Gac during B. burgdorferi infection processes and assess the mechanism by which Gaccontrols transcription of RpoN.


application_id: 11096674
project_number: 2P20GM135004-06A1
project_title: The role of ECM-mediated mechanosignaling on regional immunosuppression in GBM
administering_ic: NIGMS
award_notice_date: 2025-08-25
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 135004
suffix: A1
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9609
contact_pi_person_id: 12556833
contact_pi: CHEN, JOSEPH
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
project_abstract:
PROJECT SUMMARY (PROJECT 3  CHEN)The role of ECM-mediated mechanosignaling on regional immunosuppression in GBMRecent studies reveal that immunosuppressive regions vary substantially throughout the heterogeneousglioblastoma (GBM) tumor microenvironment. These immune-restricted niches appear to correspond to specificextracellular matrix (ECM) components that are thought to drive regional mesenchymal transition. Wehypothesize that these spatially distinct GBM mesenchymal regions both coincide with and are responsible formonocytic myeloid-derived suppressor cell (M-MDSC) infiltration. Our COBRE project hypothesis predicts thatchanges in regional hyaluronic acid (HA) ECM stiffness induce the activation of proneural GBM cell surfaceCD44 that in turn drives mesenchymal transition and increases an M-MDSC recruiting/differentiationtranscriptional program associated with cytokine secretion. Studies proposed in this phase 2 CCII COBREapplication will (1) rigorously delineate the mechanistic pathway and effectors involved by focusing on ahypothesized HACD44STAT3/ZEB1-dependent pathway and (2) delineate whether/how regional activationof this pathway results in a STAT3/ZEB1-dependent induction of IL-6/IL-17-mediated regional accumulation ofM-MDSC-dependent immune suppression in GBM. We anticipate that results from this phase 2 COBRE projectproposal will identify a new targetable axis and address a critical gap in our understanding of the impact ofbiophysical changes in GBM TME.

project_terms:
Address;Affect;Atomic Force Microscopy;Automobile Driving;Behavior;Biophysics;CD44 gene;CD8-Positive T-Lymphocytes;Cancer Center;Cell Differentiation process;Cell Line;Cell Physiology;Cell surface;Cells;Centers of Research Excellence;Data;Development;Epithelium;Extracellular Matrix;Genetic Transcription;Glioblastoma;Human;Hyaluronic Acid;Hydrogels;IL17 gene;Immune;Immune checkpoint inhibitor;Immunity;Immunocompetent;Immunosuppression;Immunotherapy;Implant;In Vitro;Infiltration;Interleukin-6;Lesion;Link;Malignant - descriptor;Malignant Neoplasms;Maps;Mechanics;Mediating;Mesenchymal;Mesenchymal Differentiation;Modeling;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Outcome;Pathway interactions;Patients;Pattern;Phase;Phenotype;Primary Brain Neoplasms;Publishing;Refractory;Regulation;Reporting;Role;STAT3 gene;Sampling;Scheme;Signal Transduction;Solid;Stains;T-Lymphocyte;Testing;Tissues;anti-tumor immune response;cancer immunotherapy;cytokine;differentiation in vitro;effective therapy;in vivo;insight;monocyte;novel;overexpression;programs;receptor;recruit;transcriptomics;transplant model;tumor;tumor immunology;tumor microenvironment


application_id: 11096673
project_number: 2P20GM135004-06A1
project_title: DP1 receptor signaling in aging-associated immune dysfunction in lung metastases
administering_ic: NIGMS
award_notice_date: 2025-08-25
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 135004
suffix: A1
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9608
contact_pi_person_id: 15121646
contact_pi: ZHENG, JIAN
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
project_abstract:
PROJECT SUMMARY (PROJECT 2  ZHENG) DP1 receptor signaling in aging-associated immune dysfunction in lung metastases Recent studies from our laboratory revealed that age-related anti-viral immune dysfunction in therespiratory tract is driven by the increased expression of an inducible phospholipase A2 group IID (PLA2G2D)enzyme and the prostaglandin D2 receptor DP1. Specifically we discovered that age-related mortality in SARs-CoV2-infected mice were largely reversed in both PLA2G2D-/- and DP1-/- mice as a consequence of enhancedlung dendritic cell (DC) mediated anti-viral-specific T cell responses. These survival benefits were subsequentlyconfirmed in mice treated with a highly specific DP1 receptor antagonist Asapiprant which is currently beingtested in phase II clinical trials. In our new preliminary studies we have confirmed this age-related immunedysfunction pathway also exists in metastatic lung tumor-bearing mice. Specifically we have found that PLA2G2Dor DP1 deficiency very effectively restricts the growth of melanoma lung metastasis in a manner that correlateswith a substantial early enrichment of -T cells. In this phase 2 CCII COBRE project we hypothesize thatPLA2G2D/PGD2-DP1 signaling contributes to primary and metastatic tumor growth in the lung and acts byinhibiting age-associated inflammasome activation in lung DCs. To test this hypothesis we will: 1) Determine themechanisms and signaling effectors underlying PLA2G2D/PGD2-DP1 signaling in lung DCs from aged tumorbearing mice and 2) Investigate the potential of the DP1-targeting small molecule Asapiprant as a potentialmono-immunotherapy in treating clinically relevant lung primary and metastatic disease models. Finally thesestudies will evaluate whether DP1 targeting in immune checkpoint blockade (ICB) resistant implantable andspontaneous tumor models is sufficient to reduce resistance/increase efficacy in combination with anti-PD-1.

project_terms:
2019-nCoV;Adoptive Transfer;Age;Aging;Animal Model;Anti-Inflammatory Agents;Biological Assay;CD8B1 gene;COVID-19 pandemic;Cancer Center;Centers of Research Excellence;Chronic;Dendritic Cells;Disease;Dopamine D2 Receptor;Enzymes;Exhibits;Formalin;Goals;Growth;Human;Immune;Immune Evasion;Immune System Diseases;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Implant;In Vitro;Inflammaging;Inflammasome;Inflammatory;Laboratories;Lesion;Leukotrienes;Link;Lipids;Lung;Lung Neoplasms;Malignant Neoplasms;Mediating;Melanoma;Metastatic Neoplasm to the Lung;Modeling;Mus;Myeloid Cells;Neoplasm Metastasis;Paraffin Embedding;Pathway interactions;Phase;Phase II Clinical Trials;Phospholipase A2;Primary Neoplasm;Process;Production;Prostaglandin D2;Prostaglandin Production;Prostaglandins;Receptor Signaling;Resistance;Respiratory System;Respiratory Tract Infections;Signal Transduction;Slide;Solid;Solid Neoplasm;T cell response;T-Lymphocyte;Testing;Thromboxanes;Transgenic Animals;Tumor Burden;Tumor Immunity;Viral;Wild Type Mouse;age related;aged;aging related;antagonist;anti-PD1 antibodies;anti-tumor immune response;antitumor effect;biobank;cancer immunotherapy;cell age;clinically relevant;disease model;fighting;immune checkpoint blockade;immunodeficiency;inducible gene expression;insight;lung metastatic;middle age;mortality;novel;old mice;pulmonary;receptor;recruit;response;small molecule;targeted treatment;therapeutic target;treatment strategy;tumor;tumor growth;tumor immunology;tumor microenvironment; T cells


application_id: 11096672
project_number: 2P20GM135004-06A1
project_title: Leveraging Zika virus driven myeloid cell responses to treat GBM
administering_ic: NIGMS
award_notice_date: 2025-08-25
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 135004
suffix: A1
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9607
contact_pi_person_id: 12629057
contact_pi: NAIR, SHARMILA
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
project_abstract:
PROJECT SUMMARY Leveraging Zika virus-driven myeloid cell responses to treat GBM Oncolytic viral therapy shows promise for high-grade solid tumors but none have been shown to providecurative potential. This study explores the potential of harnessing the natural tropism of Zika virus (ZIKV) totarget glioblastoma stem cells (GSCs) and reprogram the typically immune suppressive GBM tumor environmentto an inflammatory antigen-presenting environment that induces GBM-specific CD8+ T cell responses. The firstgoal of this proposal is to identify the cellular mechanisms that drive anti-tumor T cell responses following ZIKVtreatment. Our research will examine the functional roles of two distinct myeloid cell subsets induced followingZIKV treatment - CCR2+ monocytes in the tumor microenvironment (TME) and dendritic cell subset-2 (DC-2s) indraining lymph nodes (dLN) - in driving anti-tumor T cell responses against GBM. Additionally our study willexamine the synergistic therapeutic potential of a highly novel Flt3 ligand therapy and ZIKV combination therapyas a strategy to activate both dendritic cell subset-1 (DC-1s) and DC-2 to maximize anti-tumor CD8+ T cellresponses and subsequent GBM rejection. This research is significant because 1) it addresses the potential ofZIKV as an effective oncolytic virus for GBM treatment 2) identifies key cellular mechanisms that contribute toits anti-tumor effects and 3) addresses the current failure of immunotherapy and maps a therapeutic path forward.

project_terms:
Address;Antigen Presentation;Antigen-Presenting Cells;Automobile Driving;Brain Mapping;Brain Neoplasms;CD8-Positive T-Lymphocytes;Cancer Center;Cell Physiology;Cells;Combined Modality Therapy;Data;Dendritic Cells;Environment;FLT3 ligand;Failure;Glioblastoma;Goals;Immune;Immune response;Immunologics;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Individual;Inflammatory;LoxP-flanked allele;Macrophage;Maps;Mediating;Melanoma;Microglia;Mus;Myeloid Cells;Nature;Oncolytic;Oncolytic viruses;Patients;Recurrence;Research;Role;Solid Neoplasm;T cell response;Testing;Therapeutic;Tropism;Tumor Stem Cells;Work;Zika Virus;antitumor effect;cancer cell;cancer immunotherapy;draining lymph node;glioblastoma stem cell;improved;monocyte;novel;oncolytic Zika virus;oncolytic virotherapy;programs;radioresistant;response;survival outcome;tumor;tumor immunology;tumor microenvironment


application_id: 11096671
project_number: 2P20GM135004-06A1
project_title: Center for Cancer Immunology and Immunotherapy (CCII) - Functional Immunomics Core (FIC)
administering_ic: NIGMS
award_notice_date: 2025-08-25
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 135004
suffix: A1
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9606
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
project_abstract:
ABSTRACT In this Phase 2 of the Cancer Immunology and Immunotherapy COBRE the primary goal of theFunctional Immunomics Core (FIC) remains unchanged. We will expand and enhance the well-establishedintegrated service center that functions as a critical resource for the Research Project Leaders (RPLs) as apriority and secondarily for all investigators of the Center. Since all new COBRE projects utilize mouse modelsto explore the inter-relationships between the immune system and tumor progression with the goal of identifyingpotential new therapeutic strategies our well-established immune cell analysis platform using CyTOF willcontinue to be the major area of focus for the FIC. In the last two years we have also established imaging masscytometry (HyperionTM) allowing high resolution spatial profiling of immune cell subsets to determine the role ofheterogeneity in cell function and complex phenotypes. Additionally we have enhanced our flow sortingcapabilities by acquiring the BD FACSymphonyTM S6 cell sorter a compact machine with six-way sortingcapability and self-contained in a laminar flow hood for safe handling of human tissue samples.Another objective of the FIC is to allow rapid adaptation of novel and innovative technologies as theybecome available. The FIC has identified two important areas for development during Phase 2 of the COBREaward: 1) small animal imaging and 2) spatial biology. Jointly with the Functional Microbiomics Core of theFunctional Microbiomics Inflammation and Pathogenicity (FMIP) COBRE at the University of Louisville we haveacquired Visium CytAssist technology for executing spatial transcriptomics analysis. We also secured fundingfor establishing high resolution Molecubes PET/CT imaging system which will greatly expand the capabilities ofthe FIC during Phase 2 providing our RPLs access to these new technologies. Besides functioning as a servicecenter another major goal of the FIC is to promote the education and training of researchers primarily the RPLs.The FIC will collaborate with other Core facilities at the University of Louisville such as the GenomicsMetabolomics and Bioinformatics core facilities established with the support of other highly successfulCOBRE/INBRE programs. In particular the newly renewed Phase 2 FMIP COBRE-operated FunctionalMicrobiomics Core facility also directed by Dr. Bodduluri has several joint initiatives with the FIC including theestablishment of intravital imaging service. We have established a fee schedule for FIC services and developeda sustainability plan. Additionally we set up a Core Advisory Committee (CAC) with three highly qualifiedexperts at the University of Louisville to advise on core usage accessibility quality of service and charges. Asan independent body the CAC will provide an overall assessment of core progress and help in conflict resolution.

project_terms:
Adopted;Advisory Committees;Area;Award;Bioinformatics;Bioinformatics core;Biology;Cancer Center;Cell Physiology;Cell Separation;Cells;Centers of Research Excellence;Charge;Clinical;Collaborations;Complex;Core Facility;Cytometry;Data Analyses;Development;Equipment;Fee Schedules;Fee-for-Service Plans;Fostering;Funding;Genomics;Goals;Heterogeneity;Human;Image;Immune;Immune system;Individual;Inflammation;Infrastructure;Institution;Joints;Laboratories;Malignant Neoplasms;Mentors;Methodology;Mission;Monitor;Mus;PET/CT scan;Pathogenicity;Phase;Phenotype;Positron-Emission Tomography;Protocols documentation;Qualifying;Research;Research Personnel;Research Project Grants;Research Support;Resolution;Resources;Role;Sampling;Secure;Service setting;Services;Sorting;Specimen;System;Techniques;Technology;Tissue Sample;Tissues;Training;Training and Education;Translational Research;Universities;Work;X-Ray Computed Tomography;animal imaging;cancer immunotherapy;clinical translation;conflict resolution;data acquisition;data integration;experimental study;human tissue;imaging system;immunotherapy clinical trials;innovation;innovative technologies;instrument;intravital imaging;intravital microscopy;investigator training;metabolomics;microbiome research;mouse model;new technology;novel therapeutic intervention;operation;programs;protocol development;spatial transcriptomics;success;tumor;tumor immunology;tumor progression


application_id: 11096670
project_number: 2P20GM135004-06A1
project_title: Center for Cancer Immunology and Immunotherapy (CCII) - Admin Core
administering_ic: NIGMS
award_notice_date: 2025-08-25
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 135004
suffix: A1
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9605
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
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
project_abstract:
The goal of the Center for Cancer Immunology and Immunotherapy (CCII) COBRE Phase 2 program is to enhance and expand a thematic multidisciplinary research center of excellence at the University of Louisville. This Center focuses on improving our understanding of cancer immunology and developing novel immunotherapeutic approaches. The Administrative (Admin) Core will coordinate the professional activities of the more than 30 individuals in the CCII COBRE program. It will provide administrative fiscal and scientific oversight and planning for research project leaders (RPLs) mentors the research core a pilot project program and an advisory committee. In addition to governance functions the Admin Core will provide key research and mentoring support and assist with new recruitment for COBRE-eligible junior investigators. This support will include the awarding of project grants assignment of mentors provision of a Grant Mentorship Program (GMP) biostatistics and data science/bioinformatics support compliance and regulatory oversight and mentoring of pilot projects. The Advisory Committee (AC) which consists of three leading scientists in the CCII thematic area one senior institutional official and one senior faculty member will provide scientific guidance and constructive feedback regarding center/project/research core progress. It will also be involved in CCII strategic planning and in the selection of replacement and pilot projects. The two Center Co-Directors will direct the Admin Core with key support from a Steering Committee (SC) which comprises two co-Investigators and research core Director. The Admin core also includes two additional co-Investigators who are well qualified to oversee the essential biostatistics and data science/bioinformatics support. Their efforts will supplement a mentoring program that is anchored by nine senior investigators who are experienced mentors and have been highly productive and well-funded in the thematic area. The three specific aims of this Admin Core which encompass all of these functions are to: (1) Provide scientific leadership and administrative oversight for coordinating thematic research on cancer immunology and immunotherapy; (2) Provide support for the development of highly competitive RPLs through mentoring and career development programs within the CCII program; and (3) Expand the CCII pilot project program to further stimulate new projects and collaborations. Innovative features of the Admin Core are built on lessons learned from establishing other multidisciplinary thematic centers and include a shared governance approach that aims to ensure engagement of all participants. A holistic mentoring strategy provides comprehensive guidance for our CCII RPLs. Other innovative features of the Admin Core include a creation of two-types of pilot projects: one for junior investigators to help develop NIH R01-type award and another for team science projects that involve 3 or more faculty to provide an initial framework to pursue NIH program projects. This novel approach will help to both identify pipeline RPLs and to promote collaborative research to expand and sustain the Center.

project_terms:
Achievement;Address;Advisory Committees;Area;Award;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Cancer Patient;Centers of Research Excellence;Collaborations;Committee Members;Core Facility;Data Science;Development;Eligibility Determination;Ensure;Evaluation;Extramural Activities;Faculty;Feedback;Fostering;Funding;Future;Goals;Grant;Guidelines;Immunologic Tests;Immunooncology;Immunotherapeutic agent;Individual;Institution;Interdisciplinary Study;Journals;Kentucky;Leadership;Mentors;Mentorship;Participant;Phase;Pilot Projects;Preparation;Productivity;Program Development;Qualifying;Research;Research Personnel;Research Project Grants;Science;Scientist;Series;Services;Strategic Planning;Study Section;Technology;Testing;Training;Translational Research;Tumor Escape;United States National Institutes of Health;Universities;Work;Writing;cancer immunotherapeutics;cancer immunotherapy;career development;collaborative environment;expectation;experience;improved;innovation;meetings;member;multidisciplinary;novel;novel strategies;programs;recruit;senior faculty;symposium;tumor immunology


application_id: 11096669
project_number: 2P20GM135004-06A1
project_title: Center for Cancer Immunology and Immunotherapy (CCII)
administering_ic: NIGMS
award_notice_date: 2025-08-25
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 135004
suffix: A1
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
This renewal application is seeking continued support for the Center for Cancer Immunology & Immunotherapy (CCII) COBRE program at the University of Louisville (UofL). The mission of the CCII COBRE is to conduct outstanding research while simultaneously training the next generation of tumor immunologists to harness the power of the immune system to eradicate cancer. UofL is exceptionally qualified to make an impact in this area for many reasons including our expertise in basic cancer immunology our long track record of conducting clinical trials of immunotherapy agents and our focus on translational research. The CCII COBRE has been very successful to date. Three of the four Phase 1 Research Project Leaders (RPLs) have already obtained major NIH/DOD funding as PIs and graduated from COBRE support while the other one is on track to obtain independent R01 awards. We also rotated one new RPL into the Program. The Center has also made strong progress in terms of its publications infrastructure and pipeline. Importantly UofL is highly invested in the success of the CCII as evidenced by more than $16.8M in institutional commitments in Phase 1 and additional commitments of over $17M for Phase 2. The CCII has four specific aims for Phase 2: (1) Expand and strengthen a multidisciplinary program in research training mentoring and career development; (2) Enhance research resources to promote and expand innovative thematic research; (3) Expand the CCII Pilot Project Program (PPP); and (4) Continue working towards the long-term sustainability of the CCII. The program will continue to be led in Phase 2 by two highly regarded experts in the field who have made seminal contributions spanning from basic cancer immunology (PI Yan) to pivotal clinical trials of cancer immunotherapies (co-I Chesney). Mentors with expertise in the thematic area and a strong history of funding publications mentoring and study section service will support the Administrative Cores mentoring mission as will an Advisory Committee consisting of renowned external experts and UofL leaders. The state-of-the-art CCII Functional Immunomics Core that was created in Phase 1 will be further expanded to provide vital education expertise and equipment to support three new RPLs in Phase 2. The first cohort of selected RPLs in Phase 2 strengthen and expand the thematic research area and add new aspects (glioblastoma oncolytic viruses). We are confident that renewal of this COBRE will lead to at least four more RPLs obtaining their first independent R01-type or similar grants in Phase 2 and that as with Phase 1 many of these COBRE graduates will remain key members of the CCII to further grow the Center in the future. Most importantly our combination of rigorous basic science with highly translational animal and human specimen studies should ultimately enable the development of new treatment strategies that will help to improve the outlook for the more than 17 million people worldwide who are diagnosed with cancer each year.

project_terms:
Advanced Malignant Neoplasm;Advisory Committees;Animals;Area;Award;Basic Science;Bioinformatics;Biology;Biometry;CAR T cell therapy;Cancer Center;Career Mobility;Centers of Research Excellence;Cessation of life;Clinical;Collaborations;Conduct Clinical Trials;Core Facility;Development;Diagnosis;Disease remission;Education;Environment;Equipment;Faculty;Funding;Future;Genomics;Glioblastoma;Goals;Grant;Growth;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune system;Immunobiology;Immunologist;Immunotherapeutic agent;Immunotherapy;Infrastructure;Institution;Investments;Journals;Kentucky;Malignant Neoplasms;Mediating;Mentors;Methods;Mission;Nature;Oncolytic viruses;Patients;Peer Review;Persons;Phase;Pilot Projects;Proteins;Publications;Publishing;Qualifying;Recording of previous events;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resistance;Resources;Rotation;Schools;Science;Secure;Seminal;Services;Specimen;Study Section;Talents;Training;Translating;Translational Research;Tumor Immunity;United States;United States National Institutes of Health;Universities;Work;animal imaging;anti-cancer;cancer cell;cancer clinical trial;cancer immunotherapy;cancer therapy;cancer type;career development;cohort;experience;imaging capabilities;immune checkpoint;immunotherapy clinical trials;improved;innovation;insight;member;microbiome research;multidisciplinary;next generation;novel strategies;novel therapeutic intervention;operation;programs;recruit;response;success;treatment strategy;tumor;tumor immunology

public_health_relevance:
Decades of research have demonstrated that the immune system can eradicate cancer cells but only if immune evasion mechanisms such as immune checkpoint proteins can be overcome. Multiple new immunotherapeutic approaches have recently been developed that can induce durable remissions in patients with advanced cancers  unfortunately most patients still succumb to their cancers. The goal of this COBRE Phase 2 application is to enhance the successful Center for Cancer Immunology & Immunotherapy that focuses on understanding immune escape mechanisms developing new approaches to activate and reinvigorate anticancer immunity training promising junior cancer immunologists and improving the research infrastructure at the University of Louisville.


application_id: 11096639
project_number: 1T32DK138894-01A1
project_title: Diabetes and ObesitY research training in kENtucky (DOYEN)
project_terms: Diabetes Mellitus;Kentucky;Obesity;Research Training
administering_ic: NIDDK
award_notice_date: 2025-07-23
opportunity_number: PA-23-048
application_type: 1
activity_code: T32
ic: DK
serial_number: 138894
suffix: A1
program_official: CASTLE, ARTHUR
project_start_date: 2025-08-01
project_end_date: 2030-07-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
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
project_abstract:
ABSTRACTThe primary goal of the Diabetes and ObesitY research training in kENtucky (DOYEN) T32 program is toprepare nationally competitive predoctoral students and postdoctoral fellows at the University of Kentucky forcareers spanning from basic research to community interventions in the field of diabetes and obesity research.Having historically received low levels of support from NIH Kentucky is an Institutional Development Awards(IDeA) Program state and seeks to enhance research training that serves the unhealthy populations in theCommonwealth of Kentucky. For much of the last 30 years Kentucky has consistently ranked among thenations five least healthy states. To address these disparities DOYEN trainees who focus on clinical andimplementation research will have an unprecedented opportunity to investigate the often-understudied ruralcommunities unique to Kentucky. The need for highly trained scientists capable of conducting rigorousresearch is critical given the increase in diabetes and obesity both globally and in Kentucky. Integration of T0-T4 diabetes and obesity research themesspanning basic pre-clinical/translational clinical implementationand population healthscientifically anchors the proposed program which will challenge PhD students andpostdoctoral fellows to explore innovative concepts. The DOYEN program is scientifically unique within theNIDDK T32 portfolio in that it leverages the research interests and strong funding portfolio of 20 experiencedFaculty Mentors 7 emerging mentors and a deep pool of talented trainees from 8 colleges and 7 biomedicalprograms. Pre- and postdoctoral DOYEN trainees will gain valuable experience on their way to becomingexceptional leaders in the research workforce. Research careers in this area are especially attractive to the~25% of our trainees who originate from socioeconomically challenged areas of Kentucky where diabetes andobesity are particularly prevalent. The trainees that we recruit from this population will add diversity to theprogram and the future biomedical workforce. The goals of the DOYEN program are to: 1) provide outstandingtrainees an innovative multidisciplinary education that promotes essential and contemporary skills forconducting rigorous and impactful research focusing on metabolic diseases; 2) support 4 PhD students and 2postdoctoral fellows through stipends travel funds workshops and individual development plans; and 3)provide a critical mass of productive and established Faculty Mentors for T32 trainees both one-on-one and inteams in a scientifically rigorous broad-based ethics- and diversity-sensitive environment. Individualized andrequired training in rigorous experimental design data science and quantitative analyses team sciencescientific presentation and grant writing will provide program-specific enrichments for T32 trainees pursuingmechanistic and intervention studies among the T0-T4 themes. Trainees who receive 1-2 years of trainingthrough this multidisciplinary DOYEN program will develop world-class research skills that prepare them forcareers in innovative biomedical research that tackles complex disease processes in the diabetes and obesityfield.

public_health_relevance:
PROJECT NARRATIVEThe proposed Diabetes and ObesitY research training in kENtucky (DOYEN) program represents amultidisciplinary team-based approach involving multiple PIs to mentor predoctoral trainees and postdoctoralfellows in fundamental aspects of diabetes and obesity translational science of diabetes and advancement oftherapeutics for diabetes. DOYEN will prepare these trainees to become independent investigators who arefully integrated in multidisciplinary diabetes research teams that tackle the challenges associated with thedisproportionately high rates of diabetes and obesity in Kentucky.


application_id: 11096044
project_number: 5R01HL166280-03
project_title: Mechanisms of L-type Calcium Channel Regulation in Heart Health and Disease
administering_ic: NHLBI
award_notice_date: 2025-05-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 166280
program_official: BALIJEPALLI, RAVI C
project_start_date: 2023-07-31
project_end_date: 2027-05-31
study_section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
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:
Inotropic support for hearts progressing towards failure represents an unmet need. Direct attempts to improvesystolic function by activating -adrenergic receptor (-AR) signaling increases associated risk of heart failureand death. Calcitropes (agents influencing Ca2+ handling) that bypass -AR signaling are not necessarilyproarrhythmic. Our working global hypothesis based on our recent and ongoing work studying RAD regulationof the L-type Ca2+ channel (LTCC) is that bypassing -AR signaling to increase Ca2+-induced Ca2+ release (CICR)provides safe stable gain of function to counter heart failure progression. In this application we focus on themechanisms of Rad  LTCC interactions as a novel means to instill inotropic support to the heart. The LTCC isa macromolecular hub that integrates multiple signaling pathways including protein kinase A (PKA) and Ca2+-calmodulin kinase II (CaMKII). RAD is a member of the RGK family of monomeric G-proteins. RAD binds toauxiliary CaV2 and CaV1.2 the pore-forming subunit of the LTCC. Deletion or phosphorylation of RAD causesLTCC current (ICaL) modulation and facilitation. Modulation of ICaL is commonly observed after -AR signaling toactivate PKA; facilitation is caused by CaMKII activation. In Specific Aim 1 we will dissect how RAD integrateseach of these signaling pathways using a combination of pharmacological and genetic approaches. In SpecificAim 2 we will explore RAD  CaV1.2 structure-function using knock-in models of genetically modified mice thatallow us to explore RAD  LTCC effects retaining native stoichiometry of the LTCC heteromultimeric proteincomplex. Specific Aim 3 explores RAD  LTCC interplay as an approach to attenuate progression of heart failure.To achieve these goals we will integrate findings among Aims using in vivo ex vivo and cellular/molecularapproaches in animal models. Ex vivo human heart slices will be tested to evaluate the translational potential ofRAD  LTCC regulation in heart health and disease.

project_terms:
Acceleration;Address;Agonist;Angiotensins;Animal Model;Attenuated;Binding;Biophysics;Bypass;C-terminal;Ca(2+)-Calmodulin Dependent Protein Kinase;Calcium Channel;Cardiac health;Cessation of life;Clinical Trials;Cyclic AMP-Dependent Protein Kinases;Data;Diuretics;Down-Regulation;Failure;Family;Family suidae;Gene Modified;Goals;Health;Heart;Heart Diseases;Heart failure;Human;Hydrophobicity;Inotropism;Kinetics;Knock-in;Knock-in Mouse;Knock-out;L-Type Calcium Channels;Macromolecular Complexes;Measures;Mediating;Modeling;Modification;Molecular;Monomeric GTP-Binding Proteins;Mouse Strains;Mus;Myocardial Contraction;Pathologic;Patients;Phosphatidylinositol 45-Diphosphate;Phosphorylation;Pilot Projects;Preparation;Receptor Signaling;Regulation;Risk;Risk Reduction;Safety;Sarcomeres;Signal Pathway;Signal Transduction;Slice;Structural Models;Structure;Sympathomimetics;Testing;Therapeutic;Therapeutic Uses;United States;Work;antagonist;beta-adrenergic receptor;disease model;early phase clinical trial;follow-up;gain of function;genetic approach;heart failure with reduced ejection fraction;improved;in vivo;loss of function;member;novel;novel therapeutics;pharmacologic;phosphoric diester hydrolase;protein complex;response;sensor;stoichiometry;success;translational potential;voltage

public_health_relevance:
Heart failure is a major health problem in the United States. By definition heart failure involves the inability ofthe heart to generate sufficiently forceful contractions - defined as an insufficient inotropic response. Thisproposal tests foundational molecular interactions that regulate force of heart contractions.


application_id: 11095842
project_number: 5T32AA027488-07
project_title: Interdisciplinary Training in Alcohol Research
project_terms: Training;alcohol research
administering_ic: NIAAA
award_notice_date: 2025-07-30
opportunity_number: PA-23-048
application_type: 5
activity_code: T32
ic: AA
serial_number: 027488
program_official: GRAKALIC, IVANA
project_start_date: 2019-05-01
project_end_date: 2029-04-30
study_section: ZAA1-CC(32)
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: PRENDERGAST, MARK A
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
AbstractThis competing continuation application seeks an additional five years of support for a pre-doctoralinterdisciplinary training program in research on alcohol and alcohol use disorders. The training program ledby co-directors Drs. Fillmore and Prendergast is based in the Psychology Department at the University ofKentucky but includes preceptors from five departments and two colleges across the UK campus. The programprovides graduate students with interdisciplinary training to effectively investigate and discover the intricaciesand complexities of alcohol use disorders at all levels of investigation from the cellular and neurophysiologicalsystems to the roles of personality social and environmental factors. The need for a translational andinterdisciplinary program in the investigation of alcohol use disorders is great as advancements anddiscoveries continue to be made across multiple levels of investigation. This core expertise among our trainingfaculty allows us to deliver a true interdisciplinary laboratory training experience on alcohol use disorders notreadily available or duplicated elsewhere. The first period of this T32 award witnessed impressiveaccomplishments by our trainees as indicated by their publications scholarly awards including F31s and post-doctoral placements in research and clinical centers specializing in alcohol use disorders. This continuationapplication seeks to build on that success during the next award period.

public_health_relevance:
The purpose of this renewal application is to continue a translational and interdisciplinary training program inalcohol research. This multidisciplinary program provides training in bio-behavioral factors associated withinalcohol-use disorders at the pre-doctoral level; graduates of this program are actively involved in researchteaching publishing articles and becoming independent researchers in the alcohol field. We aim to advanceour program of excellence in translational or interdisciplinary research training because the need for atranslational or interdisciplinary program is greater today than ever before and the proposed continuation ofthis training program fills a unique niche in alcohol research.


application_id: 11095816
project_number: 5R01DK131786-04
project_title: Role of SMPDL3B in obesity-associated non-alcoholic fatty liver disease
administering_ic: NIDDK
award_notice_date: 2025-04-28
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 131786
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
arra_indicator: N
project_abstract:
Obesity is an independent risk factor for development of non-alcoholic fatty liver disease (NAFLD). With theepidemic burden of obesity and metabolic diseases NAFLD occurrence is steadily rising along with the needfor therapeutic options of this disease. Preliminary data from rodent and human studies provide strongevidence to support the hypothesis that monocyte/macrophage-derived TSP1 in obesity downregulates livermacrophage SMPDL3B and this downregulation feeds back to increase TSP1 binding to its receptor-CD36.This positive feedback loop together with SMPDL3Bs action on TLR pathways further amplifies livermacrophage pro-inflammatory signaling and leads to NAFLD progression. In this proposal how SMPDL3Bregulates CD36 function and then TSP1-CD36 dependent pro-inflammatory signaling in macrophages will bedetermined in Aim 1. The in vivo importance of macrophage SMPDL3B in NAFLD development andprogression in both animal models and human liver organoids will be determined in Aim 2. Whether specificblockade of TSP1/CD36 interaction upregulates liver macrophage SMPDL3B and attenuates liver pro-inflammatory signaling and NAFLD development and progression will be determined in Aim 3. Completingthese studies will provide novel information on the mechanisms by which suppressed macrophage SMPDL3Benhances liver macrophage pro-inflammatory signaling and its critical role in the progression of obesity-associated NAFLD to NASH. Further testing a novel therapeutic application of a peptide nanoparticleconjugate to block TSP1/CD36 interaction in obesity-associated NASH in vivo will have translationalsignificance.

project_terms:
3-Dimensional;Acids;Affect;Animal Model;Animals;Attenuated;Back;Binding;CD36 Antigens;CD36 gene;Cell membrane;Ceramides;Data;Development;Diet;Disease;Disease Progression;Down-Regulation;Epidemic;Fatty Liver;Feedback;Feeds;Fibrosis;GPI Membrane Anchors;Human;In Vitro;Infiltration;Inflammation;Inflammatory;Knock-out;Knowledge;Kupffer Cells;Lipids;Liver;Liver Fibrosis;Liver diseases;Macrophage;Macrophage Activation;Maps;Mediating;Membrane Lipids;Membrane Microdomains;Membrane Proteins;Metabolic Diseases;Modeling;Modification;Obesity;Organoids;Pathogenesis;Pathway interactions;Patients;Peptides;Phenotype;Process;Production;Proteins;Reducing diet;Risk Factors;Rodent;Role;Signal Transduction;Sphingomyelinase;TLR4 gene;Testing;Therapeutic;Thrombospondin 1;Western World;chronic liver disease;cytokine;in vitro Model;in vivo;knock-down;monocyte;mouse model;nanoparticle;new therapeutic target;non-alcoholic fatty liver;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutic intervention;novel therapeutics;obesity treatment;overexpression;peripheral blood;receptor;recruit;targeted treatment;therapy development

public_health_relevance:
With the epidemic burden of obesity and metabolic diseases non-alcoholic fatty liver disease (NAFLD) isbecoming one of the most common hepatic diseases worldwide. Our project proposes to study themechanisms underlying liver macrophage pro-inflammatory activation and the contribution of this process toNAFLD development and progression. Knowledge gained from our studies may lead to novel therapeuticstrategies in the treatment of obesity-associated NAFLD/NASH.


application_id: 11095316
project_number: 1R25AG092311-01
project_title: Kentucky Postbaccalaureate Alzheimers Disease Research Education Program (KYPAD)
administering_ic: NIA
award_notice_date: 2025-08-14
opportunity_number: RFA-AG-24-012
application_type: 1
activity_code: R25
ic: AG
serial_number: 092311
program_official: CHAKROBORTY, SHREAYA
project_start_date: 2025-08-15
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-L (J1)]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BRADLEY, LUKE H
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Recent years have seen some modest success in developing therapies for the treatment of Alzheimers Disease and related dementias (ADRD). As we look towards a future of improving ADRD care and reducing its societal burden a critical issue is the potential shortfall of new and innovative scientific talent. This pending shortage is particularly acute in terms of our national need to expand our pool of scientific researchers. A major barrier to the successful recruiting of trainees is that a significant proportion of potential candidates have had little or no access to immersive research opportunities at their undergraduate institutions many of which are smaller and traditionally under resourced. The University of Kentucky Postbaccalaureate Alzheimers Disease (KYPAD) Research Education Program will provide an in-depth research experience in ADRD for recent baccalaureate recipients in the biomedical and behavioral sciences. This cross-disciplinary program  based at an established AD Research Center  will create an intensive research experience with the primary goal of preparing recent graduates for the transition into research-focused advanced degree programs in AD- related disciplines. Postbaccalaureate trainees will work on focused research projects in labs studying a wide range of AD and AD-related biomedical problems will interact extensively with trainees and faculty at various levels of career development and engage in carefully tailored professional development activities. This program will be led by two senior faculty with experience in establishing successful R25 and T32 programs successful mentoring track records and a dedication to expanding access to scientific training. Potential trainees will be able to select from a broad pool of University of Kentucky faculty with active research programs and history of NIH funding in the ADRD field covering the full bench-to-bedside continuum of molecular and cellular biology preclinical translational approaches neuroimaging biomarker development neuropathology clinical research and data science. The majority of these mentors are faculty in the University of Kentucky Sanders Brown Center on Aging which includes a long-standing NIA-funded Alzheimers Disease Research Center (ADRC) and belong to multiple basic and clinical departments. Trainees will participate in a structured educational program that includes graduate level coursework training in the responsible conduct of research methods to enhance reproducibility data science and regular workshops and seminars and will also participate in the annual Markesbery Symposium on Aging and Dementia. This R25 program will uniquely position postbaccalaureate trainees to pursue further advanced training in ADRD research.

project_terms:
Academia;Acceleration;Acute;Address;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Appalachian Region;Basic Science;Behavioral Sciences;Career Choice;Clinical;Clinical Research;Communities;Data Science;Dedications;Degree program;Dementia;Development;Direct Costs;Discipline;Early Diagnosis;Education;Education Projects;Educational workshop;Ensure;Environment;Ethics;Exposure to;Faculty;Feeling;First Generation College Students;Funding;Future;Goals;Immersion;Individual;Institution;Instruction;Interdisciplinary Study;International;Kentucky;Learning;Literature;Measures;Mentors;Methods;Molecular and Cellular Biology;Neurosciences;Neurosciences Research;Outcome;Participant;Positioning Attribute;Postbaccalaureate;Postdoctoral Fellow;Productivity;Publications;Recording of previous events;Records;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Southeastern United States;Structure;Students;Talents;Training;Translational Research;United States National Institutes of Health;Universities;Work;bench to bedside;biomarker development;career;career development;cross disciplinary program;dementia care;design;education research;experience;faculty mentor;improved;innovation;interdisciplinary collaboration;investigator training;neuroimaging;neuropathology;outreach;peer;pre-clinical;pre-doctoral;prevent;programs;recruit;research education experience;responsible research conduct;role model;senior faculty;success;supportive environment;symposium;synergism;therapy development;tool;translational approach;undergraduate student

public_health_relevance:
The University of Kentucky Postbaccalaureate Alzheimers Disease (KYPAD) Research Education Program will provide an in-depth research experience in AD and related dementias (ADRD) for recent baccalaureate recipients in the biomedical and behavioral sciences. This cross-disciplinary program  based at an established AD research center  will create an intensive research experience with the primary goal of preparing recent graduates for the transition into research-focused advanced degree programs in AD-related disciplines.


application_id: 11095162
project_number: 2P20GM130456-06
project_title: Helmy Project
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9182
contact_pi_person_id: 78775561
contact_pi: HELMY, YOSRA A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  PROJECT 9 (HELMY)Salmonella is the leading cause of bacterial foodborne illnesses with significant public health implicationsworldwide. Poultry is the main source and reservoir of human infections. Treating poultry with antibiotics is acommon strategy to prevent Salmonella outbreaks in humans and vaccines are not effective at reducingfoodborne illnesses. Antibiotics are also required to treat severe illnesses associated with Salmonella infectionsin humans. As a consequence the emergence of antibiotic-resistant Salmonella has become an emergingconcern. Additionally untreated Salmonella infections have been linked to various chronic health issues such ascolon and gallbladder cancers associated with Salmonella Typhi and Enteritidis respectively. Therefore thereis a critical need for antibiotic alternatives to control infections in poultry and to mitigate the risk of Salmonellafoodborne illness outbreaks antimicrobial resistance and cancer in humans. Quorum sensing plays a criticalrole in the survival pathogenicity virulence biofilm formation motility and antibiotic production of severalbacteria including Salmonella. Therefore inhibition of QS using QS inhibitors (QSI) is an attractive antibiotic-free strategy to eradicate or limit Salmonella infections thereby preventing the transmission to humans and theassociated diseases due to acute and chronic infection. Since QSIs do not interfere with the metabolic processesof the bacteria they will not exert selection pressure on the bacteria during treatment. Thus bacteria are lesslikely to develop resistance to QSIs. Through the screening of 1900 compounds to identify the QS/AI-2 inhibitorsagainst Salmonella Typhimurium we identified 6 structurally diverse compounds that inhibited the QS/AI-2production of Salmonella Typhimurium (95%; at 10 M final concentration) without affecting bacterial growth.We compared their efficacy to the benchmark QSIs identified in previous studies and found that our compoundsare >10-fold more potent than the benchmark comparators. We hypothesize that selective QSIs will show highefficacy in vitro and in vivo and will open the door to identifying potential novel antimicrobial strategies. In thisproposal we will identify and evaluate the efficacy of the selected QSIs in vitro (Aim 1) evaluate the efficacy ofthe lead QSIs in the reservoir animal host (chickens Aim 2) and identify the QSI target(s) of the selected leads(Aim 3). Completion of these aims will contribute to our long-term objective of developing new anti-Salmonellatherapeutics that control the emergence of antibiotic-resistant Salmonella associated with poultry production andthus mitigate the risk of food illnesses and gallbladder and colon cancers in humans. CTCB mentorship andresearch support cores will facilitate this project in several key ways. Specifically the Bio Core will continue tosupport the Aim 1 screening effort to advance hit prioritization and for new targets identified (Aim 3) engage onsubsequent target-based screens. For priority hits probe optimization and SAR will be conducted by the ChemCore. This will also be augmented by a CTCB mentorship team with extensive expertise in the gut microbiomebacteriology infectious disease and pharmaceutical science.

project_terms:
Affect;Affinity;Anabolism;Animals;Antibiotic Resistance;Antibiotics;Antimicrobial Resistance;Bacteria;Bacteriology;Benchmarking;Biological Assay;Biology;Campylobacter jejuni;Cell Wall;Cells;Centers of Research Excellence;Chemicals;Chickens;Chronic;Collaborations;Colon Carcinoma;Communicable Diseases;DNA metabolism;Disease;Disease Outbreaks;Domestic Fowls;Dose;Ensure;Experimental Designs;Food;Formulation;Genes;Growth;Health;Human;Immune response;In Vitro;Infection;Infection Control;Infrastructure;Intestines;Lead;Link;Liver;Malignant Neoplasms;Malignant neoplasm of gallbladder;Mass Spectrum Analysis;Maximum Tolerated Dose;Measures;Mentors;Mentorship;Metabolism;Metagenomics;Microbial Biofilms;Motility;Muscle;Organoids;Outcome;Pathogenicity;Pharmacodynamics;Pharmacologic Substance;Play;Predisposition;Production;Protein Biosynthesis;Proteome;Proteomics;Public Health;Research Support;Resistance;Resistance development;Role;Safety;Salmonella;Salmonella enteritidis;Salmonella infections;Salmonella typhi;Salmonella typhimurium;Science;Source;Structure-Activity Relationship;Testing;Therapeutic;Tissues;Toxic effect;VAI-2;Vaccines;Virulence;acute infection;antimicrobial;chronic infection;dysbiosis;efficacy evaluation;efficacy study;experience;foodborne illness;gut microbiome;gut microbiota;in vivo;inhibitor;lead optimization;metabolomics;meter;microbial;microbiota;novel;pathogenic bacteria;pressure;prevent;quorum sensing;risk mitigation;screening;transmission process


application_id: 11095161
project_number: 2P20GM130456-06
project_title: Czuba Project
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9181
contact_pi_person_id: 11987895
contact_pi: CZUBA, LINDSAY CHRISTINE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  PROJECT 8 (CZUBA)The human apical sodium-dependent bile acid transporter (ASBT) is critical for gut-liver signaling and bile acidflux yet it is unknown how it is dynamically regulated to rapidly adapt to regulatory signals. Prior work suggeststhat basal expression of ASBT is regulated in part at the post-translational level and involves tyrosinephosphorylation. In contrast ubiquitination and subsequent proteasomal degradation are implicated in thedestabilization of ASBT. In obesity ASBT membrane expression is increased but the mechanism is unknown.Currently there is a critical gap regarding which residues are involved in the ubiquitination of ASBT and themechanisms by which they become modified. The goal of this research is to identify the degrons that signalASBT ubiquitin-mediated degradation provide insight into how that process is mediated at the cellular level anddevelop chemical biology approaches that can monitor these transient interactions. We hypothesize thatASBTs ubiquitination surface expression and stability is determined by discrete proteoforms which facilitateregulatory protein-protein interactions. This overarching hypothesis will be tested in the following Specific Aims:1) develop and assess novel fluorescent transport assays for the rapid assessment of ASBT function andexpression; 2) identify lysine ubiquitination sites on ASBT and characterize their impact on the functionalregulation and modulation of ASBT interactions; and 3) identify the mechanisms that regulate ASBTsubiquitination status and stability using small molecules and genetic knockdown. The approach is innovativeand timely due to the integration of modern advances in chemical biology with transporter biology needs andrepresents a paradigm shift for studies of bile acid transport in the gut-liver axis through the emphasis ofmodulating cellular and molecular dynamics. Successful completion of this project will elucidate the degron andinteractome that promotes the destabilization of ASBT. This is significant as it will facilitate the identification ofnovel drug targets for modulating ASBT function and expression. Integrated CTCB core support andmentorship will facilitate this project in a number of key ways. Specifically the Bio Core will support assaydevelopment and optimization (Aims 1 and 3) and the Chem Core will synthesize a series of novel fluorescentbile acids (Aim 1 and 3) and assist in click chemistry optimization (Aim 1). This will be augmented by a CTCBmentorship team with extensive expertise in membrane transport membrane receptors pharmaceutical scienceand drug development.

project_terms:
ASBT protein;Acids;Address;Adverse event;Amber;Amino Acyl-tRNA Synthetases;Bile Acids;Binding;Biological;Biological Assay;Biological Process;Biology;Biotinylation;Carrier Proteins;Cells;Centers of Research Excellence;Chemicals;Chemistry;Cholesterol;Codon Nucleotides;Collaborations;Complement;Data;Development;Diabetes Mellitus;Engineering;Genetic;Goals;Homeostasis;Human;Immunofluorescence Immunologic;Immunoprecipitation;In Vitro;Infrastructure;Kinetics;Lipids;Liver;Location;Lysine;Malabsorption Syndromes;Mediating;Membrane;Membrane Transport Proteins;Mentorship;Modeling;Modernization;Modification;Molecular;Monitor;Obesity;Participant;Pharmacologic Substance;Post-Translational Protein Processing;Post-Translational Regulation;Process;Proteins;Proteomics;Public Health;Regulation;Reporting;Research;Rodent;Science;Series;Shotguns;Signal Transduction;Site;Small Interfering RNA;Surface;System;Testing;Tissues;Transmembrane Transport;Tyrosine Phosphorylation;Ubiquitin;Ubiquitination;Work;assay development;blood glucose regulation;comorbidity;drug development;drug discovery;experience;gastrointestinal;genetic regulatory protein;gut-liver axis;improved;inhibitor;innovation;insight;knock-down;molecular dynamics;multicatalytic endopeptidase complex;mutant;new therapeutic target;non-alcoholic fatty liver disease;novel;overexpression;permissiveness;pharmacologic;pharmacophore;protein expression;protein phosphatase inhibitor-2;protein protein interaction;rapid test;receptor;small molecule;tool;trafficking;ubiquitin isopeptidase;ubiquitin ligase;unnatural amino acids


application_id: 11095160
project_number: 2P20GM130456-06
project_title: Alam Project
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9180
contact_pi_person_id: 12197847
contact_pi: ALAM, M. ASHFAQUL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  PROJECT 7 (ALAM)Campylobacter jejuni is the primary pathogen responsible for bacterial gastrointestinal infections worldwide andis the leading cause of enteric inflammation in the United States which can further lead to late-onset diseasessuch as Guillain Barr Syndrome colorectal cancers IBD and IBS. Importantly C. jejuni has been designatedas a serious antibiotic resistance threat by both WHO and CDC. The numerically vast and taxonomically diversegut microbial communities affect the health and bacterial infection in the intestine. We and others have shownthat the intestinal bloom of dysbiotic E. coli is strongly associated with exacerbated C. jejuni infection. Howeverthere is a critical knowledge gap in developing potential agents that target only specific pathogens withoutdisturbing the entire gut microbiota. This proposals objective is to elucidate the chemical biology of microbialmetabolites and small molecules selective against intestinal C. jejuni and E. coli pathogens that cause intestinalinfection and inflammation. Our exciting preliminary metomics analysis identified increased abundances of E.colis lysine decarboxylase (CadA) system during C. jejuni infection in mice. The CadA enzyme catabolizes lysineto polyamine cadaverine but C. jejuni fails to synthesize cadaverine. Interestingly the dysbiotic E. coli throughits CadA enzyme and metabolite cadaverine promote C. jejuni infection by augmenting chemotaxis motilityantibiotic susceptibility and toxin production. We also found that cadaverine activates C. jejunis transducer-likeprotein Tlp3. A C. jejuni tlp3 mutant displayed attenuated chemotaxis and virulence indicating Tlp3 as apotential anti-virulent target. Through a combined CTCB Bio Core CadA virtual and wet-bench screen weidentified 6-aminohexanoate as a prototype CadA inhibitor. Our central hypothesis is that the cadaverine-producing CadA enzyme and cadaverine-sensing chemoreceptor Tlp3 are druggable targets to eliminate E. coliand C. jejuni by inhibiting chemotaxis survival and virulence during intestinal infection. Aim 1 will investigate theinhibitory impact and efficacy of top-ranked hit compounds on CadA in cadaverine production bacterial growthand C. jejuni pathogenesis. In Aim 2 we will virtually and experimentally screen small molecules that inhibitC. jejunis chemotactic receptor Tlp3. Finally in Aim 3 we will assess the combined impact of CadA and Tlp3inhibitors on C. jejuni-mediated infection in the mouse model. This project is both conceptually and technicallyinnovative in developing a selective anti-virulent agent for C. jejuni. Integrated CTCB core support andmentorship will facilitate this project in a number of key ways. Specifically the CTCB Bio Core will support CadAand Tlp3 virtual and wet-bench screening (Aims 1 and 2) and simple antibacterial and eukaryotic toxicityassessments for hits while the Chem Core will support de novo CadA and Tlp3 ligand design and ligandoptimization chemistries (Aims 1 and 2) and preformulation and stability studies in the context of proposed animalstudies (Aim 3). This will be augmented by a CTCB mentorship team with extensive expertise in polyaminebiosynthesis and signaling gut microbiome pharmaceutical science and antibiotic drug development.

project_terms:
Adherence;Affect;Affinity;Anabolism;Animals;Anti-Bacterial Agents;Antibiotic Resistance;Antibiotic susceptibility;Antibiotics;Attenuated;Bacterial Infections;Binding;Biological Assay;Biology;Cadaverine;Campylobacter infection;Campylobacter jejuni;Centers of Research Excellence;Chemicals;Chemistry;Chemoreceptors;Chemotaxis;Chemotaxis Inhibition;Colitis;Collaborations;Colorectal Cancer;Disease;Drug Targeting;Enteral;Enterocytes;Enzymes;Epithelial Cells;Epithelium;Escherichia coli;Feces;Formulation;Growth;Guillain Barr Syndrome;Gut Mucosa;Health;Human;Infection;Inflammation;Inflammatory;Infrastructure;Intestinal Mucosa;Intestines;Invaded;Irritable Bowel Syndrome;Knowledge;Late-Onset Disorder;Lead;Ligand Binding;Ligands;Lysine;Lysine decarboxylase;Mediating;Mentorship;Metabolism;Metagenomics;Motility;Mucous Membrane;Mus;Pathogenesis;Peptides;Pharmacologic Substance;Polyamines;Production;Proteins;Proteobacteria;Public Health;Reporting;Resistance;Roentgen Rays;Science;Signal Transduction;Structure;System;Taxonomy;Testing;Toxic effect;Toxin;Transducers;United States;Validation;Virulence;Virulent;acid stress;cytokine;design;drug development;druggable target;dysbiosis;economic cost;enteric infection;gastrointestinal infection;gut inflammation;gut microbiome;gut microbiota;humanized mouse;in vitro activity;indexing;inhibitor;innovation;insight;intestinal epithelium;metabolomics;metaproteomics;microbial;microbiota;mouse model;mutant;new therapeutic target;pathogen;prototype;receptor;reconstitution;screening;small molecule;targeted agent;virtual


application_id: 11095159
project_number: 2P20GM130456-06
project_title: Chem Core
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9179
contact_pi_person_id: 7842243
contact_pi: PRISINZANO, THOMAS EDWARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  CHEM CORE The primary goals of the Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) are to support junior faculty recruitment and mentorship mission-critical research cores and growth of an innovative and broad-reaching interdisciplinary translational chemical biology research community. The Centers theme intersects chemical biology molecular pharmacology and pharmaceutical science. CTCB is unique to and synergistic with the University of Kentuckys (UKs) biomedical research enterprise that offers a wealth of innovative models and potential new drug targets linked to Appalachian Kentucky health disparities. As such the Center provides a new unifying framework for faculty to create leverage and advance novel chemical probes for the study and control of diverse disease-relevant biology. Within this context the CTCB Chem Core is one of two independent Phase 2 research support cores that in conjunction with the CTCB Bio Core operate as an integrated unit to strategically support probe and project development. As the only synthetic chemistry core at UK the Chem Core will provide infrastructure and expertise to enable computational ligand design medicinal chemistry strategic scale-up chemistries and probe-based target identification and imaging. As new Phase 2 Chem Core resources the Core will further grow and leverage its exclusive Natural Products Repository and develop new computational platforms for virtual screening and de novo ligand design. In early Phase 2 the Chem Core will support probe optimization and medicinal chemistry of hits identified by the Bio Core for CadA and Tlp3 (Project 7 Alam) quorum-sensing (QS) autoinducer-2 (AI-2) signaling (Project 9 Helmy) and PAC1 receptor (Ignite Scholar Jaramillo). The Chem Core will also advance bile acid (Project 8 Czuba) and veraguamide (Ignite Scholar Tidgewell) structure-activity-relationship (SAR) studies. In addition the Core will leverage new computational methods for de novo CadA and Tlp3 inhibitor design (Project 7) and facilitate new conjugation and click chemistries for human apical sodium-dependent bile acid transporter (ASBT) assay development (Project 8). Continuing rigorous Chem Core tracking and evaluation by the Administrative Core in Phase 2 will ensure efficient Core responsiveness and exemplary services and establish a quantitative cost basis for prospective Chem Core user fees for long-term core sustainability.

project_terms:
ASBT protein;Appalachian Region;Applications Grants;Bile Acids;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Chemistry;Collaborations;Communities;Complement;Computer software;Computing Methodologies;Consultations;Data;Data Analyses;Development;Disease;Ensure;Equipment;Evaluation;Faculty;Faculty Recruitment;Fees;Fermentation;Goals;Grant;Growth;Human;Image;Infrastructure;Institution;Intellectual Property;Kentucky;Lead;Leadership;Libraries;Ligands;Link;Mentorship;Methods;Mission;Modeling;Molecular;Natural Products;PACAPR-1 protein;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Publications;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Science;Services;Signal Transduction;Structure-Activity Relationship;Synthesis Chemistry;Training;Translational Research;Universities;VAI-2;assay development;career development;computational platform;cost;design;drug discovery;health disparity;inhibitor;innovation;interdisciplinary collaboration;member;new therapeutic target;novel;pre-clinical;primary outcome;programs;prospective;quorum sensing;repository;research study;scale up;sharing platform;stem;translational scientist;virtual screening

public_health_relevance:
The University of Kentucky (UK) Phase 2 Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) will continue to serve as a unique comprehensive center for translational chemical biology research. The center will support junior faculty recruitment and career development advance impactful chemical biology probes and early-stage drug leads and stimulate transdisciplinary collaboration and innovation.


application_id: 11095158
project_number: 2P20GM130456-06
project_title: Bio Core
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9178
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  BIO CORE The primary goals of the Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) are to support junior faculty recruitment and mentorship implement and sustain mission-critical research support cores and provide the foundation for an innovative and broad-reaching interdisciplinary translational chemical biology research community at the University of Kentucky (UK). The Centers theme intersects chemical biology molecular pharmacology and pharmaceutical science. CTCB is unique to and synergistic with UKs biomedical research enterprise that offers a wealth of innovative models and potential new drug targets linked to Appalachian Kentucky health disparities. As such the Center provides a new unifying framework for faculty to create leverage and advance novel chemical probes and leads for the study and control of diverse disease-relevant biology. Within this context the CTCB Bio Core is one of two independent Phase 2 research support cores that in conjunction with the CTCB Chem Core operate as an integrated unit to strategically support probe and project development. As UKs only assay development and screening core the CTCB Bio Core will support enabling assay development and virtual and wet-bench screening. As new Phase 2 Bio Core resources the Core will further grow and leverage its exclusive Natural Products Repository develop and implement state-of-the-art target-guided assays and develop new computational platforms for virtual screening. In early Phase 2 the Bio Core will support target-based virtual screens (Project 7 Alam) pharmacophore-based virtual screens (Projects 7 and 9 Alam and Helmy respectively) and wet-bench cytotoxicity and antimicrobial (Projects 7 and 9) thermofluor ligand-binding (Project 7) and GCPR reporter (Ignite Scholar Jaramillo) assays. The Core will also leverage new machine-learning-based methods for virtual screening (Projects 7 and 9) and develop new wet-bench enzyme activity (CadA Project 7) quorum-sensing (Project 9) human apical sodium-dependent bile acid transporter (ASBT Project 8 Czuba) and calcium imaging (Ignite Scholar Tidgewell) assays. In addition the CTCB Administrative Core will continue rigorous Bio Core tracking and evaluation in Phase 2 to ensure efficient core responsiveness and exemplary services and establish a quantitative cost basis for prospective Bio Core user fees for long-term core sustainability.

project_terms:
ASBT protein;Appalachian Region;Applications Grants;Biological Assay;Biology;Biomedical Research;Calcium;Centers of Research Excellence;Chemicals;Collaborations;Communities;Complement;Computer software;Consultations;Data;Data Analyses;Development;Disease;Ensure;Enzymes;Equipment;Evaluation;Faculty;Faculty Recruitment;Fees;Foundations;Goals;Grant;Human;Image;Infrastructure;Institution;Intellectual Property;Kentucky;Lead;Leadership;Libraries;Ligand Binding;Link;Mentorship;Methods;Mission;Modeling;Molecular;Natural Products;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Publications;Reporter;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Science;Services;Training;Translational Research;Universities;Validation;antimicrobial;assay development;career development;computational platform;cost;cytotoxicity;design;drug discovery;enzyme activity;health disparity;innovation;interdisciplinary collaboration;machine learning method;member;new therapeutic target;novel;pharmacophore;pre-clinical;primary outcome;programs;prospective;quorum sensing;repository;research study;screening;sharing platform;stem;translational scientist;virtual;virtual screening

public_health_relevance:
The University of Kentucky (UK) Phase 2 Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) will continue to serve as a unique comprehensive center for translational chemical biology research. The center will support junior faculty recruitment and career development advance impactful chemical biology probes and early-stage drug leads and stimulate transdisciplinary collaboration and innovation.


application_id: 11095157
project_number: 2P20GM130456-06
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
subproject_number: 9177
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  ADMINISTRATIVE CORE The primary goals of the Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) are to support junior faculty recruitment and mentorship mission-critical research cores and growth of an innovative and broad-reaching interdisciplinary translational chemical biology research community. The Centers theme intersects chemical biology molecular pharmacology and pharmaceutical science. CTCB is unique to and synergistic with the University of Kentuckys (UKs) biomedical research enterprise that offers a wealth of innovative models and potential new drug targets linked to Appalachian Kentucky health disparities. As such the Center provides a new unifying framework for faculty to create leverage and advance novel chemical probes for the study and control of diverse disease-relevant biology. Within this context the CTCB Administrative Core will support center communication coordination oversight and integration of all CTCB operations activities projects pilots recruitment efforts and research support cores. The Core will provide fiscal management and resource oversight overall coordination of mentoring and career development activities resource allocation data management support and infrastructure and program evaluation to ensure program effectiveness. The Administrative Core will also facilitate interactions with affiliated UK colleges programs and centers to foster synergy and coordination of resources. The Core will facilitate the Centers engagement of junior faculty and mentors from multiple UK Colleges (including but not limited to: Agriculture Food & Environment; Arts and Sciences; Engineering; Medicine; and Pharmacy) to create a vibrant center that seamlessly integrates resources personnel and expertise across disciplinary boundaries and fosters scientific innovation collaboration and career development. As new Phase 2 Administrative Core refinements CTCB will add an experienced Program Associate Director data management and sharing infrastructure and a grants development boot camp as well as streamline mentoring teams to further refine and enhance overall CTCB support. The Center will also continue rigorous tracking and evaluation in Phase 2 to ensure efficient progress and responsiveness for all components and establish a quantitative cost basis for prospective CTCB core user fees and long-term core sustainability.

project_terms:
Agriculture;Appalachian Region;Arts;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Collaborations;Communication;Communities;Decision Making;Development;Development Plans;Disease;Engineering;Ensure;Environment;Evaluation;Faculty;Faculty Recruitment;Fees;Food;Fostering;Goals;Grant;Growth;Human Resources;Infrastructure;Institution;Kentucky;Knowledge;Leadership;Link;Medicine;Mentors;Mentorship;Mission;Modeling;Molecular;Outcome;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacy facility;Phase;Process;Program Effectiveness;Program Evaluation;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Structure;Universities;career;career development;college;cost;data management;data sharing;experience;faculty research;health disparity;innovation;interdisciplinary collaboration;member;new therapeutic target;novel;operation;outreach;primary outcome;programs;prospective;recruit;stem;success;supportive environment;synergism

public_health_relevance:
The University of Kentucky (UK) Phase 2 Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) will continue to serve as a unique comprehensive center for translational chemical biology research. The center will support junior faculty recruitment and career development advance impactful chemical biology probes and early-stage drug leads and stimulate transdisciplinary collaboration and innovation.


application_id: 11095156
project_number: 2P20GM130456-06
project_title: COBRE for Translational Chemical Biology
administering_ic: NIGMS
award_notice_date: 2025-07-23
opportunity_number: PAR-23-063
application_type: 2
activity_code: P20
ic: GM
serial_number: 130456
program_official: FRINCU, CRINA
project_start_date: 2020-03-01
project_end_date: 2030-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C2)]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The primary goals of the Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology (CTCB) are to support junior faculty recruitment and mentorship mission-critical research cores and growth of an innovative and broad-reaching interdisciplinary translational chemical biology research community. The Centers theme intersects chemical biology molecular pharmacology and pharmaceutical science. CTCB is unique to and synergistic with the University of Kentuckys (UKs) biomedical research enterprise that offers a wealth of innovative models and potential new drug targets linked to Appalachian Kentucky health disparities. Within this context the center provides a new unifying framework for faculty to create leverage and advance novel chemical probes for the study and control of diverse disease-relevant biology. CTCBs framework and thematic focus cuts through traditional boundaries and enables the engagement of diverse scientific expertise perspectives and approaches in research project development and implementation. The Centers mentorship and research cores emphasize stringent criteria in chemical probe development and serve as a fundamental cornerstone for advancing new drug leads. CTCB will support and mentor three outstanding junior faculty Research Project Leaders (RPLs) in early Phase 2 all with research programs that intersect the gut-microbiome-disease axis. The Center will implement a new Phase 2 comprehensive Pipeline Program that encompasses new junior faculty recruitment a pilot project program and a voucher fund the combined goal of which is to expand CTCB research core use and enable growth of a critical mass of translational chemical biology researchers at UK. In addition the Center will further develop and leverage two independent research support cores in Phase 2 that operate as an integrated unit to strategically support probe and project development. As UKs only assay development and screening core the CTCB Bio Core will support enabling virtual and wet-bench screening. The complementary CTCB Chem Core UKs only synthetic chemistry core will provide computational ligand design medicinal chemistry and probe-based target identification and imaging. As new Phase 2 research resources CTCB will further grow and leverage its exclusive Natural Products Repository and develop new computational platforms for virtual screening and de novo ligand design. CTCB will also add an experienced Program Associate Director streamline mentoring teams and develop a grants development boot camp in Phase 2 to further refine and enhance overall CTCB support. The Center will continue rigorous tracking and evaluation in Phase 2 to ensure efficient progress and rapid response for all components an emphasis of which will be to establish a cost basis for CTCB core user fees and sustainability.

project_terms:
Appalachian Region;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Communities;Development;Discipline;Disease;Drug Targeting;Ensure;Environment;Evaluation;Extramural Activities;Faculty;Faculty Recruitment;Fees;Fostering;Funding;Goals;Grant;Growth;Growth and Development function;Image;Interdisciplinary Study;Kentucky;Lead;Legal patent;Ligands;Link;Mentors;Mentorship;Mission;Modeling;Molecular;Natural Products;Outcome;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Pilot Projects;Publications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resource Development;Resources;Science;Synthesis Chemistry;Training;Universities;Validation;assay development;career development;computational platform;cost;design;experience;faculty research;faculty support;gut microbiome;health disparity;improved;innovation;interdisciplinary collaboration;investigator training;new therapeutic target;novel;novel therapeutics;outreach;pre-clinical;programs;recruit;repository;response;screening;stem;success;tool;tool development;translational impact;virtual;virtual screening;voucher


application_id: 11094106
project_number: 5T32DA035200-28
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2025-05-15
opportunity_number: PA-20-142
application_type: 5
activity_code: T32
ic: DA
serial_number: 035200
program_official: FALCON-MORALES, EDGARDO
project_start_date: 1998-08-01
project_end_date: 2028-06-30
study_section: ZDA1-MXS-W(01)S
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: RUSH, CRAIG R
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
project_abstract:
ABSTRACT/SUMMARY This continuation application proposes to support three (3) pre-doctoral and three (3) post-doctoral traineeswith 24 faculty from six (6) colleges and 10 departments across the University of Kentucky. Theaccomplishments of our trainees exemplify the success of this training program. Forty-seven (47) percent oftrainees from 15 years ago have received funding from NIH. Trainees from the past 10 years are alsobeginning to experience success in terms of acquiring extramural funding (i.e. 17% obtained NIH funding).Trainees (N=14) from the most recent funding period authored 157 publications and regularly presented theirresearch findings at local national or international conferences. All of these trainees remain involved inresearch or academics. Individuals from under-represented minorities comprised the 14% of the most recentcohort. Individuals from disadvantaged backgrounds comprised the 21% of the most recent cohort of trainees. The program is designed to prepare trainees to assume translational and multidisciplinary researchresponsibilities in academic and other scientific organizations concerned with substance-use disorders (SUDs).Pre-doctoral trainees concentrate in translational and interdisciplinary aspects of SUDs as part of a doctoralprogram in a behavioral science discipline (e.g. psychology sociology). Post-doctoral fellows have a doctoratein a behavioral science discipline and are preparing for a research role in SUDs or they are healthprofessionals seeking translational and interdisciplinary training in a behavioral orientation in SUDs research.Basic elements of the program include: (1) training in the basic building blocks of research (e.g. experimentaldesign data analysis) and independent research competence; (2) a translational and interdisciplinaryorientation taking students beyond their basic discipline and providing exposure to key theoretical conceptsand methodological issues of the related behavioral sciences along with a bio-behavioral conceptualization; (3)professional development to support a career in SUDs research; (4) exploration of SUDs topics from amedical-behavioral perspective through courses offered by training faculty; and (5) opportunities for researcharound relevant questions in SUDs constituting a dissertation project for pre-doctoral trainees. We individuallytailor the post-doctoral program to the objectives of the fellows to build on their previous knowledge andexperience while drawing on the core elements of the training program. The rich environment provides opportunities for translational and multidisciplinary bio-behavioral research.This T32 is unique in being the only institutional training grant at the University Kentucky funded by NIDA anddedicated to the study of SUDs. The need for a translational and interdisciplinary program such as the oneproposed for continuation here is greater today than ever before. The United States is gripped by anunprecedented SUD and overdose crisis.

public_health_relevance:
PROJECT NARRATIVEThe purpose of this application is to continue a highly successful training program of nearly 25 yearsin translational and interdisciplinary research on substance use disorders and offers research training on bio-behavioral factors in substance use disorders at the pre-doctoral and post-doctoral levels. Graduates of thisprogram are actively involved in research teaching publishing articles and becoming independent addictionresearchers. We aim to continue this record of success in the next funding period because the need for atranslational or interdisciplinary program is greater today than ever before and the proposed training programfills a unique niche in substance use disorder research.


application_id: 11093190
project_number: 1R25CA298892-01
project_title: Educating Social Workers in Palliative and End of Life Care - Oncology
administering_ic: NCI
award_notice_date: 2025-08-05
opportunity_number: PAR-23-276
application_type: 1
activity_code: R25
ic: CA
serial_number: 298892
program_official: ELJANNE, MARIAM
project_start_date: 2025-08-07
project_end_date: 2030-07-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 11646396
contact_pi: SCHAPMIRE, TARA J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Excellent care of patients diagnosed with cancer requires the integration of palliative care and the close collaboration of professionalsall practicing at the top of their licenses. Data from the 2019 NASEM Report Integrating Social Care into the Delivery of Health Care: Moving Upstream to Improve the Nations Health reveal conclusively that social contexts influence the delivery and outcomes of healthcare. The burden on front-line oncology social workers to deliver best practices that address the structural and contextual factors influencing health outcomes has significantly increased. There is a growing need for ongoing education in primary palliative care skillsincluding biopsychosocial assessment communication advocacy and leadershipto promote adjustment and coping and provide clear role definition in addressing patient and family distress. This competency gap is especially critical in healthcare settings serving communities facing elevated health riskssuch as those experiencing high rates of multimorbidity complex psychosocial challenges limited access to high-quality care low health literacy and adverse living conditions. The situation is further intensified in under-resourced healthcare systems where staff shortages and limited opportunities for professional development are common.The Overall Aim of this comprehensive multimodal educational program is to offer an oncology-tailored evidence-based curriculum with engaging content and leadership skills training to support the integration of primary palliative care skills for 240 competitively selected oncology social workers. Using reliable adult learning strategies we will target learner skill achievement through knowledge development self-efficacy (competence and confidence) and mentorship in the implementation and enhancement of the delivery of cancer care. A pre/post-test design will assess the impact of the curriculum on process and learner outcomes. The curriculum is constructed using a pedagogically sound integration of the primary principles of palliative care and real-world oncology patient scenarios. Learners will be supported through an innovative combination of self-study in-person training and practice sessions (monthly webinars and monthly mentorship) geared towards improved competence and confidence in creating meaningful and sustainable changes in the delivery of cancer care. The Specific Aims of this program are: 1) Expand the oncology-specific evidence-based multimodal Educating Social Workers in Palliative and End-of-Life Care-Oncology (ESPEC-O) national training program for oncology social worker skill development and implementation guidance in palliative care to enhance the delivery of cancer care. 2) Train and mentor 240 competitively selected oncology social workers in five annual training cycles in the development of palliative care skills to enhance and strengthen their interprofessional oncology practice. 3) Evaluate the success of the training program and its impact on learners and their institutions through assessment of (a) learner skill achievement and (b) progress toward achievement of learners stated goals for clinical change within their settings.

project_terms:
Achievement;Address;Adult;Advocacy;American Society of Clinical Oncology;Attention;Cancer Patient;Caring;Chaplain;Clinical;Collaborations;Communication;Communities;Competence;Complex;Consensus;Data;Development;Diagnosis;Discipline;Distress;Education;Educational Curriculum;Educational process of instructing;Effectiveness;Engineering;Family;Geographic Locations;Goals;Health;Health Care;Health Care Systems;Inpatients;Institution;Knowledge;Leadership;Learning;Licensing;Malignant Neoplasms;Medicine;Mental Health Services;Mentors;Mentorship;National Comprehensive Cancer Network;Nurses;Nursing Education;Oncology;Outcome;Outpatients;Palliative Care;Patient Care;Patients;Persons;Physicians;Policies;Positioning Attribute;Practice Guidelines;Process;Prognosis;Program Evaluation;Provider;Psychologist;Quality of Care;Quality of life;Reporting;Resources;Risk;Role;Self Efficacy;Social Conditions;Social Environment;Social Work;Social Workers;Testing;Time;Training;Training Programs;United States National Academy of Sciences;biopsychosocial;cancer care;cancer palliative treatment;care delivery;care outcomes;clinical practice;contextual factors;coping;design;end of life care;evidence base;experience;health care delivery;health care resources;health care service utilization;health care settings;improved;innovation;learning strategy;lens;low health literacy;multimodality;multiple chronic conditions;oncology program;oncology service;palliative;programs;psychosocial;service delivery;skill acquisition;skills;skills training;social;social health determinants;sound;structural determinants;success;theories;webinar

public_health_relevance:
Excellent care of patients diagnosed with cancer requires the integration of palliative care and the close collaboration of professionals all practicing at the top of their licenses. The Overall Aim of this comprehensive multimodal educational program is to offer an oncology-tailored evidence-based curriculum with engaging content and leadership-skills training to support the integration of primary palliative care skills for 240 competitively selected oncology social workers. As a result learners will enhance and strengthen their roles for more effective interprofessional practice and enhance the delivery of cancer care.


application_id: 11092708
project_number: 5R44ES032380-03
project_title: Development of Smart Flocculants for the Treatment of PFAS Contaminated Water
administering_ic: NIEHS
award_notice_date: 2025-04-16
opportunity_number: PA-22-176
application_type: 5
activity_code: R44
ic: ES
serial_number: 032380
program_official: HENRY, HEATHER F
project_start_date: 2020-09-10
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1-MCST-S(12)B]
contact_pi_person_id: 80214061
contact_pi: ROWLANDS, CLAIRE E
other_pis: HILT, JAMES ZACH
congressional_district: 06
department: Unavailable
primary_duns: 078529087
primary_uei: M9JMGN342NR5
duns_number: 078529087
uei: M9JMGN342NR5
fips: US
organization_id: 10032361
organization_name: BLUEGRASS ADVANCED MATERIALS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPer- and polyfluoroalkyl substances (PFAS) are a family of manmade congeners with dual hydro- and oleo-phobic properties which is why they have been widely used in firefighting foams as well as in a multitude ofother products such as food packaging paints pesticides and microelectronics. Given their extensive use highwater solubility and resistance to conventional wastewater treatment methods PFAS have been detected inpublic water supplies all over the country causing concern for potential toxic human health effects given theirenvironmental persistence. Flocculation is a widely used separation technique in the removal of suspendedsolids from water and wastewater. However traditional flocculants (e.g. inorganic salts and polymeric systems)form aggregate flocs that are usually loosely packed contain a large amount of water due to their hydrophilicityand as such require large settling tanks due to the slow process of separation that is required to collect thesolids. Furthermore they have seldom been used to remove dissolved species like PFAS. To address theseissues BAM has developed EnviroFloc: an innovative smart polymeric flocculant that consists of a temperatureresponsive compound N-isopropylacrylamide (NIPAAm) modified with cationic co-monomers and/or fluorinatedco-monomers. The combination of these three components results in a polymer which can rapidly capture thedissolved PFAS molecules and form insoluble solid aggregates at temperatures above the lower critical solutiontemperature (LCST) The core advantages of this system include: (1) Low water retention in the sedimented floc:dissolved PFAS molecules are captured by the dissolved polymer at ambient temperature and then collectedinto an insoluble densely packed solid pellet above the transition temperature resulting in a smaller solid wastestream compared to other remediation technologies. (2) Fast kinetics flocculation occurs within seconds tominutes as compared to several hours for other flocculant systems. (3) Relatively low energy input required toflocculate given EnviroFlocs LCST being close to ambient temperature. (4) Little-to-no pretreatment needed ofthe contaminated stream when applied as secondary treatment for challenging PFAS wastes RO concentrateand IX brine. More specifically aim 1 focuses on the development of EnviroFloc polymer flocculants foroptimized flocculation performance. Specific Aim 2 will evaluate EnviroFloc regeneration via temperatureassisted solid-liquid extraction to determine removal efficiency and EnviroFloc reusability and specific Aim 3 willdemonstrate EnviroFloc performance efficiency as a secondary treatment step in multiple case studies (e.g. ROconcentrates and IX brine). Finally specific Aim 4 will design simulate and demonstrate feasibility of a PFAStreatment unit. This Phase II SBIR project will accomplish the key tasks necessary to prepare forcommercialization of BAMs EnviroFloc and the associated treatment unit specifically for PFAS water treatment.

project_terms:
Acceleration;Address;Adopted;Affect;Affinity;American;Behavior;Biodegradation;Carbon;Case Study;Child Behavior;Cholesterol;Country;Data;Development;Dust;Effectiveness;Electrostatics;Evaluation;Excision;Family;Filtration;Flocculation;Food Packaging;Friction;Future;Goals;Growth;Health;Heating;Hormones;Hour;Human;Immune system;Industrialization;Ion Exchange;Ion Exchange Resins;Kinetics;Legal patent;Life Cycle Stages;Liquid substance;Malignant neoplasm of testis;Marketing;Methods;N-isopropylacrylamide;Natural regeneration;Osmosis;Paint;Performance;Pesticides;Phase;Poa plant;Poly-fluoroalkyl substances;Polymers;Pre-Eclampsia;Prevalence;Process;Property;Recovery;Regulation;Renal Carcinoma;Residual state;Resistance;Resources;Risk;Route;Safety;Salts;Small Business Innovation Research Grant;Solid;Specificity;Stream;System;Techniques;Technology;Temperature;Transition Temperature;Treatment Step;Validation;Water;Water Supply;aqueous;commercialization;contaminated water;copolymer;cost;cost effective;design;drinking water;economic evaluation;effective therapy;experimental study;exposed human population;ground water;hydrophilicity;innovation;landfill;learned behavior;man;manufacture;microelectronics;nano;operation;remediation;simulation;wasting;water flow;water sampling;water solubility;water treatment

public_health_relevance:
Project NarrativeIn this project a smart flocculant system is proposed to easily remove per- and polyfluoroalkyl substances(PFAS) from water systems minimizing settling times and additional dewatering steps found in current flocculanttechnology. The novelty of the proposed polymer flocculant is that it combines a thermoresponsive compound(N-isopropylacrylamide (NIPAAm)) with cationic and fluorinated co-monomers. These co-monomers providehigh affinity for PFAS molecules through a variety of interactions (e.g. electrostatic) which enhances affinity forPFAS compounds and greatly accelerates the flocculation and reduces the water retention in the resultingsediment ultimately producing innovative smart flocculants with enhanced solid-liquid separation performancefor removing PFAS from contaminated water.


application_id: 11092312
project_number: 5R01DK133184-04
project_title: The Role of DENND5B in Dietary Lipid Absorption
administering_ic: NIDDK
award_notice_date: 2025-09-03
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 133184
program_official: SENGER, STEFANIA
project_start_date: 2022-07-15
project_end_date: 2027-05-31
study_section: Nutrition and Metabolism in Health and Disease Study Section[NMHD]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPostprandial plasma triacylglyceride levels are independently associated with risk of cardiovasculardisease. The intestine plays a key role in the regulation of dietary triacylglyceride absorption bypackaging and secreting lipids in chylomicron particles. The intracellular steps of chylomicronbiogenesis and transport have been fairly well described however there is a significant gap in ourunderstanding of the mechanism for the final steps of chylomicron secretion by enterocytes specificallypost-Golgi transport and secretion. We recently identified a protein that plays a critical role in thispathway DENND5B. Our newly generated Dennd5b-/- mouse demonstrates an essential role for thisgene in Golgi to plasma membrane transport of chylomicron secretory vesicles. Dennd5b-deficient miceare resistant to diet-induced: obesity changes in plasma lipids and atherosclerosis. In humans exomesequencing studies reveal that a common DENND5B variant is correlated with body mass index. Thesestudies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequentinfluence on body composition and peripheral lipoprotein metabolism. The overall objective of thisproposal is to gain fundamental knowledge about the process of dietary lipid absorption by the intestineand to examine the impact of this process on systemic metabolic health. This objective aligns well withthe NIH mission to seek fundamental knowledge about living systems and to apply this knowledge toenhance health. The Specific Aims of this proposal use our novel mouse model and in vitroexperiments to examine the mechanistic role of DENND5B in the intestine and its systemic metaboliceffects. Aim 1 will quantify the impact of Dennd5b on dietary lipid absorption and generate acomprehensive spatial single-cell RNAsequencing data set for examination of gene networks thatparticipate in regulation of dietary lipid absorption. Aim 2 will examine the mechanism underlyingDennd5b action in CM transport. Furthermore this aim will use mass spectrometry and interactomicsanalysis to expand our understanding of this process by identifying other interacting proteins which mayform a complex to facilitate chylomicron secretion by the intestine. Aim 3 will determine the impact ofDennd5b on enterocyte metabolic function and peripheral lipid metabolism. Successful completion ofthis proposal will fill a significant knowledge gap in the process of dietary lipid absorption. This work willadvance the field by providing mechanistic details for a key step in chylomicron secretion that can affectsystemic lipid homeostasis and metabolic health.

project_terms:
AGFG1 gene;Acute;Address;Affect;Apolipoproteins B;Atherosclerosis;Autophagocytosis;Biogenesis;Bioinformatics;Body Composition;Body mass index;Cardiometabolic Disease;Cardiovascular Diseases;Cell membrane;Cells;Chylomicrons;Circulation;Co-Immunoprecipitations;Complex;Conscious;Data;Data Set;Diet;Dietary Fats;Dyslipidemias;Enterocytes;Equilibrium;Esterification;Exhibits;Fasting;Fat-Soluble Vitamin;Fatty acid glycerol esters;Fistula;Foundations;Genes;Golgi Apparatus;Guanine Nucleotide Exchange Factors;Health;High Fat Diet;Homeostasis;Human;In Vitro;Ingestion;Insulin Resistance;Intestinal Absorption;Intestinal Secretions;Intestines;Knowledge;Link;Lipids;Lipolysis;Lipoproteins;Literature;Lymph;Maintenance;Mass Spectrum Analysis;Measurement;Measures;Membrane Fusion;Metabolic;Metabolism;Methods;Missense Mutation;Mission;Mitochondria;Modeling;Mucous Membrane;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;Obesity;Organism;Particle Size;Pathway interactions;Peripheral;Plasma;Play;Process;Proteins;Publishing;Regulation;Resistance;Risk Factors;Role;Secretory Vesicles;Sucrose;Tissues;Tracer;Transmembrane Transport;Triglycerides;United States National Institutes of Health;Variant;Very low density lipoprotein;Wild Type Mouse;Work;absorption;cardiometabolism;cardiovascular disorder risk;cardiovascular risk factor;cell type;crosslink;dietary;exome sequencing;experimental study;gene network;gene regulatory network;improved;insight;intestinal epithelium;lipid metabolism;mouse model;novel;particle;response;single-cell RNA sequencing;trafficking;transcriptome;uptake

public_health_relevance:
Project NarrativeThe absorption of dietary lipids and their transport to the circulation is essential for the maintenance ofwhole-body lipid metabolism and energy homeostasis; however elevated postprandial plasma lipidspecifically triacylglyceride (TAG) is a significant independent risk factor for cardiovascular disease.This project will provide mechanistic insight into a newly discovered role for the protein DENND5B inthe absorption of dietary TAG and its impact on cardiometabolic health. The overall objective of thisproposal is to gain fundamental knowledge about the process of dietary lipid absorption by the intestineand its impact on metabolic health.


application_id: 11092256
project_number: 5R01DK133076-03
project_title: Origins of Skeletal Fragility in Type 1 Diabetes
administering_ic: NIDDK
award_notice_date: 2025-04-29
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 133076
program_official: MALOZOWSKI, SAUL N
project_start_date: 2023-07-25
project_end_date: 2027-04-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 6741266
contact_pi: FOWLKES, JOHN L
other_pis: NYMAN, JEFFRY STEPHEN
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
arra_indicator: N
project_abstract:
Humans with type 1 diabetes mellitus (T1D) experience several disorders of skeletal health includingdecreased bone mineral density (BMD) and increased risk for fragility fractures (i.e. osteoporosis). Thesefeatures are the primary clinical characteristics of diabetic bone disease (DBD). Evidence suggests that DBDoccurs early in the progression of T1D; involves impaired bone formation; results in micro-architecturalabnormalities and poor bone matrix quality; and coincides with hyperglycemia and a decline in endogenousinsulin and insulin-like growth factor-1 production. While many have postulated that skeletal deficits in diabetesoccur as a direct result of glucose dysregulation our pre-clinical studies in mouse models supported byobservational studies in humans show that impairment in the production and action of insulin and insulin-likegrowth factor-1 (IGF-1) may be root causes of DBD. Specifically our laboratory and others have demonstratedthat in rodent models of T1D: 1) deficits in bone formation occur in the context of insulin-deficiency; 2) near-normalization of serum glucose alone is not sufficient to prevent DBD; 3) insulin and IGF-1 therapy improvefracture resistance and new bone formation; and 4) both insulin and IGF-1 utilize similar down-streampathways to promote osteoblastogenesis and bone formation. To clarify the mechanisms and signalingpathways by which insulin and/or IGF-1 modulate osteogenesis; to understand how deficiencies or impairedsignaling of each may contribute to DBD; and to delineate how each may contribute to therapeutic approachesto prevent or treat DBD we propose to 1) determine how insulin and IGF-1 deficiencies contribute to DBD atthe tissue cellular and molecular level and 2) how each hormone may perform overlapping and independenteffects through specific downstream signaling pathways that may ultimately become therapeutic targets forpreventing and/or reversing DBD.

project_terms:
Ablation;Affect;Architecture;Bone Density;Bone Matrix;Characteristics;Clinical;Critical Pathways;Development;Diabetes Mellitus;Effectiveness;Event;Evolution;Exposure to;FOXO1A gene;Fracture;Gene Modified;Glucose;Health;Homologous Gene;Hormones;Human;Hyperglycemia;Impairment;Insulin;Insulin Signaling Pathway;Insulin deficiency;Insulin-Dependent Diabetes Mellitus;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;Knockout Mice;Laboratories;Ligands;Maps;Molecular;Mus;Observational Study;Osteoblasts;Osteogenesis;Osteoporosis;PI3 gene;Pathway interactions;Personal Satisfaction;Persons;Pharmacotherapy;Predisposition;Prevention;Production;Proto-Oncogene Proteins c-akt;Resistance;Risk;Rodent Model;Serum;Signal Pathway;Signal Transduction;Therapeutic;Tissues;bone;bone health;bone strength;diabetic;diabetic bone disease;experience;fragility fracture;improved;inhibitor;mechanical properties;mouse model;osteoporosis risk;osteoprogenitor cell;preclinical study;prevent;receptor;response;skeletal;skeletal disorder;therapeutic target;transcriptomics

public_health_relevance:
Humans with Type 1 diabetes (T1D) are susceptible to diabetic bone disease and are more likely to suffer afragility fracture than humans without T1D. Despite this now well-recognized increased risk of osteoporosis andfracture in persons with T1D it is still not well understood how insulin or its homolog insulin-like growth factor1 (IGF-1) directly affects skeletal well-being in this condition. The studies described in this project will define therelative contributions of insulin and IGF-1 to the molecular cellular and tissue-level events involved in thedevelopment of diabetic bone disease as well as explore the therapeutic potential of insulin and IGF-1 inpreventing and treating diabetic bone disease.


application_id: 11092254
project_number: 5R36DA061317-02
administering_ic: NIDA
award_notice_date: 2025-05-09
opportunity_number: PAR-23-194
application_type: 5
activity_code: R36
ic: DA
serial_number: 061317
program_official: ZUR, JULIA BETH
project_start_date: 2024-06-01
project_end_date: 2026-05-31
study_section: Special Emphasis Panel[ZRG1-F16-H(20)L]
contact_pi_person_id: 77907134
contact_pi: BOOTY, MARISA D.
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-06-01
project_title:
Examining the Impact of the Criminal Legal System on Opioid Use Disorder Treatment and Recovery: A Socioecological Perspective

project_abstract:
Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text.The proposed R36 dissertation project will advance scientific understanding of the criminal legal systems (CLS) influence on opioid use disorder (OUD) recovery. CLS involvement is common among those with OUD and for many the CLS facilitates access to recovery services either through provision of treatment or connection to care upon release. There is an inherent role contradiction present here; since the CLS also is tasked with maintaining public safety there could be unintended consequences on a person's recovery. The proposed mixed-methods study aligns with the NIDA Services Research Branch priority to better understand the impact of CLS involvement on substance use service engagement and recovery. This project uses a socioecological framework to enhance understanding of the community interpersonal and individual-level influence of CLS involvement on OUD treatment and recovery. Aim 1 examines the impact of the CLS on OUD treatment and recovery language among people residing and working in communities highly impacted by the opioid epidemic (community). This is achieved via qualitative thematic analysis of Photovoice group transcripts (N = 45 participants) from the Kentucky HEALing Communities Study Photovoice protocol. Aim 2 analyzes the effect of social network factors on prison substance use disorder (SUD) treatment completion (interpersonal). Aim 2 is achieved by conducting secondary data analysis using data from the Geographic variation in Addiction Treatment Environment (GATE) study a longitudinal cohort study examining medication use for OUD treatment and other recovery outcomes of individuals who participated in SUD treatment programming while incarcerated (N = 320). Aim 2 uses logistic regression to analyze whether internalized stigma mediates the relationship between social network factors and SUD treatment completion. Finally Aim 3 uses GATE study data to evaluate CLS-related predictors of participation in mutual aid support groups (e.g. Narcotics Anonymous) post-release (individual). Negative binomial logistic regression analyzes the effect of CLS-related factors on the number of mutual support groups attended in the 6-months after release. Results of this project highlight the urgent need to address the multi-level impact of the CLS on OUD recovery to combat the opioid epidemic among people involved with the CLS. The R36 aims will serve as the applicants dissertation. OUD recovery is not merely an individual process so barriers to recovery must be addressed at multiple levels of CLS influence to best effect change and have a sustained public health impact. The R36 dissertation project outlined in this application launches the Principal Investigator on a path towards becoming an NIH independent investigator.

project_terms:
Address;Caring;Communities;County;Creativeness;Data;Data Analyses;Disease;Environment;Evidence based intervention;Health;Health Services Administration;Health Services Research;Imprisonment;Individual;Institution;Justice;Kentucky;Knowledge;Language;Learning;Legal system;Length;Logistic Regressions;Longitudinal cohort study;Maximum Likelihood Estimate;Mediating;Mental Health Services;Methodology;Methods;Morals;Narcotics Anonymous;National Institute of Drug Abuse;Opioid;Outcome;Overdose reduction;Participant;Pathway Analysis;Persons;Pharmaceutical Preparations;Play;Predictive Factor;Principal Investigator;Prisons;Process;Protocols documentation;Provider;Public Health;Quality of Care;Recommendation;Recovery;Research Personnel;Risk;Role;Safety;Scientific Advances and Accomplishments;Self Direction;Services;Social Network;Social support;Substance Use Disorder;Support Groups;Surveys;Symptoms;Text;Transcript;United States National Institutes of Health;addiction;career;combat;community reentry;experience;geographic difference;healing;improved;innovation;internalized stigma;meetings;member;opioid epidemic;opioid use;opioid use disorder;outreach;overdose death;recovery services;response;service delivery;service engagement;substance abuse treatment;substance use;substance use treatment;treatment program;treatment services;uptake

public_health_relevance:
This project highlights the urgent need to address the multi-level impact of the CLS on OUD treatment and recovery to combat the opioid epidemic among people involved with the CLS. The Substance Use and Mental Health Services Administration defines recovery as a self-directed process and this project examines ways in which institutions and networks limit an individuals agency in their recovery efforts. Because substance use recovery is not merely an individual process it is important to address barriers and facilitators at all levels of impact to best effect change and have a sustained public health impact.


application_id: 11092033
project_number: 5U18FD006155-09
project_title: Equipment Purchases for Breathitt Veterinary Center
administering_ic: FDA
award_notice_date: 2025-06-23
opportunity_number: PAR-22-063
application_type: 5
activity_code: U18
ic: FD
serial_number: 006155
program_official: CERIC, OLGICA
project_start_date: 2017-08-01
project_end_date: 2027-05-31
study_section: ZFD1-CVM-R(03)1
contact_pi_person_id: 80387127
contact_pi: NARAYAN, PAUL CHANDRA
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract CVM Vet-LIRN Veterinary Diagnostic Laboratory ProgramPAR-22-063 Breathitt Veterinary Center (BVC) seeks funding to maintain the high quality levelof testing through participation in the CVM Vet-LiRN Veterinary Diagnostic LaboratoryProgram. This funding will be used for the following: Maintain BVC's Antimicrobial Resistance Study participation Maintenance Contract for equipment Fund Proficiency Testing by BVC lab sections Training for BVC staff Travel by BVC staff to training sessions appropriate meetings and conferences Membership dues for scientific organizations

public_health_relevance:
Project NarrativeCVM Vet-LiRN Veterinary Diagnostic Laboratory Program (U18)PAR-22-063 Breathitt Veterinary Center (BVC) will utilize funding from this program to improve the qualityof testing by staff members through proficiency testing and staff training. Funding will also support theAntimicrobial Resistance Study being conducted at BVC in collaboration with other labs in the Vet-LiRNnetwork and provide a maintenance contract for the SensiTitre instrument.


application_id: 11091411
project_number: 5P20GM121327-09
project_title: Regulation of one-carbon metabolism and purine synthesis by YRDC in hepatocellular carcinoma
administering_ic: NIGMS
award_notice_date: 2024-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: GARTRELL, KYUNGSOOK
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 7998
contact_pi_person_id: 16489042
contact_pi: ALI, EUNUS
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
project_abstract:
Hepatocellular carcinoma (HCC) accounts for >80% of patients with liver cancer and is one of the leading causes of cancer-associated mortalities both worldwide and in the United States. Recent evidence highlights the involvement of YRDC (YrdC-threonylcarbamoyltransferase domain-containing protein) a tRNA modifying enzyme in tumor growth via N6-threonylcarbamoylation (t6A) of tRNA in various cancer types including HCC. Additionally YRDC has been shown to be overexpressed in different types of cancer and associated with chemotherapeutic drug resistance as well as poor prognosis in HCC patients. However the precise molecular mechanisms underlying YRDC overexpression in cancers and its involvement in the regulation of tumor metabolism remain unknown. The objective of our study is to define the mechanisms by which YRDC drives cellular growth and investigate the potential of targeting YRDC in cancers with a specific focus on HCC. Our preliminary data employing metabolomic and isotope tracing approaches have shown that YRDC can act as a novel regulator of one-carbon metabolism and purine synthesis in several cancer cells including HCC cells. We demonstrate that YRDC depletion reduces flux through one-carbon metabolism thereby restricting the availability of substrates for the synthesis of de novo purine nucleotides. In light of these findings this proposal focuses on studying YRDC and its impact on tumor metabolism using HCC as a model. We hypothesize that YRDC promotes tumor growth by activating one-carbon metabolism thereby stimulating de novo purine synthesis. Consequently targeting YRDC represents a potentially effective strategy against HCC. We will define the mechanisms underlying YRDC upregulation in HCC we will use isogenic cell settings deleted for the tumor suppressor P53 and expressing mutant KRAS and examine the role of the MAPK/ERK downstream of KRAS in the regulation of YRDC mRNA and protein levels (Aim1). Then we will determine the molecular mechanisms by which YRDC stimulates one-carbon metabolism and purine synthesis in HCC cells (Aim2). Finally we will examine the therapeutic potential of suppressing YRDC to improve HCC and/or sensitize HCC to chemotherapy (Aim3). Overall the proposal is significant because it will identify novel regulators of onecarbon metabolism and the de novo purine synthesis pathways clarify the tumor pro-growth function of YRDC and identify a novel drug target in HCC treatment. The project is highly innovative because to date YRDC has not been linked to the regulation of one-carbon metabolic pathway. The proposal will provide a stepping-stone to aid the applicant to establish an independent research career and the work performed under this award will be used to generate NIH R01 grant proposals.

project_terms:
Applications Grants;Award;Cancer Center;Cancer Etiology;Carbon;Cells;Data;Drug resistance;Enzymes;Growth;Isotopes;KRAS2 gene;Kentucky;Light;Link;MAP Kinase Gene;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Messenger RNA;Metabolic Pathway;Metabolism;Modeling;Molecular;Pathway interactions;Patients;Primary carcinoma of the liver cells;Prognosis;Protein Overexpression;Proteins;Purine Nucleotides;Purines;Regulation;Research;Role;TP53 gene;Therapeutic;Transfer RNA;Tumor Promotion;United States;United States National Institutes of Health;Universities;Upregulation;Work;cancer cell;cancer type;career;cell growth;chemotherapeutic agent;chemotherapy;improved;innovation;metabolomics;mortality;mutant;new therapeutic target;novel;overexpression;tumor;tumor growth;tumor metabolism


application_id: 11090681
project_number: 1R35GM158223-01
project_title: Molecular Biophysics of Dynamic Bacterial Nanomachines
administering_ic: NIGMS
award_notice_date: 2025-09-02
opportunity_number: PAR-22-180
application_type: 1
activity_code: R35
ic: GM
serial_number: 158223
program_official: FLICKER, PAULA F
project_start_date: 2025-09-05
project_end_date: 2030-08-31
study_section: Maximizing Investigators' Research Award A Study Section[MRAA]
contact_pi_person_id: 11309989
contact_pi: SHAFFER, CARRIE
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYInterdisciplinary research in the Shaffer lab centers on discovering fundamental molecular mechanismsunderpinning unilateral cargo delivery across biologically diverse membranes. Using the Helicobacter pylori cagtype IV secretion system (cag T4SS) as a robust model system our studies focus on understanding the biologyand biophysics of intercellular DNA translocation through dynamic bacterial nanomachines assembled byevolutionarily divergent microbes. Although H. pylori is a significant carcinogenic bacterium that stimulates thedevelopment of infection-associated gastric malignancies the projects outlined in this MIRA application do notseek to study determinants of bacterial pathogenesis or aspects of microbial carcinogenesis. Rather our studiesleverage the versatile cag T4SS nanomachine as a paradigm for understanding how a single molecular devicetransports disparate microbial payload into target eukaryotic cells in a physiologically relevant context. Whereasconjugative T4SS machineries secrete nucleoprotein complexes into recipient prokaryotes the capacity totranslocate a bacterial oncoprotein and an expanded repertoire of fragmented nucleic acids lipopolysaccharidebiosynthetic metabolites and peptidoglycan substrates into human cells distinguishes the cag T4SS from othernanomachines. Our current and future studies are uniquely poised to fill long-standing knowledge gaps in T4SSbiology to strengthen our understanding of mechanisms underscoring interbacterial and trans-kingdom cargodelivery though diversified machineries. Studies performed by my group over the past five years yielded novelmolecular details of cag T4SS substrate translocation and led to the discovery of mechanisms underlying trans-kingdom DNA conjugation in the context of human infection. In the next five years we will address three majordeficiencies in our understanding of T4SS architecture biogenesis and function. First despite many decadesof research we do not understand how the cag T4SS apparatus orchestrates cargo selection and secretion andthe mechanisms by which discordant payload is coupled to the translocation channel are unresolved. Secondwhile multiple bacterial nanomachines exhibit substructure symmetry mismatch the biological significance ofT4SS architectural asymmetry is unknown. Third while DNA processing has been extensively investigated inprototypical interbacterial conjugation systems the mechanisms governing trans-kingdom DNA transfer acrossdonor and recipient membranes have not been elucidated in the context of human infection. Our studies willemploy powerful chemical biology genetic and biochemical approaches in combination with in situ cryo-electrontomography (cryo-ET) and high-resolution fluorescence microscopy to extend our fundamental understanding ofT4SS biology and eliminate numerous black boxes that obscure the inner workings of these dynamic machines.Collectively our multidisciplinary approach and collaborative efforts will continue to generate novel insights intoT4SS structural and functional diversity and will provide a mechanistic framework for the development ofinnovative biotherapeutics for precision medicine.

project_terms:
Bacteria;Biochemical;Biogenesis;Biological;Biological Models;Biological Response Modifier Therapy;Biology;Biophysics;Black Box;Cells;Chemicals;Complex;Coupled;Cryo-electron tomography;DNA;Development;Devices;Disparate;Eukaryotic Cell;Exhibits;Fluorescence Microscopy;Future;Genetic;Helicobacter pylori;Human;In Situ;Infection;Interdisciplinary Study;Knowledge;Lipopolysaccharides;Membrane;Microbe;Molecular;Nucleic Acids;Nucleoproteins;Oncoproteins;Pathogenesis;Peptidoglycan;Physiological;Process;Prokaryotic Cells;Research;Resolution;Stomach;System;Systems Biology;Type IV Secretion System Pathway;carcinogenesis;carcinogenicity;improved;innovation;insight;interdisciplinary approach;malignant stomach neoplasm;microbial;nanomachine;novel;novel therapeutic intervention;precision medicine;system architecture

public_health_relevance:
PROJECT NARRATIVEEvolutionarily divergent microbes use specialized type IV secretion system (T4SS) nanomachines to deliverdiverse cargo into target cells. Using the gastric bacterium Helicobacter pylori as a model system we proposeto investigate the basic biological mechanisms governing DNA transport through the versatile T4SS apparatus.These studies will improve our fundamental understanding of conserved processes that facilitate intercellularDNA transfer from microbes to humans and will inform the development of novel therapeutic strategies.


application_id: 11090566
project_number: 5R01DE012505-28
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2025-03-24
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 012505
program_official: MCNEALY, TAMARA L
project_start_date: 1998-09-01
project_end_date: 2028-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: POTEMPA, JAN S;URIARTE, SILVIA M
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:
AbstractPolymicrobial infections are inherently more complex than monospecies infections and this complexity hasbeen a significant barrier to both a fuller appreciation of pathogenic mechanisms and to the development ofeffective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases andare among the most common infections of humans. Although certain organisms such as Porphyromonasgingivalis are considered key pathogens it is the polymicrobial community as a whole that initiates anddrives the disease. Interspecies interactions within communities shape overall pathogenic potential andwork supported by this project has uncovered a dynamic and multilevel interaction between P. gingivalisand its community partners. The pathogenicity of P. gingivalis can be constrained by the streptococcaldiffusible metabolite para-amino benzoic acid (pABA) which is as a precursor of de novo folate synthesis inthe physiologically essential one-carbon metabolism (OCM) pathway. However as physically integratedcommunities develop interspecies co-adhesion results in suppression of streptococcal pABA production andadditionally partner organisms such as Streptococcus gordonii and Fusobacterium nucleatum enhanceoverall community pathogenicity. Sensing of both pABA and interspecies physical contact by P.gingivalis is transduced through a protein tyrosine phosphorylation signaling circuit. The tyrosine kinasePtk1 controls flux through OCM as well as the production of virulence factors including the gingipainproteases which can modulate interactions with neutrophils. Indeed Ptk1 is required for pathogenicity inboth murine abscess and alveolar bone loss models of disease. In this proposal we will define the role ofPtk1 as a master regulator which can integrate OCM with pathogenicity. In the first Aim we will examine howPtk1-mediated phosphorylation of gingipains is necessary for their processing and secretion. We willdetermine where non-phosphorylated gingipains remain localized in P. gingivalis and investigate whichcomponents of the type IX secretion system machinery malfunction in the absence of phosphorylation.Additionally we will follow post-translational maturation of non-phosphorylated gingipains to uncover the roleof phosphorylation in catalytic removal of the N-terminal peptide the haemagglutinin domains or the C-terminal domain as is required for the assembly of fully activated proteases. In the second Aim we shallfunctionally dissect the contribution of phosphorylation to the activity of the pABA synthesis enzyme PabC anddecipher a negative feedback loop whereby pABA can inhibit Ptk1. Aim 3 will address the impact of Ptk1 onthe activation state of neutrophils and their potential for tissue destructive responses to P. gingivalis.Completion of this project will provide novel insights into the context-dependent pathophysiology of P.gingivalis which could ultimately be translated into therapeutic strategies designed to target thecommunity-based pathogenesis that underlies periodontal disease.

project_terms:
Abscess;Alveolar Bone Loss;Amino Acids;Bacteria;Benzoic Acids;Binding;C-terminal;Calibration;Carbon;Communication;Communities;Complex;Cues;Data;Development;Dimensions;Disease;Environment;Enzymes;Equilibrium;Event;Excision;Feedback;Folic Acid;Functional disorder;Fusobacterium nucleatum;Goals;Human;Immune response;Infection;Inflammatory;Inflammatory Response;Innate Immune Response;Measures;Mediating;Metabolic;Metabolism;Microbe;Modeling;Molecular;Mus;N-terminal;Neutrophil Activation;Neutrophil Infiltration;Organism;Pathogenesis;Pathogenicity;Pathway interactions;Peptide Hydrolases;Peptides;Periodontal Diseases;Phosphorylation;Physiological;Physiology;Polysaccharides;Porphyromonas gingivalis;Process;Production;Property;Protein Tyrosine Kinase;Proteins;Regulation;Role;Shapes;Signal Transduction;Signaling Molecule;Streptococcus;Streptococcus gordonii;System;Testing;Therapeutic;Tissues;Translating;Tyrosine Phosphorylation;Virulence;Virulence Factors;Work;community partners;design;disease model;dysbiosis;extracellular;gingipain;in vivo;insight;microbial community;neutrophil;novel;oral infection;oral plaque;pathogen;polymicrobial disease;prevent;response

public_health_relevance:
NarrativeDiseases caused by mixtures of bacteria are often more serious and harder to treat that those caused by asingle organism. Periodontal (gum) diseases are caused by mixtures of microbes that communicate with eachother to regulate the level of disease-causing potential of the microbial community. In this proposal we shallstudy the communication mechanisms that allow periodontal bacteria to increase production of toxicproducts become more metabolically active and resist killing by the host.


application_id: 11090346
project_number: 5R01AR078316-04
administering_ic: NIAMS
award_notice_date: 2025-06-02
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AR
serial_number: 078316
program_official: WASHABAUGH, CHARLES H
project_start_date: 2021-08-05
project_end_date: 2027-05-31
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: FRY, CHRISTOPHER
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-06-01
project_title:
Sex-based Muscular Adaptations Capillary dysfunction and functional decline impact Knee-related psychosocial outcomes after acute knee injury (SMACK)

project_abstract:
AbstractFollowing an Anterior Cruciate Ligament (ACL) reconstruction females have worse outcomes; howeverskeletal muscle biology and function have preferentially been studied in males. These observations suggestthat there are sex-based differences in the biological mechanisms contributing to recovery of muscle function.Intriguing pilot data in this proposal show preferential impairment in the recovery of quadriceps muscle andfunction and diminished psychosocial recovery in females as compared to males following ACL reconstruction.This proposal seeks to test the novel hypothesis that following an ACL injury females experience exaggeratedmuscle cellular and molecular deficits hindering their recovery of strength resulting in pronounced deficienciesin gait mechanics and disproportionally worse psychosocial recovery compared to males. By identifying thecellular and molecular foundation of sex-based differences subsequent clinical trials can test sex specificapproaches to improve outcomes for women after ACL injury. We will in Aim 1 define the molecular cellularand morphological sex-based differences in quadriceps muscle after ACL injury and reconstruction. In Aim 2determine the effect of sex on knee function after an ACL reconstruction. Lastly in Aim 3 will determine thetiming and magnitude of psychosocial recovery differences between females and males following an ACLreconstruction. Results from this work will exert an immediate impact on clinical practice guidelines as well asidentify critical therapeutic targets needed to propel subsequent evidence-based clinical trials designed toimprove rehabilitative outcomes for females.

project_terms:
Acute;Atrophic;Biofeedback;Biological;Biology;Biopsy;Biopsy Specimen;Blood capillaries;Capillarity;Caring;Clinical;Clinical Practice Guideline;Clinical Trials;Clinical Trials Design;Combined Modality Therapy;Complement;Data;Development;Exhibits;Female;Fiber;Foundations;Functional disorder;Future;Gait;Gait abnormality;Gene set enrichment analysis;Growth;Hypertrophy;Immunohistochemistry;Impairment;Injury;Intervention;Joints;Knee;Knee Injuries;Knee joint;Knowledge;Limb structure;Mechanics;Molecular;Molecular and Cellular Biology;Morphology;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Operative Surgical Procedures;Orthopedic Surgery;Outcome;Pathway Analysis;Pathway interactions;Patient Outcomes Assessments;Phenotype;Physical Function;Physical therapy;Positioning Attribute;Postoperative Care;Procedures;Protocols documentation;Recovery;Recovery of Function;Regenerative capacity;Rehabilitation Outcome;Rehabilitation therapy;Reporting;Self Efficacy;Sex Differences;Skeletal Muscle;Testing;Time;Work;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;clinical development;density;endurance exercise;evidence base;exercise training;experience;follow-up;functional decline;improved;improved outcome;knee mechanics;limb injury;male;multidisciplinary;muscle strength;new therapeutic target;novel;novel therapeutic intervention;pharmacologic;psychosocial;psychosocial outcome;quadriceps muscle;regenerative rehabilitation;resilience;response;response to injury;sex;sex as a biological variable;statistics;therapeutic target;transcriptome sequencing;vastus lateralis;women's outcomes;women's treatment

public_health_relevance:
Project NarrativeAnterior Cruciate Ligament reconstructions are a common procedure resulting in significant impairments in thequadriceps muscle and females have worse outcomes than males. The identification of biological targetsunderlying poorer recovery in females after injury is lacking limiting the development of evidence-basedtherapies. We propose to define the muscle molecular and cellular sex-based differences underlying poorfunctional recovery the recovery of muscle function and gait mechanics as well as determine the timing andmagnitude of the psychosocial recovery differences between females and males to define sex as a biologicalvariable across scales to mitigate these differences in recovery through novel interventions.


application_id: 11089952
project_number: 3R01HL163818-03S1
project_title: Systematic identification of cardiotoxic e-cigarette flavorants
administering_ic: NHLBI
award_notice_date: 2024-08-28
opportunity_number: PA-23-189
application_type: 3
activity_code: R01
ic: HL
serial_number: 163818
suffix: S1
program_official: POSTOW, LISA
project_start_date: 2022-04-22
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1(56)-R]
contact_pi_person_id: 11702638
contact_pi: CARLL, ALEX PERROW
other_pis: NYSTORIAK, MATTHEW A
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Parent Grant Abstract. The use of e-cigarettes (e-cigs) has increased substantially since they were firstintroduced in 2003. E-cig devices aerosolize e-liquids that typically consist of humectants with variable levels ofnicotine and flavoring chemicals. Although there are thousands of commercially available flavor mixtures theyroutinely overlap in individual flavor chemicals (flavorants) which are far fewer in number. Many of theseflavorants belong to common chemical classes and are generally recognized as safe for ingestion. Howevertheir direct and indirect cardiac effects following heating and inhalation particularly in combination with nicotineremain mostly unknown. Direct exposure to nicotine alone distinctly affects the cardiac action potential waveformpotentially contributing to the high incidence of arrhythmias and sudden cardiac death among smokers. Recentevidence also suggests that nicotine in e-cigs may similarly promote adverse cardiac outcomes. Yet theinfluence of flavorants on the cardiac effects of e-cig aerosols remains untested. In our ongoing work we foundthat exposure to nicotine-containing e-cig aerosols of various flavors acutely and differentially altered theelectrocardiogram (ECG) in mice variably inducing QT interval prolongation increasing heart rate and evokingarrhythmia. As well two separate e-liquids with the same characterizing flavorant consistently increasedventricular arrhythmias. Furthermore we observed in cardiomyocytes that treatment with several flavorantscommon to e-cigs directly altered contractility rhythmicity and action potential duration. Nonetheless it remainsunknown how individual flavorants in e-cig aerosols exert direct or indirect cardiac effects in vivo. Consideringthe growing popularity of e-cigarettes and the urgent need for studying the in vivo toxicological profile ofconstituents in these products we propose to test the hypothesis that e-cigarette flavorants modify the effects ofe-cig aerosol exposures on cardiac electrophysiology leading to arrhythmias and functional remodeling of theheart. To test this we will systematically identify both acute and long-term effects of flavorant exposure on cardiacelectrophysiology using a combination of state-of-the-art in vivo in vitro and ex vivo approaches. Specificallywe will: 1) Identify the acute effects of flavored e-cig aerosol inhalation on cardiac electrophysiology invivo 2) Examine the direct impact of flavorants on cardiac electrophysiology in vitro and ex vivo and3) Elucidate deleterious impacts of acute and chronic flavorant aerosol exposure on cardiacelectrophysiology structure and function. These studies which are responsive to the research priorities ofthe FDA/CTP will provide new data showing how different flavor chemicals affect cardiac excitability andpotentially promote arrhythmogenesis. Such results would aid in formulating policies regulating the manufacturedistribution and marketing of flavored e-cigarettes.

project_terms:
Action Potentials;Acute;Adrenergic Agents;Adult;Adverse effects;Aerosols;Affect;Anatomy;Arrhythmia;Attention;Blood Vessels;Breeding;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac Myocytes;Cardiotoxicity;Cardiovascular system;Cause of Death;Chemicals;Child;Chronic;Compensation;Data;Devices;Echocardiography;Electrocardiogram;Electronic cigarette;Event;Exposure to;Fellowship;Female;Fibrosis;Flavoring;Frequencies;Health;Heart;Heart Rate;Heating;Human;Hypertrophy;Impairment;In Vitro;Incidence;Individual;Inflammation;Ingestion;Inhalation;Isolectin;Knowledge;Long-Term Effects;Marketing;Maternal Mortality;Mechanics;Morbidity - disease rate;Mus;Necrosis;Nicotine;Outcome;Performance;Periodicity;Physiology;Policies;Population;Positioning Attribute;Postdoctoral Fellow;Predisposition;Pregnancy;Pregnant Women;Regulation;Research Priority;Risk;Risk Factors;Signal Transduction;Smoker;Solvents;Stains;Stress;Structure;Telemetry;Testing;Time;Tissues;Toxic effect;Toxicology;Ventricular;Ventricular Arrhythmia;Work;aerosolized;air filter;cardiovascular effects;cardiovascular risk factor;combustible cigarette;density;e-cigarette aerosols;electronic cigarette use;electronic cigarette user;electronic liquid;heart cell;heart rate variability;hemodynamics;in vivo;manufacture;mortality;nicotine exposure;parent grant;post pregnancy;pregnant;pressure;research faculty;sex;skills;sudden cardiac death;tobacco advertising

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


application_id: 11089841
project_number: 2R35GM138636-07
administering_ic: NIGMS
award_notice_date: 2025-05-26
opportunity_number: PAR-22-180
application_type: 2
activity_code: R35
ic: GM
serial_number: 138636
program_official: MASKERI, BAISHALI
project_start_date: 2020-08-01
project_end_date: 2030-07-31
study_section: Maximizing Investigators' Research Award A Study Section[MRAA]
contact_pi_person_id: 9202423
contact_pi: EBBERT, MARK T W
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-08-01
project_title:
Understanding how structural mutations and individual RNA isoforms are involved in human health and disease

project_abstract:
In todays efforts to personalize medicine it does not seem reasonable to personalize medicinewithout understanding the nuances of individual RNA and protein isoforms across the humangenome. Despite the central dogma of biology having been established for decades major gapsin our understanding remain including why human protein-coding genes average eight RNAisoforms resulting in many unique protein products. Given the complexity of human biology withpotentially up to 400 unique major cell types and a vast range of developmental and aging stagesit seems unlikely that a mere 20000+ protein-coding genes all performing a single function couldenable such remarkable complexity. A next critical step in all of biology research especially inhuman health and disease research will be to determine individual isoform function. Some ofthese differences may be subtle but may explain many of the subtleties we observe in humanhealth (e.g. sex differences response to vaccines drug treatments disease development &progression complex traits etc.). For practical reasons standard short-read RNA sequencingstudies treat all isoforms as a single genean oversimplification of the underlying biology. Wewant to help determine what purpose individual RNA and protein isoforms play in human healthand disease and are employing long-read sequencing technologies to accomplish these goals.

project_terms:
Affect;Aging;Biology;Code;Complex;Development;Disease;Genes;Goals;Health;Human;Human Biology;Human Genome;Individual;Pharmacotherapy;Play;Protein Isoforms;Proteins;RNA;Research;Role;Sex Differences;Technology;Vaccines;cell type;long-read sequencing;personalized medicine;response;structural mutation;trait;transcriptome sequencing

public_health_relevance:
There are many subtleties in human health and disease that remain unexplained. In our effortsto help personalize medicine we seek to better understand how individual RNA isoforms affecthuman health disease by helping characterize them and their roles in human health anddisease.


application_id: 11089608
project_number: 5R01AA030756-03
administering_ic: NIAAA
award_notice_date: 2025-07-25
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AA
serial_number: 030756
program_official: WANG, JOE
project_start_date: 2023-08-15
project_end_date: 2028-05-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-06-01
project_title:
Characterization of the role of neuropeptide VIP-mediated fucosylation in alcohol associated liver disease

project_abstract:
Alcohol-induced changes in gut flora and intestinal metabolites increase portal endotoxin level which is directlyassociated with intestinal barrier dysfunction and is one of the well-recognized contributing factors to thepathogenesis of ALD. Gut fucosylation is a key force in maintaining a homeostatic relationship between the gutand its microbiota. Nevertheless it is unclear how host fucosylation machinery contributes to alcohol-associatedbarrier function and microbial translocation. It is shown that epithelial 12-fucosylation regulates the colonizationof E. faecalis which causes more severe alcoholic hepatitis. Our initial studies found that alcohol consumptionreduces the levels of neurons-derived peptide VIP in the gut. Neuropeptide VIP has previously been implicatedin circadian regulation food consumption and goblet cell mucus secretion. Our preliminary data further foundthat neuropeptide VIP administration or deletion of VIP receptor (VIPR1) can regulate intestinal fucosylation.Membrane-bound fucosylated glycoproteins on mucosal ECs function as important communication toolsbetween the host and luminal microbes. Many intestinal Bifidobacteria use 12-L-fucosidases to ferment theglycans of host glycoconjugates to produce fucose for its colonization. We found that fucose-derived propionatecould contribute to the induction of IL-22 producing group 3 innate lymphoid cells (ILC3s) which can regulateepithelial integrity in ALD. Therefore we hypothesize that a high amount of alcohol consumption isassociated with disturbances in gut VIP secretion reductions in IECs fucosylation and beneficialsymbionts and subsequently overgrowth of cytolysin-positive E. faecalis all of which lead to intestinalbarrier dysfunction and contribute to the development of ALD. We postulate that prebiotic and probioticsupplementation will attenuate alcohol-induced intestine and liver injury in part by inhibiting of E.faecalis colonization and increasing IL-22+ ILC3 in the intestine. Following specific aims will be carried out:Aim 1: Determine the impact of VIP signaling on the gut fucosylation and the effects of this impact on intestinalbarrier integrity in ALD. We will document the impact of VIP/VIPR1 signaling changes on intestinal fucosylationand integrity in ALD; We will explore the mechanisms by which fucosylation is enhanced by VIP. Aim 2:Investigate whether probiotic fucosidase-producing Bifidobacterium attenuates ALD via inhibition of E. faecaliscolonization and activation of IL-22+ILC3. We will examine the effect of fucosidase-producing Bifidobacteriumand fucose-derived propionate on E. faecalis colonization; We will investigate whether fucosidase-producingBifidobacterium attenuates ALD via the activation of gut ILC3 and IL-22/ IL-22RA signaling. Aim 3: Evaluate theefficacy of VIP-fucosylation-based therapeutic interventions in ALD. We will first evaluate and compare theefficacy of dietary prebiotic 2'-FL with VIP supplementation in the treatment of experimental ALD. We will alsodetermine the effect of metabolite propionate treatment with/without dietary 2'-FL supplementation on ALD inWT mice or ILC3-deficient mice. We propose that exploiting this mechanism will allow the design of novelstrategies to manipulate these forces to increase barrier function and/or prevent/delay the development of ALD.

project_terms:
Alcohol abuse;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Anti-Inflammatory Agents;Attenuated;Bacteria;Bifidobacterium;Binding;Communication Tools;Cytolysins;Data;Development;Endotoxins;Enterococcus faecalis;Epithelial Cells;Epithelium;Fatty Liver;Fermentation;Fucose;Fucosidase;Fucosyltransferase;Functional disorder;Glycoconjugates;Glycopeptides;Glycoproteins;Goblet Cells;Growth;Immune Tolerance;Immune system;Inflammation;Intestines;Knockout Mice;Ligands;Liver diseases;Lymphoid Cell;Mediating;Membrane;Microbe;Mucous Membrane;Mucous body substance;Mucus-Secreting Cell;Mus;Neurons;Neuropeptides;Oral;Pathogenesis;Pathologic;Penetration;Peptides;Play;Polysaccharides;Probiotics;Production;Propionates;Propylene Glycols;Receptor Signaling;Recombinants;Role;Secretor blood group alpha-2-fucosyltransferase;Shapes;Signal Transduction;Stress;Supplementation;Symbiosis;Therapeutic Intervention;Tight Junctions;Toll-like receptors;Vasoactive Intestinal Peptide Receptors;Volatile Fatty Acids;Work;adherent junction;alcohol abuse therapy;alcohol response;antimicrobial;circadian regulation;commensal bacteria;comparative efficacy;cytokine;design;dietary;efficacy evaluation;food consumption;gastrointestinal epithelium;glycosylation;gut inflammation;gut microbiota;interleukin-22;intestinal barrier;intestinal epithelium;intestinal injury;liver injury;loss of function;metabolomics;microbial;microbial host;microbiome;microbiota;new therapeutic target;novel strategies;pathogenic bacteria;prebiotics;prevent;probiotic supplementation;response;stool sample;symbiont

public_health_relevance:
Project NarrativeThis proposal provides the basis for a better understanding of the mechanisms for alcohol-induced intestinalfucosylation and barrier function in the development of ALD and may lead to the identification of novel therapeutictargets.


application_id: 11089397
project_number: 5R61MH133665-02
project_title: Engaging Higher-Order Mechanisms of Psychopathology: A Parsimonious Approach to Precision Medicine
administering_ic: NIMH
award_notice_date: 2025-05-01
opportunity_number: PAR-21-135
application_type: 5
activity_code: R61
ic: MH
serial_number: 133665
program_official: TALKOVSKY, ALEXANDER MAXWELL
project_start_date: 2024-05-15
project_end_date: 2026-10-31
study_section: ZMH1-ERB-N(01)
contact_pi_person_id: 9522329
contact_pi: SAUER-ZAVALA, SHANNON E
other_pis: SOUTHWARD, MATTHEW WAYNE
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTDespite considerable investments in treatment development for psychological conditions response rates formost interventions are quite modest (30-40%)23 and the prevalence of mental disorders remains persistentlyhigh.4 A new approach to psychological treatment is clearly needed to move the needle on the disease burdenof mental illness. In the last decade researchers have identified a manageable number of personality dimensions(i.e. neuroticism [low] agreeableness [low] conscientiousness) that can account for a broad range ofpsychopathology and be directly targeted in treatment. The overarching goal of the proposed study is to provideinitial evidence that targeting this limited number of higher-order personality-based dimensions represents amore potent parsimonious and personalized approach to mental healthcare. The goal of the R61 phase is todemonstrate target engagement by determining whether discrete therapy modules each designed to directlyaddress one higher-order personality dimension engage their intended personality targets using multi-modalassessments of clinician-rated self-report and behavioral indicators. A single-case experiment to testengagement of each higher-order target (n = 10 in each sub-study) will be conducted. Participants will complete(1) an assessment-only baseline period to establish stability in the targeted personality dimension withouttreatment (2) a 6-session intervention phase targeting the personality mechanism in which they demonstratedan elevation and (3) a 4-week assessment-only follow-up. The proposed R33 project will be conducted if at leastone personality-focused therapy module leads to improvement in its corresponding higher-order personalitydimension (i.e. go/no go criteria). The goal of the R33 phase is to demonstrate target validation by determiningwhether improvement in higher-order personality targets leads to improvement in downstream clinical endpoints(i.e. DSM-5 disorder symptoms). Participants (N = 204) will be randomized to receive the personality-basedtreatment modules (6-18 sessions) corresponding to their clinically significant elevations or to a waitlistcondition. We will recruit participants with borderline personality disorder in both study phases as this disorderis characterized by combinations of high neuroticism low agreeableness and low conscientiousness62858 andfrequently co-occurs with a variety of DSM-5 disorders that are accounted for by different personality domains.

project_terms:
Address;Anxiety;Anxiety Disorders;Behavioral;Borderline Personality Disorder;Clinical;DSM-V;Data;Diagnosis;Dimensions;Disease;Functional disorder;Goals;Intervention;Investments;Mental Health;Mental Health Services;Mental disorders;Modeling;National Institute of Mental Health;Needles;Negative Valence;Neurotic Disorders;Participant;Patient Recruitments;Patient Self-Report;Patients;Personality;Persons;Phase;Positive Valence;Prevalence;Process;Proliferating;Psychopathology;Public Health;Randomized;Research;Research Domain Criteria;Research Personnel;Risk;Social Processes;Specific qualifier value;Symptoms;System;Taxonomy;Techniques;Testing;Validation;Waiting Lists;Work;associated symptom;burden of illness;clinically significant;comorbidity;data reduction;depressive symptoms;design;experimental study;follow-up;improved;interest;multimodality;novel strategies;personalized approach;personalized care;precision medicine;primary outcome;psychologic;recruit;reduce symptoms;response;therapy development

public_health_relevance:
PROJECT NARRATIVEDespite considerable investments in treatment development for psychological conditions response rates formost interventions are quite modest (30-40%). Given the limitations of our current psychological interventionsystem the overarching goal of the proposed study is to provide initial evidence that targeting a limited numberof high-order personality-based dimensions represents a more potent parsimonious and personalizedapproach to mental healthcare.


application_id: 11089355
project_number: 5R01AG075583-04
project_title: Blood-Brain Barrier Repair in Alzheimers Disease with Epilepsy
administering_ic: NIA
award_notice_date: 2025-05-02
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 075583
program_official: NEWMAN, ELIZABETH
project_start_date: 2022-05-01
project_end_date: 2027-04-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
other_pis: BAUER, BJOERN
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:
More than 25% of patients with Alzheimers disease (AD) develop epilepsy as co-morbidity. In AD with epilepsy(ADxEpi) seizures accelerate cognitive decline and further reduce life expectancy compared to AD alone. Onehallmark of both AD and epilepsy is blood-brain barrier dysfunction. We discovered that barrier dysfunction ismore severe in ADxEpi patients compared to seizure-free AD patients. Collectively our data suggest that acombination of Ab and seizure-released glutamate (A/Glu) triggers a dual positive feedback loop which exac-erbates barrier dysfunction seizures and cognitive decline in ADxEpi. However the detailed mechanism(s) thatleads to barrier dysfunction in ADxEpi is/are unknown and treatment options for ADxEpi patients are limited toanti-seizure drugs that by themselves accelerate cognitive decline. This knowledge gap represents a critical andunmet need which will prevent us from achieving therapeutic advances for ADxEpi patients. Our overall objectivein this application is to define the mechanism that underlies barrier dysfunction in ADxEpi and to develop atherapeutic intervention. Based on preliminary data the central hypothesis is that blocking A/glutamate signal-ing repairs barrier dysfunction reduces seizure burden and slows cognitive decline in AD with epilepsy. Therationale for the proposed research is that its completion will provide the basis for a novel therapeutic interventionto successfully treat ADxEpi patients. The hypothesis will be tested by pursuing three specific aims: 1) Identifythe mechanism responsible for A/glutamate-mediated barrier dysfunction. 2) Define the relation between barrierdysfunction cognition and seizures in AD patients with epilepsy. 3) Develop a therapeutic intervention that re-pairs barrier dysfunction in AD with epilepsy. In Aim 1 we will determine signaling steps that lead to A/Glu-mediated neurovascular inflammation and barrier leakage in isolated mouse brain capillaries and verify thesefindings in vivo. In Aim 2 we will determine barrier dysfunction in brain tissue from ADxEpi patients and correlatethe degree of barrier dysfunction with seizure burden and patient cognition scores. In Aim 3 we will develop anintervention therapy designed to repair barrier dysfunction and we will evaluate the benefit of this interventionin two rodent ADxEpi models. The proposed research is innovative because it represents a substantive departurefrom the status quo by shifting the focus from traditional anti-seizure drugs to targeting molecular pathways torepair barrier dysfunction thereby improving seizure burden and slowing cognitive decline in ADxEpi. The pro-posed research is significant because it holds the promise of a new therapeutic approach that has translationalpotential for clinical use to advance the treatment of ADxEpi patients.

project_terms:
Acceleration;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid beta-Protein;Anticonvulsants;Attenuated;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Brain;Characteristics;Clinical;Cognition;Cyclooxygenase Inhibitors;Data;Disease Progression;Epilepsy;Extravasation;Feedback;Functional disorder;Glutamates;Health;Impaired cognition;Inflammation;Intervention;Knowledge;LOX gene;Life Expectancy;Link;Matrix Metalloproteinases;Mediating;Mission;Modeling;Molecular Target;Mus;National Institute of Neurological Disorders and Stroke;Nervous System Disorder;Outcome;Oxidative Stress;Oxidative Stress Induction;Pathway interactions;Patients;Personal Satisfaction;Preclinical data;Process;Public Health;Research;Rodent;Seizures;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;Work;brain tissue;cerebral capillary;comorbidity;design;epilepsy patient;glutamatergic signaling;improved;in vivo;innovation;neurovascular;novel therapeutic intervention;prevent;repaired;therapy design;translational potential

public_health_relevance:
The proposed research is relevant to public health because it is expected to advance understanding of themechanisms underlying blood-brain barrier dysfunction in Alzheimers disease with epilepsy as comorbidity. Theresearch is designed to provide a novel therapeutic intervention that repairs blood-brain barrier dysfunction toimprove seizure control and reduce cognitive decline in patients that have Alzheimers disease with epilepsy.Thus the proposed research is relevant to the missions of the NIH/NINDS and the NIH/NIA that pertain todeveloping fundamental knowledge that will help reduce the burden of neurological disease and improve thehealth and well-being in aging.


application_id: 11088808
project_number: 5R01AG037868-10
project_title: Chronic Stress Glucocorticoids and Progesterone in Brain Aging
administering_ic: NIA
award_notice_date: 2025-04-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: HAAKENSON, CHELSEA MARIE
project_start_date: 2011-03-01
project_end_date: 2026-05-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Evidence indicates that prolonged/ repeated behavioral stress promotes brain aging. This is thought to be dueat least in part to stress associated glucocorticoid (GC) secretion which in turn binds to glucocorticoid receptorsexerting transcriptional and other effects. A key downstream mediator in this signaling pathway serum-and-glucocorticoid kinase 1 (Sgk1) accelerates and the female sex steroid progesterone (P4) blunts the effects ofGCs. However despite the negative clinical consequences of chronic stress exposure with aging and/or infemale subjects little work has examined how aging may change the stress response the mechanisms throughwhich stress may accelerate brain aging the degree to which stress-accelerated aging is dependent on GC isdriven by Sgk1 or is inhibited by P4. Our preliminary data suggests that hippocampal Sgk1 is upregulated byaging stress and GCs in white matter oligodendrocytes and that the female sex hormone progesterone (P4)blunts the effects of stress/GCs and may serve as an endogenous protectant that is lost with age in females.To address these knowledge gaps we propose 3 aims to investigate: the age-course of the response to chronicstress or chronic GCs in males and females; whether viral overexpression of Sgk1 exacerbates or systemic P4administration ameliorates stress-accelerated aging; and whether the pharmacologic sensitivity of hippocampaltissue to GC and P4 is shifted with age or chronic stress/GC. Cognitive and anxiety-related behavior bloodhormone measures and a novel panel of 205 hippocampal genes that are robustly changed with aging acrossmultiple studies will be used to test for stress/GC-accelerated aging and intervention effects as will downstreamgray and white matter Sgk1 expression and microglial response to microinjury- two processes demonstrated tobe glucocorticoid sensitive and exaggerated in white vs. gray matter in preliminary data. Thus the proposedstudies will yield essentially the first comprehensive test of the hypothesis that chronic stress acceleratestranscriptional brain aging and will illuminate sex differences in stress responsiveness and the potential roles ofGC P4 and Sgk1 in gray and white matter. Even if all of our working hypotheses are rejected by the results theproposed studies should have translational value for geriatric medicine.

project_terms:
Acceleration;Acute;Address;Age;Age Months;Aging;Agonist;Astrocytes;Behavioral;Bilateral;Binding;Biological Assay;Biological Markers;Blood;Cells;Chronic;Chronic stress;Clinical;Cognitive;Corticosterone;Data;Dependence;Dimethyl Sulfoxide;Dose;Female;Gene Expression Profile;Genes;Genetic Transcription;Geriatrics;Glucocorticoid Receptor;Glucocorticoids;Gonadal Steroid Hormones;Health;Hippocampus;Hormone Responsive;Hormones;Hypertrophy;Immunohistochemistry;Injury;Intraperitoneal Injections;Knowledge;Measures;Mediating;Mediator;Microglia;Microinjections;Mifepristone;Modeling;Myelin;Neurons;Oligodendroglia;Oral;Outcome;Outcome Measure;Phosphotransferases;Preparation;Process;Progesterone;Rattus;Research Support;Rodent Model;Role;Serum;Sex Differences;Signal Pathway;Signal Transduction;Slice;Stress;Stress Tests;System;Testing;Therapeutic Uses;Tissues;Upregulation;Viral;Work;acute stress;age acceleration;age effect;aged;aging biomarker;aging brain;aging related;animal age group;antagonist;anxiety-related behavior;biological adaptation to stress;cell type;cytokine;female sex hormone;gray matter;indexing;intervention effect;laser capture microdissection;mRNA Expression;male;morris water maze;nanostring;neuroinflammation;novel;novel strategies;overexpression;pharmacologic;receptor;reproductive hormone;response;sex;stress reduction;transcriptome sequencing;treatment group;uptake;white matter;women subjects

public_health_relevance:
The proposed studies in rodent models will yield essentially the first comprehensive test of the hypothesis thatchronic stress accelerates transcriptional markers of brain aging. The studies will illuminate sex differences instress and stress hormone responsiveness and the potential protective and mediating roles respectively ofprogesterone and SGK1 (a key effector in glucocorticoid system signaling) in gray and white matter. Even if ourworking hypotheses are rejected the proposed studies should have translational value for geriatric medicine.


application_id: 11088784
project_number: 5R01AT008617-09
project_title: Mechanisms underlying edible exosome-like nanoparticles for prevention of brain inflammation
administering_ic: NCCIH
award_notice_date: 2025-06-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AT
serial_number: 008617
program_official: KIM, HYE-SOOK
project_start_date: 2015-12-01
project_end_date: 2027-05-31
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Brain chronic inflammation is a hallmark of the aging process and promotes the progression of many braindiseases. Compelling evidence shows that healthy edible plants have important physiological roles for normalbrain function and can prevent neuroinflammatory processes. However mechanistic studies in the brain haveprimarily focused on single or individual factors from edible plants which most likely do not represent the resultsgenerated from multiple factors that are provided in a healthy diet consumed daily.Recently a tiny nanoparticle called an exosome-like nanoparticle (ELN) has been isolated from a number ofedible plants. ELNs consists of lipids proteins and RNAs. We have demonstrated that ELNs like prebioticsare taken up by intestinal bacteria resulting in inhibition of mouse colitis. However whether these edible plant-derived nanoparticles have a direct effect on the brain is not clear.In this study we will provide cellular and molecular insight into how ELNs modulate neuroimmune function via agut-brain axis by targeting microglial cells that benefits the brain. Indispensable to this proposal is the use of amouse aging model to investigate mechanistic details that will facilitate developing ELNs as a potential new classof prebiotic to target specific components involved in brain inflammation. Based on these findings it is temptingto speculate that the clinical profile of at least some brain anti-inflammation therapeutics can be improved byinterventions relying on one or more edible plant-derived ELNs. This finding urgently awaits experimentalconfirmation which is what we proposed to investigate in this proposal. From a clinical application standpointand as proof-of-concept in this study our hypothesis is that multiple factors carried by garlic ELNs (GaELN)target to microglial cells simultaneously to inhibit brain inflammation in aged mice. This will be tested ina mouse aging model that mimics human aging process. The plan to test our hypothesis is outlined in threespecific aims. Our proposed studies will determine: (1) Determine and evaluate if garlic ELN (GaELN)phosphatidic acid (PA) stimulated BASP1 domain(s) that binds to calmodulin (CaM) prevents c-MYC mediatedbrain inflammation in aged mice; (2) Evaluate whether GaELN nc-sRNA21 contributes to inhibition of braininflammation by enhancing the transporting of c-MYC-nick into exosomes in a Rab11a dependent manner; and(3) Evaluate whether GaELN induces a switch to secretion of CYLD+exosomes with immune tolerant cargos.Upon accomplishing this proposed study the study will lead to identification of new therapeutic targets andpotential ELN based interventions for treating brain inflammation. In addition findings will provide a foundationto further study whether oral administration of customized ELNs isolated from different plants will have asynergistic/additive effect on prevention or treatment of chronic inflammatory brain related diseases. Thereforethis study is a highly translational study aimed at finding new therapeutic targets for brain inflammation.

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

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


application_id: 11088739
project_number: 5U18FD006179-09
administering_ic: FDA
award_notice_date: 2025-06-23
opportunity_number: PAR-22-063
application_type: 5
activity_code: U18
ic: FD
serial_number: 006179
program_official: CERIC, OLGICA
project_start_date: 2017-08-01
project_end_date: 2027-05-31
study_section: ZFD1-CVM-R(03)1
contact_pi_person_id: 16558681
contact_pi: ROMANO, MEGAN C
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-06-01
project_title:
FDA Vet-LIRN Veterinary Diagnostic Laboratory Cooperative Agreement Program funding to increase sample analysis in the event of animal food or drug related illness

project_abstract:
Romano 2022 Project Summary/AbstractThe objective of this Food and Drug Administration (FDA) Veterinary Laboratory Investigationand Response Network (Vet-LIRN) Cooperative Agreement Program is to maintain increasedsample analysis capabilities for the FDA through partnership with Vet-LIRN laboratories. Ananimal food- or drug-related illness or other large scale animal food/feed emergency eventrequires surge capacity testing of implicated diagnostic or animal food samples. Testingincludes chemical and microbiological analysis of samples such as animal food/feed/drugsenvironmental samples related to animal food/feed/drug production and animal diagnosticnecropsy or clinical samples. In the event of a large-scale chemical or biological contaminationaffecting animal food or drug products the UKVDL performs selected analyses of diagnosticsamples collected and supplied to the laboratory by FDA or other government agencies. Federalor State surveillance assignments will also be a source of samples for analyses.The overall goal of the cooperative agreement is to continue developing improving and usinguniversity state and federal veterinary diagnostic laboratory testing capabilities in concert torespond to large-scale events. The cooperative program will also continue to standardizeanalyses performed at member laboratories by encouraging use of standardized analyticalmethods and equipment analytical worksheets and electronic reporting of results. Training andproficiency testing will continue to be provided for new methods and Quality Managementsystems will be further enhanced. Small scale method development and method validationprojects will continue as directed by the Vet-LIRN Program Office. Funding will be used forsupplies equipment maintenance and personnel time.

public_health_relevance:
Romano 2022 Project NarrativeThe FDA Vet-LIRN Cooperative Agreement Program will strengthen the nation's food safetysystem by increasing capacity and expanding capabilities to detect adulterated livestock feedsand pet foods. Contaminated livestock feeds could affect animals raised for humanconsumption either via excessive tissue residues or animal losses. Many ingredients used incompanion animal foods are also used in human food products and contamination of theseingredients could also affect humans.


application_id: 11088735
project_number: 5R01AG069909-05
project_title: The role of satellite cells in skeletal muscle hypertrophy with aging
administering_ic: NIA
award_notice_date: 2025-04-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 069909
program_official: BOYCE, AMANDA T
project_start_date: 2021-08-15
project_end_date: 2026-04-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: WEN, YUAN
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe loss of skeletal muscle mass with age is of clinical importance because it is associated with increasedmorbidity and mortality as well as a marked deterioration in the quality of life. There is also a heightenedinterest in the identification of cellular and molecular mechanisms responsible for the lack of an anabolicresponse of aged muscle to hypertrophic stimuli. The use of satellite cells to treat loss of skeletal muscle massis considered a promising therapeutic strategy given their stem cell characteristics and essential role in post-natal muscle growth and regeneration. The results of our studies have prompted us to perform mechanisticanalyses of both of the well-known function of satellite cells; fusion to myofibers to provide additional nuclei forhypertrophic growth to other functional consequences of satellite cell expansion that occurs in response tovarious exogenous stimuli such as exercise as the increase in satellite cell abundance in response tomechanical overload far exceeds myonuclear accretion associated with increased myofiber size. We reportedsatellite cells were necessary for optimal long-term hypertrophic growth of skeletal muscle by regulating theextracellular matrix. Activated satellite cells repressed fibroblast collagen production via extracellular vesicle(EV) delivery of miR-206 revealing a previously unrecognized function of satellite cells in addition to providinga mechanism through which satellite cells communicate with other cells within muscle. We now have in vivosingle-cell (sc)RNA-seq evidence from Pax7-tdT reporter mice of a satellite cell intercellular communicationnetwork in which satellite cells communicate with FAPs/fibrogenic cells and endothelial cells duringhypertrophic growth. Aim 1 will test the hypothesis that aging negatively impacts this communication networkinhibiting proper remodeling of the extracellular matrix thereby inhibiting hypertrophy. We have also developeda novel mouse model that allows us to simultaneously deplete satellite cells and label resident myonuclei Aim2 will use this model and single-myonuclear (smn)RNA-seq to characterize age-dependent changes in theresident myonuclear transcriptome and identify mechanisms that enable short term hypertrophy in the absenceof satellite cells in adult mice which is lost in old age. Aim 3 will use an additional newly developed reportermouse that enables specific and stable labeling of satellite cell nuclei to determine how aging alters thesatellite cell-derived myonuclear transcriptome in response to a hypertrophic stimulus. We hypothesize that inaged muscle satellite cell-derived myonuclei have altered transcriptional output that does not promote ahypertrophic response and that impaired fusion of satellite cells or defective satellite cells may negativelyimpact resident myonuclear transcriptional activity contributing to impaired growth. Defining fusion-dependentand -independent roles of satellite cells and age-associated changes that negatively impact muscle adaptabilitywill identify potential new targets to promote skeletal muscle growth in the face of inactivity during aging and inthe face of muscle wasting diseases.

project_terms:
Ablation;Adult;Affect;Age;Aging;Cell Communication;Cell Nucleus;Cells;Chronic;Clinical;Collagen;Communication;Deterioration;Doxycycline;Elderly;Endothelial Cells;Exercise;Extracellular Matrix;Female;Fibroblasts;Fibrosis;Foundations;Gene Expression;Genes;Genetic Transcription;Grant;Growth;Human;Hypertrophy;Immunohistochemistry;Impairment;In Vitro;Label;Mechanics;Messenger RNA;MicroRNAs;Modeling;Molecular;Mononuclear;Morbidity - disease rate;Mus;Muscle;Muscle satellite cell;Muscular Atrophy;Natural regeneration;Output;Phenocopy;Plantaris muscle;Population;Population Dynamics;Process;Production;Quality of life;Reporter;Reporting;Repression;Rodent;Role;Skeletal Muscle;Stimulus;Systemic disease;Tamoxifen;Testing;Therapeutic;Therapeutic Uses;Time;Transcript;Wasting Syndrome;age related changes;aged;extracellular vesicles;in vivo;intercellular communication;interest;male;mortality;mouse model;muscle aging;muscle form;muscle hypertrophy;muscle progenitor cell;novel;old age;old mice;patient population;physical inactivity;postnatal;prevent;progenitor;response;sarcopenia;single-cell RNA sequencing;skeletal muscle growth;skeletal muscle wasting;stem cells;stemness;transcriptome;transcriptome sequencing;young adult

public_health_relevance:
NarrativeA decrease in skeletal muscle mass is of clinical importance because it is associated with increased morbidityand mortality as well as a marked deterioration in the quality of life. A broad patient population is affected bysignificant losses in muscle mass including those afflicted by various systemic diseases chronic physicalinactivity and sarcopenia. The purpose of this grant is to better understand the role of skeletal muscle stemcells (satellite cells) in the blunted growth response to exercise in the elderly thereby providing a foundation fortheir therapeutic use to prevent or restore losses in skeletal muscle mass during aging.


application_id: 11088251
project_number: 5R01CA207772-09
project_title: Roles of Hsp47 in Breast Cancer Progression
administering_ic: NCI
award_notice_date: 2025-04-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 207772
program_official: GRIL, BRUNILDE M
project_start_date: 2017-03-03
project_end_date: 2025-10-17
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and poor survivaloutcomes. One feature of obese adipose tissue is the excess extracellular matrix (ECM)deposition/remodeling in the form of fibrosis. However function and regulation of obesity-related ECMdeposition/remodeling in cancer progression largely remain to be determined. We recently identifiedHsp47 a chaperone protein facilitating collagen secretion as a hub of the ECM transcription network.Our new data showed that Hsp47 was highly expressed in adipose tissue. Importantly increased Hsp47expression in human and mouse adipose tissues was significantly associated with obesitydevelopment. We found that adipocyte-specific deletion of Hsp47 was sufficient to suppress high fatdiet (HFD)-induced obese and mammary tumor growth which is accompanied by reduced collagendeposition/alignment and macrophage infiltration in adipose tissue. The overall objective of thisproposal is to define the mechanism by which adipocyte Hsp47 promotes obese-related fibrosis andbreast cancer progression and to explore the value of Hsp47 as a potential target to suppress obesity-associated cancer progression. Using unbiased proteomics analysis we identified asporin as a newtarget of Hsp47 in adipocytes. Based on these data the central hypothesis of this proposal is thatHsp47 induces obesity-related fibrosis by facilitating asporin secretion in adipocytes and subsequentlyenhances adipocyte plasticity and breast cancer progression. Following aims are proposed to test ourhypothesis: Aim 1. Elucidate the molecular mechanism by which adipocyte Hsp47 induces obesity- andcancer-associated ECM remodeling; Aim 2. Determine how Hsp47 regulates obesity-associated andcancer-induced adipocyte plasticity; Aim 3. Define the potential of targeting Hsp47 to suppress obesity-associate fibrosis inflammation and breast cancer progression/metastasis.

project_terms:
3-Dimensional;Adipocytes;Adipose tissue;Binding;Bioinformatics;Biological Assay;Blood Platelets;Breast;Breast Cancer Risk Factor;Cardiovascular Diseases;Co-Immunoprecipitations;Coculture Techniques;Collagen;Data;Deposition;Diabetes Mellitus;Epithelium;Extracellular Matrix;Fibrosis;Funding;Genetic Transcription;High Fat Diet;Human;Infiltration;Inflammation;Knockout Mice;Knowledge;Lineage Tracing;Link;Macrophage;Malignant Breast Neoplasm;Malignant Neoplasms;Mammary Neoplasms;Mesenchymal;Modeling;Molecular;Molecular Chaperones;Mus;Nature;Neoplasm Metastasis;Non obese;Obesity;Obesity associated cancer;Pathologist;Pathway interactions;Patients;Play;Positioning Attribute;Proteins;Proteomics;Regulation;Repression;Research;Role;Scheme;Signal Transduction;Surface Plasmon Resonance;Testing;Tissue Sample;Tissues;Transgenic Organisms;Tumor Tissue;adipocyte differentiation;asporin;breast cancer metastasis;breast cancer progression;cancer cell;cancer cell stemness;cancer recurrence;carcinogenesis;diet-induced obesity;digital;experimental study;immune cell infiltrate;in vivo;inhibitor;insight;mammary gland development;mouse model;multidisciplinary;nanostring;novel;obesity development;recruit;second harmonic generation imaging;single-cell RNA sequencing;survival outcome;tissue culture;tumor growth;tumor progression

public_health_relevance:
Defining roles of adipocyte Hsp47 in obesity- and cancer-associated fibrosis and adipocyte plasticity will fillcritical gaps in our knowledge of the remodeling of tissue microenvironment during cancer progression. Thestudy of Hsp47 in regulating asporin in adipocytes will reveal a novel pathway in regulating collagen depositionand alignment; and further defining roles of the Hsp47/asporin axis in cancer metastasis will identify a potentialtarget to halt obesity-associated breast cancer progression.


application_id: 11088133
project_number: 5P30ES026529-08
project_title: Center for Appalachian Research in Environmental Sciences-Pilot Project Program (PPP)
administering_ic: NIEHS
award_notice_date: 2025-06-16
opportunity_number: RFA-ES-20-006
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8173
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  Pilot Project Program The University of Kentucky Center for Appalachian Research and Environmental Science (UKCARES) Pilot Project Program (PPP) aims to support highly innovative and collaborative research studies that will enhance the ability to identify and capitalize on the Centers science themes and build community-academic partnerships across the translational spectrum. This goal will be accomplished by providing pilot funds along with guidance and support for innovative timesensitive preliminary studies and community projects that improve our understanding of environmental exposures human biology and disease. Specifically the aims of the PPP are to 1) support new opportunities for innovative collaborative environmental health research; 2) enhance interactions and expand the critical mass of investigators with expertise and experience in multi - disciplinary translational environmental health research at UK and in Appalachian communities; 3) provide guidance and support to ensure the success of UK-CARES Pilot Projects; and 4) evaluate utilization efficiency quality and impact of the PPP. Strong institutional support of the PPP from UK is a hallmark of our proposal. In fact UK entities will provide matching funds representing 37% of the total funds allocated for pilot projects. The PPP will provide three general categories of pilot research funding opportunities consistent with the science themes and strategic vision of UKCARES. First Pilot grants will generate new preliminary data and support (a) established Center members to catalyze new research opportunities consistent with Center science themes; (b) nonmember scientists to expand collaborations and bring new dimensions to the Center; and (c) creative early-stage investigators to establish competitive research programs. Second Community grants will provide direct support to community organizations with a UK faculty collaborator to address a priority science theme. Third Mini grants will foster rapid time-sensitive development of or access to new and novel technologies as well as community-engaged research. The PPP will communicate collaborate coordinate and create synergy across Center cores and programs to ensure that pilot-funded investigators receive the assistance they need to develop and carry out their pilot projects. The PPP will engage investigators and community stakeholders both within UK-CARES and outside the Center as reviewers and grantees to address questions related to environmental pathways (e.g. water air) to exposures human biology and new contaminants and emerging threats. The overall progress of the PPP and how effectively it has promoted environmental health research will be monitored through the existing tracking and evaluation component of UKs Center for Clinical and Translational Science in coordination with the Administrative Core. Incorporating pilot-funded faculty into the Center will have a major impact on expanding the ability of our Center to examine important questions related to emerging environmental health issues and novel technologies and to bolster the development of the next generation of environmental health scientists.

project_terms:
Address;Air;Appalachian Region;Award;Categories;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Creativeness;Data;Development;Dimensions;Discipline;Disease;Ensure;Environmental Exposure;Environmental Health;Environmental Science;Evaluation;Exposure to;Faculty;Fostering;Funding;Funding Opportunities;Goals;Grant;Human Biology;IACUC;Institution;Institutional Review Boards;Investigation;Kentucky;Legal patent;Manuscripts;Monitor;Pathway interactions;Pilot Projects;Publishing;Research;Research Personnel;Research Support;Science;Scientist;Strategic vision;Time;Translational Research;Universities;Water;Work;clinical center;community academic partnership;community building;community engaged research;community organizations;design;electronic data;experience;high risk;improved;innovation;meetings;member;multidisciplinary;new technology;next generation;novel;population based;pre-clinical;programs;research study;success;synergism;translational pipeline


application_id: 11088130
project_number: 5P30ES026529-08
project_title: Center for Appalachian Research in Environmental Sciences-Community Engagement Core (CEC)
administering_ic: NIEHS
award_notice_date: 2025-06-16
opportunity_number: RFA-ES-20-006
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8172
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY- Community Engagement Core (CEC) The University of Kentucky Center for Appalachian Research in Environmental Sciences (UKCARES) Community Engagement Core (CEC) will grow maintain and enhance strong sustained multidirectional community-academic partnerships that 1) support meaningful community engagement; 2) build environmental health literacy; 3) reduce environmental health risks; and 4) decrease poor health outcomes in rural Appalachia. Aging water infrastructure has resulted in community concerns about water quality as well as emerging environmental health threats. The CEC will build on a strong foundation of successful community engagement and support environmental health science (EHS) by connecting investigators with community partners to promote projects consistent with the three science themes of the Center (a) Health Impacts of Waterborne Contaminants; (b) Health Impacts of Indoor & Outdoor Airborne Contaminants; and (c) Emerging Environmental Health Threats. The CEC will use an iterative multidirectional process that brings local knowledge into the Center leverages UK-CARES investigator strengths and institutional support reports back research findings with at-risk communities and encourages solution-focused communication among community and organizational stakeholders. Specifically the aims of the CEC are to: 1) foster and cultivate multidirectional community-academic partnerships engaged in UK-CARES research that is responsive to regional environmental health issues needs and concerns; 2) translate and disseminate EHS findings through science communication training to foster clinical decision making; and 3) strengthen partnerships with community and healthcare stakeholders in UKCARES environmental health research across the translational spectrum. First we will engage our Stakeholder Advisory Board members to offer culturally appropriate insight that will inform and assist Center investigators in their research. The CEC will use formal (e.g. focus groups) and informal (e.g. listening sessions) means to engage in multi-directional dialogue with community stakeholders to assess environmental health concerns. In turn the CEC will serve as a bridge to and from the community to facilitate community engagement in EHS that leverages the strengths of UK-CARES and is responsive to community concerns. Second will provide training in effective science communication with healthcare providers faculty and community stakeholders. We will build on our impactful science communication training curriculum to prepare scientists for effective communication of research findings. Lastly we will collaborate with the TRSC to create tailored multi-modal report back approaches to reach healthcare providers to promote clinical decision making related to how the environment affects health in the region.

project_terms:
Address;Affect;Aging;Air;Appalachian Region;Back;Collaborations;Communication;Communication Programs;Communities;Community Health Care;Educational Curriculum;Ensure;Environment;Environmental Health;Environmental Science;Faculty;Floods;Focus Groups;Fostering;Foundations;Grant;Health;Health Care;Health Personnel;Infrastructure;Institution;Kentucky;Knowledge;Link;Natural Disasters;Process;Public Health;Reporting;Research;Research Methodology;Research Personnel;Risk;Rural Appalachia;Science;Scientist;Training;Translating;Universities;Water;Work;clinical decision-making;community academic partnership;community engaged research;community engagement;community organizations;community partners;health assessment;health communication;health literacy;health science research;insight;investigator training;member;multimodality;poor health outcome;translational pipeline;water quality;waterborne


application_id: 11088127
project_number: 5P30ES026529-08
administering_ic: NIEHS
award_notice_date: 2025-06-16
opportunity_number: RFA-ES-20-006
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8171
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_title:
Center for Appalachian Research in Environmental Sciences - Analytical Chemistry Core for Environmental Sciences (ACCESS)

project_abstract:
PROJECT SUMMARY- Analytical Chemistry Core for Environmental Sciences (ACCESS) The University of Kentucky Center for Appalachian Research in Environmental Sciences (UKCARES) ACCESS will provide Center investigators with priority access to biological and environmental sample analysis using state-of-the-science technologies services and instrumentation for studies related to the UK-CARES three science themes: Health Impacts of Waterborne Contaminants (WATER); Health Impacts of Indoor and Outdoor Airborne Contaminants (AIR); and Emerging Environmental Health Threats (EMERGING THREATS). To optimize efficiency ACCESS uses the following two existing laboratory facilities to leverage resources available to these facilities and extend the capabilities ACCESS: the Environmental Chemistry and Toxicology Laboratory (College of Agriculture Food and Environment) and the Small Molecule Mass Spectrometry Facility (College of Medicine) to measure organic chemical environmental pollutants trace-elements their metabolites and related molecules of interest to UK-CARES investigators. Effective use of these facilities by UK-CARES investigators will require both routine analysis and new method development and validation. Specifically Aim 1 of ACCESS is to provide measurements of panels of environmental chemicals. We will provide technically robust methods for detection and quantification of a range of halogenated organics: polychlorinated biphenyls dioxins trihalomethanes and haloacetonitriles per- and polyfluorinated alkyl substances non-halogenated organics including flame-retardants environmental phenols and trace-elements to support EHS research across the translational spectrum. Aim 2 is to develop or adapt novel methods to support ongoing needs of UK-CARES investigators. Methods will be developed de novo or adapted from the literature. We will use our Thermo TSQ Altis Plus triple stage quadrupole mass spectrometer to develop and validate survey methods that can profile environmental chemicals in multiple classes using a single analytical workflow and use high-resolution MS methods employing our Thermo Exploris 240 orbitrap mass spectrometer for untargeted profiling of environmental chemicals in relevant matrices. Techniques for spatial analysis microanalysis and speciation analysis of trace-elements are refined for environmental health studies using our Agilent 7900 ICP-MS and associated peripherals. Aim 3 is to work with administrative and data management functions of the Center to enable robust fiscal oversight project management sample tracking and data reporting. We will work in tandem with the Integrated Health Sciences Facility Core and the Administrative Core to ensure that Center members receive priority access that the activities of ACCESS are aligned with the UK-CARES strategic vision of the three science themes and that services and outcomes are tracked through the online IHSFC Research Support Portal. ACCESS will provide reliable technically robust methods and services while pursuing opportunities for innovation. Services provided by the core will support UK-CARES members efforts to make innovative contributions to environmental health science.

project_terms:
Agriculture;Analytical Chemistry;Appalachian Region;Biological;Core Facility;Data Reporting;Dioxins;Environment;Environmental Health;Environmental Pollutants;Environmental Science;Flame Retardants;Food;Health;Health Sciences;Inductively Coupled Plasma Mass Spectrometry;Kentucky;Laboratories;Literature;Mass Spectrum Analysis;Measurement;Measures;Medicine;Methods;Office of Administrative Management;Organic Chemicals;Outcome;Peripheral;Phenols;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Research;Research Personnel;Research Support;Resolution;Resources;Sampling;Science;Services;Strategic vision;Survey Methodology;Techniques;Technology;Trace Elements;Translational Research;Trihalomethanes;Universities;Validation;Work;college;data management;detection method;environmental chemical;environmental chemistry;environmental toxicology;halogenation;innovation;instrumentation;interest;laboratory facility;mass spectrometer;member;method development;novel;small molecule;translational pipeline;waterborne


application_id: 11088126
project_number: 5P30ES026529-08
administering_ic: NIEHS
award_notice_date: 2025-06-16
opportunity_number: RFA-ES-20-006
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8170
contact_pi_person_id: 6457660
contact_pi: BAUER, JOHN ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_title:
Center for Appalachian Research in Environmental Sciences-Integrated Health Sciences Facility Core (IHSFC)

project_abstract:
PROJECT SUMMARY  Translational Research Support Core (TRSC) The University of Kentucky Center for Appalachian Research in Environmental Sciences (UKCARES) Translational Research Support Core (TRSC) will facilitate translational research in environmental health science (EHS) ranging from basic clinical exposure assessment and communication research to support and sustain collaborative multidisciplinary connections and academic-community partnerships. A key element of the TRSC is the formation of four EHS translational research hubs: 1-Molecular Toxicology; 2-Clinical Research and Data Sciences; 3- Community Exposure Assessment; and 4-Environmental Health Communication. Each hub will provide content expertise support and access to EHS methodologies and services and facilitate project development across the translational research spectrum. The TRSC will support campuswide integration and cross-Center communication. The TRSC will build on our record of early success refining our operational model and targeting new partnerships among Center members while providing expert consultation translational research support and team building strategies across the Centers re-aligned science themes: (a) Health Impacts of Waterborne Contaminants (WATER); (b) Health Impacts of Indoor and Outdoor Airborne Contaminants (AIR); and (c) Emerging Environmental Health Threats (EMERGING THREATS). Specifically the TRSC aims to 1) provide access to EHS research services 2) deliver EHS project support and 3) enhance translational research partnerships. First the TRSC Research Support Portal will direct the flow of investigator requests to TRSC staff and relevant hub leaders who will link Center members to the appropriate cores (e.g. Analytical Chemistry Core for Environmental Sciences and Community Engagement Core) and resources (e.g. data management and statistical analysis) for project facilitation. The Portal will facilitate coordination prioritization tracking and use of facility core services Center-wide. Second TRSC hub leaders will provide EHS best practices workshops and training sessions in collaboration with the Career Development Program. Third we will establish Rapid Response Teams comprised of the hub leaders and other Center members to promote research translation and partnerships enabling prompt responses to community identified EHS threats and new exposures. The IHSFC will fulfill the need for a centralized and accessible core that supports multidirectional EHS research activities within the Center across UK campus with community investigators and with other EHS Core Centers providing timely consultation and support for an impactful portfolio of EHS research projects while fostering a highly collaborative institutional EHS culture. The TRSC will expand expertise and services enhancing the cores central role in daily UK -CARES operations and provide the infrastructure to facilitate the progression and expansion of EHS from fundamental questions into testing clinical practice and public health impact to improve public health and clinical practice in environmental health.

project_terms:
Address;Analytical Chemistry;Appalachian Region;Back;Clinical;Clinical Data;Clinical Research;Collaborations;Communication;Communication Research;Communities;Consultations;Core Facility;Data;Data Science;Development;Disasters;Educational workshop;Elements;Environmental Exposure;Environmental Health;Environmental Science;Fostering;Health;Health Sciences;Infrastructure;Institution;Kentucky;Leadership;Link;Methodology;Modeling;Molecular Toxicology;Patients;Process;Program Development;Public Health;Public Health Practice;Reporting;Research;Research Activity;Research Methodology;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Science;Services;Statistical Data Interpretation;Testing;Training;Translational Research;Universities;Water;career development;clinical practice;cohort;community academic partnership;community building;community collaboration;community engagement;data management;health assessment;health communication;health science research;health training;high risk;improved;member;multidisciplinary;novel strategies;operation;prevent;repository;response;success;translational health science;translational impact;translational pipeline;waterborne


application_id: 11088124
project_number: 5P30ES026529-08
project_title: Center for Appalachian Research in Environmental Sciences-Administrative Core
administering_ic: NIEHS
award_notice_date: 2025-06-16
opportunity_number: RFA-ES-20-006
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8169
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN 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:
PROJECT SUMMARY  Administrative Core The University of Kentucky Center for Appalachian Research in Environmental Sciences (UKCARES) Administrative Core will coordinate oversee and evaluate all programmatic and scientific activities and lead cross-disciplinary career development initiatives while providing and receiving support from the Translational Research Support Core the Analytical Chemistry Core for Environmental Sciences the Community Engagement Core the Pilot Project Program and our community partners. The Administrative Core leadership is comprised of highly regarded senior scientists and research mentors who are well qualified to operate an Environmental Health Sciences Core Center (EHS CC) that is responsive to the concerns of people in rural Appalachia and to advance EHS across the translational spectrum. The Administrative Core will actively collaborate with all Center members community and academic promoting their research and involving them in Center decision-making and strategic programmatic activities as well as engaging with other UK Centers and EHS CCs. The organizational structure of UK-CARES will allow for optimal multidirectional Center-Community-University communications and institutional support. Three Advisory Boards will inform our research provide advice and support help us form and maintain robust community-academic partnerships and evaluate program progress: 1) a 12- member Stakeholder Advisory Board representing higher education environmental organizations healthcare and public health in rural Appalachia; 2) an Internal Advisory Board comprised of 10 high-level campus and community decision makers; and 3) a 4-member External Advisory Board of prominent national leaders in EHS. The Administrative Core has four Aims to: 1) coordinate monitor and evaluate the Centers scientific and programmatic activities; financial oversight and regulatory compliance; productivity; and effectiveness as intellectual needs change; 2) facilitate internal multidirectional communication and responsible conduct of research; 3) facilitate external multidirectional communication; and 4) cultivate careers in EHS. The Core will ensure effective internal and external communications by directing monthly Executive Committee meetings; coordinating an Annual Scientific Retreat monthly scientific work groups with Center members and a seminar series; and partnering with key community and state partners via social media our website and other scientific and professional venues. The Cores Career Development Program will recruit and support early-stage investigators (ESIs) to become independent EHS researchers and facilitate established investigators to transition to an EHS research focus through maximizing the use of Center services crossdisciplinary activities and mentorship. Career Development Program funding will support independent investigators newly recruited to UK from outside UK- CARES or Center member ESIs with partial salary support. In the first cycle the Administrative Core has grown the Center as a recognizable entity in EHS and public health in rural Appalachia.

project_terms:
Analytical Chemistry;Appalachian Region;Clinical;Collaborations;Communication;Communities;Decision Making;Discipline;Educational workshop;Effectiveness;Ensure;Environmental Health;Environmental Science;Funding;Health Care;Institution;Kentucky;Lead;Leadership;Mentors;Mentorship;Monitor;Persons;Pilot Projects;Population;Productivity;Professional Organizations;Program Development;Public Health;Public Relations;Qualifying;Research;Research Personnel;Research Support;Rural Appalachia;Scientist;Senior Scientist;Series;Services;Superfund;Translational Research;Universities;Wages;career;career development;community academic partnership;community center;community engagement;community partners;higher education;meetings;member;organizational structure;programs;recruit;responsible research conduct;social media;translational pipeline;web site;working group


application_id: 11088123
project_number: 5P30ES026529-08
project_title: Center for Appalachian Research in Environmental Sciences
administering_ic: NIEHS
award_notice_date: 2025-06-16
opportunity_number: RFA-ES-20-006
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
program_official: THOMPSON, CLAUDIA L
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS(P)]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentucky Center for Appalachian Research in Environmental Sciences (UKCARES) will build on our early successes capitalize on lessons learned and enhance our mission through a dual focus on better understanding exposure pathways and emerging environmental health threats and optimizing research translation. Our Mission is to focus on exposure pathways to better match with community concerns and to emphasize research translation. Our Values reflect strong multidirectional community-academic partnerships with a renewed commitment to meaningful processes and procedures that effectively address environmental health issues. Responsible conduct of research is at the foundation of our Center appreciating the essential value of rigorous and reproducible multidisciplinary team science. Our goals are to (a) advance multidisciplinary environmental health science (EHS); (b) analyze organic contaminants and trace elements; (c) cultivate early-stage stage and established investigators; (d) learn with and from the community helping to inform and translate our research; and (e) build science communication skills with investigators and community partners to boost research translation. We will advance EHS across the translational spectrum around three highly integrated science themes informed by residents of rural Appalachia: 1) Health Impacts of Waterborne Contaminants (WATER); 2) Health Impacts of Indoor and Outdoor Airborne Contaminants (AIR); and 3) Emerging Environmental Health Threats (EMERGING THREATS). The central hypothesis is that exposure to established contaminants via environmental exposure pathways (e.g. water air) and emerging environmental health threats combined with lifestyle and societal risk factors contributes to the disproportionately high incidence of chronic diseases in rural Appalachia. UK-CARES draws on a strong base of EHS and community-engaged research to meet the needs of communities in rural Appalachia. We will support and mentor investigators so they can reach the translational milestones in research: (1) asking fundamental questions; (2) applying and synthesizing; (3) implementing and adjusting; (4) moving ideas to practice; and (5) creating impact. In short UKCARES will leverage its resources to enhance EHS at UK while also reducing the impact of chronic diseases in rural Appalachia. A Translational Research Support Core Analytical Chemistry Core for Environmental Sciences and Community Engagement Core are integral to this effort as these cores will provide dedicated support in analytical chemistry trace-elements analysis biospecimen management and bioinformatics and bridge Center and community priorities. The Pilot Project Program supports developing research and new scientific directions advancing the careers of scientists interested in tackling challenging environmental health questions. UK-CARES will positively impact rural Appalachia through collaborative EHS designed to generate and disseminate new knowledge and translate research to inform clinical decision making.

project_terms:
Address;Air;Analytical Chemistry;Appalachian Region;Area;Asthma;Atherosclerosis;Bioinformatics;Career Mobility;Chemicals;Childhood;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Complex;Computational Biology;Dedications;Diabetes Mellitus;Discipline;Disease;Economically Deprived Population;Educational workshop;Effectiveness;Environmental Exposure;Environmental Health;Environmental Risk Factor;Environmental Science;Exposure to;Fostering;Foundations;Funding;Genetic Predisposition to Disease;Goals;Health;Health Care;Heart Diseases;Human;Incidence;Individual;Infrastructure;Kentucky;Knowledge;Learning;Life Style;Malignant neoplasm of lung;Medical;Medical center;Mentors;Mentorship;Mission;Monitor;National Institute of Environmental Health Sciences;Obesity;Outcome;Particulate;Pilot Projects;Poly-fluoroalkyl substances;Population;Positioning Attribute;Procedures;Process;Productivity;Professional Organizations;Public Relations;Radon;Reproducibility;Research;Research Personnel;Research Support;Resources;Risk;Risk Factors;Rural Appalachia;Science;Scientist;Series;Superfund;Trace Elements;Training;Translating;Translational Research;Translations;Universities;Water;base;career;career development;clinical decision-making;community academic partnership;community engaged research;community engagement;community partners;design;early life exposure;exposure pathway;health science research;innovation;interest;life span;member;metabolomics;multidisciplinary;neonate;organic contaminant;programs;responsible research conduct;rural area;rural dwellers;skills;social media;socioeconomic disadvantage;success;translational pipeline;waterborne;web site

public_health_relevance:
The University of Kentucky Center for Appalachian Research in Environmental Sciences (UKCARES) will enhance programmatic and scientific capacity to facilitate innovative discovery and new understandings of environmental exposure pathways of concern to our community (e.g.water air emerging threats). Further the Center will foster career development of environmentalhealth scientists interested in tackling challenging environmental health questions facing ruralAppalachia. UK-CARES will achieve these goals by providing advanced infrastructure andexpertise cross-disciplinary training and mentorship and multidirectional community-academicpartnerships to reduce chronic disease health risks in rural Appalachia.


application_id: 11087895
project_number: 3R01DC021325-02S1
project_title: Impact of a DFNA20 Gamma Actin Mutation on Mechanotransduction-Dependent Stereocilia Remodeling
administering_ic: NIDCD
award_notice_date: 2024-07-09
opportunity_number: PA-23-189
application_type: 3
activity_code: R01
ic: DC
serial_number: 021325
suffix: S1
program_official: FREEMAN, NANCY
project_start_date: 2023-06-07
project_end_date: 2025-05-31
study_section: ZDC1(41)
contact_pi_person_id: 12084410
contact_pi: VELEZ ORTEGA, ALEJANDRA CATALINA
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT Inner ear hair cells have actin-filled projections known as stereocilia on the apical surface. Thesestereocilia are microvilli-like structures that are arranged in highly organized rows of increasing heightsknown as hair bundles. The stereocilia possess mechano-electrical transduction (MET) channels attheir tips where sound-induced vibration and head motion are converted into electrical signals.Previously Velez-Ortega et al. (Elife 2017) demonstrated that the actin cytoskeleton in stereociliaexhibits MET-dependent remodeling as the stability of the stereocilia was crucially affected by alterationsto the constant entry of calcium through MET channels (which are partially open at rest). The actincytoskeleton within stereocilia is comprised of two actin isoforms beta and gamma which are producedby two separate genes. Prior studies have elucidated that although hair cells can develop hair bundlesin the absence of either actin isoform these bundles quickly degenerate resulting in hearing loss (Perrinet al. PLoS Genet 2010). Thus it is apparent that both actin isoforms are required for proper stereociliastability and maintenance. Here we hypothesize that a specific mutation in the gamma actin gene leadsto progressive hearing loss (in both human and mouse models) through the exaggeration of MET-dependent remodeling of the aforementioned actin cytoskeleton. To investigate this hypothesis Aim 1will analyze MET-dependent changes to the morphology of stereocilia through scanning electronmicroscopy after exposing gamma actin mutant mice and littermate controls to MET channel blockers oran increase in intracellular calcium buffering. Given that beta and gamma actin exhibit different rates ofpolymerization and depolymerization in the presence of calcium (Bergeron et al. J Biol Chem 2010)Aim 2 will evaluate how MET-dependent alterations affect the ratio of the beta and gamma actin isoformsin both the stereocilia and cuticular plate of auditory hair cells in mutant mice and littermate controls usingimmunohistochemistry and high-resolution confocal microscopy. Overall results from this supplementmay elucidate the molecular mechanism that triggers stereocilia degeneration in sensorineuralprogressive hearing loss when a mutation in the gamma actin gene is present.

project_terms:
Actins;Affect;Antibodies;Apical;Auditory;Brain;Buffers;Calcium;Cellular Morphology;Confocal Microscopy;Cytoskeleton;Data;Development;Exhibits;F-Actin;Filament;Genes;Genets;Hair;Hair Cells;Head;Head Movements;Height;Heterozygote;Immunohistochemistry;Impairment;Inner Hair Cells;Kinetics;Labyrinth;Lead;Link;Maintenance;Microfilaments;Molecular;Morphology;Motion;Mus;Mutant Strains Mice;Mutation;Natural regeneration;Noise;Organelles;Pharmaceutical Preparations;Phenocopy;Phenotype;Play;Polymers;Predisposition;Protein Isoforms;Proteins;Resolution;Rest;Role;Scanning Electron Microscopy;Sensory;Shapes;Signal Transduction;Stereocilium;Structure;Surface;Testing;Thinness;beta Actin;cell motility;cellular microvillus;channel blockers;crosslink;depolymerization;gamma Actin;hearing impairment;human model;mechanotransduction;mouse model;mutant;polymerization;premature;progressive hearing loss;repaired;sound;vibration

public_health_relevance:
PROJECT NARRATIVE Filaments made of beta and gamma actin are proteins that provide the shape and stability ofstructures known as stereocilia within the inner ear. Stereocilia detect vibrations and convert them intoelectrical signals that the brain eventually comprehends as sound or head movement. This projectcenters around how a specific gamma actin mutation alters the structure and stability of the stereocilia tounderstand its associated hearing loss.


application_id: 11087664
project_number: 5R21AI185681-02
project_title: Saturating transposon mutagenesis for Chlamydia
administering_ic: NIAID
award_notice_date: 2025-04-14
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 185681
program_official: VINCENT, LEAH REBECCA
project_start_date: 2024-05-10
project_end_date: 2027-03-31
study_section: Prokaryotic Cell and Molecular Biology Study Section[PCMB]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
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:
ABSTRACT Chlamydia species are important pathogens that represent a paradigm for understandingsuccessful obligate intracellular parasitism. C. trachomatis is a prevalent human pathogenexerting a tremendous negative impact on reproductive fitness particularly in females. Acomplete understanding is lacking regarding how these bacteria create and maintain anintracellular niche avoid/subvert host defense mechanisms and cause disease. Thisinformation is particularly important in the absence of an efficacious preventative vaccine. Theability to genetically manipulate an organism is essential for the definitive investigation ofrelevant biology. Forward genetic approaches provide one of the most powerful strategiesavailable to accomplish untargeted elucidation of genes contributing to a particular phenotype.For obligate intracellular bacteria the full power of forward genetics has been generallyconfounded by factors such as low transformation efficiency complex developmental cyclesand a requirement for cultivation under selective conditions. The utility of transposon-mediatedrandom mutagenesis in supporting forward genetics is well established in a multitude ofgenetically tractable systems. Although initial progress has been made in Chlamydia significantbarriers remain that preclude leveraging the full benefit of transposon mutagenesis. We haveengineered a platform that promises to overcome these barriers. We will build on initial progressto i) create a robust reproducible and user-friendly transposon system and ii) provide genome-scale evidence for which genes are essential for chlamydial survival in HeLa cells. Both goalswill result in reagents and techniques capable of supporting down-stream studies interrogatingchlamydial biology.

project_terms:
Address;Alleles;Attenuated;Bacteria;Biology;Cell Culture Techniques;Cells;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Collection;Complex;Coupled;Couples;DNA Transposable Elements;Data;Detection;Development;Disease;Dissection;Engineering;Essential Genes;Female;Fluorescence;Future;Gene Silencing;Generations;Genes;Genetic;Genetic Techniques;Genome;Goals;Growth;Health;Hela Cells;Host Defense Mechanism;Human;Individual;Infection;Investigation;Libraries;Maintenance;Mediating;Molecular;Mutagenesis;Organism;Pathogenesis;Phase;Phenotype;Plasmids;Preventive vaccine;Production;Productivity;Reagent;Recombinants;Replication Origin;Replicon;Reporting;Reproducibility;Resources;System;Techniques;Testing;Toxic effect;Transposase;Virulence;Work;comparative;design;fitness;forward genetics;gene product;genetic analysis;genetic approach;genetic manipulation;genome sequencing;genome-wide;human pathogen;innovation;intracellular parasitism;loss of function mutation;mutant;novel;obligate intracellular parasite;pathogen;reproductive fitness;reverse genetics;screening;tool;user-friendly;whole genome

public_health_relevance:
Chlamydia trachomatis is a common human pathogen yet a full understanding of howChlamydia causes disease is lacking. This proposal contains work designed to create atransposon system to enable mutagenesis capable of supporting forward genetic analyses. Thiscapability has proven essential in other bacterial systems to fully comprehend pathogenesis.


application_id: 11087611
project_number: 5R01AA031043-02
project_title: An ethanol-sensitive Bmp-PCP dependent pathway regulating endoderm cell behaviors
administering_ic: NIAAA
award_notice_date: 2025-05-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AA
serial_number: 031043
program_official: DUNTY, JR, WILLIAM
project_start_date: 2024-05-15
project_end_date: 2029-03-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 10890031
contact_pi: LOVELY, CHARLES BENJAMIN
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryFetal Alcohol Spectrum Disorders (FASD) describe a continuum of ethanol-induced developmental defects withjaw defects being common. Genetic risk factors lie at the heart of FASD and are major drivers of FASD etiologyproviding insight into the cellular and molecular processes potentially disrupted in FASD. However we know littleof these processes. From our studies in zebrafish we have established an in vivo model for FASD wheremutations in the Bone Morphogenetic Protein (Bmp) and Wnt/Planar Cell Polarity (PCP) signaling pathwayssensitize embryos to ethanol-induced jaw defects by disrupting the cell behaviors driving tissue morphogenesisduring jaw development. Jaw formation involves complex signaling interactions between the neural crest andthe anterior pharyngeal endoderm (anterior PE). Critical to these interactions anterior PE morphogenesisrequires Bmp- and PCP-dependent actin-based cell movements polarity and adhesion. Bmp signaling isrequired for endodermal E-cadherin localization and PCP receptor expression while PCP regulates cell polarityand adhesion. Mutations in the Bmp and PCP pathways sensitize embryos to ethanol-induced malformations ofthe anterior PE and jaw. Work in mouse liver indicates that ethanol reduces Bmp signaling at the level of thereceptors. Altogether this suggests that an ethanol-sensitive Bmp-PCP signaling cascade contributes toanterior PE morphogenesis. Yet how ethanol modulates the Bmp and PCP pathways and their crosstalkdisrupting anterior PE morphogenesis remain unknown. We hypothesize that ethanol attenuates Bmp signalingthere by decreasing PCP component expression levels and disrupting actin dynamics cell polarity adhesionand migration during anterior PE morphogenesis. Using a unique combination of zebrafish-based approacheswe will test our hypothesis in the following aims. In Specific Aim 1 we will a) analyze an ethanol dose responseon total and phosphorylated Bmp receptor and Smad proteins b) use scRNA-seq to examine endoderm-specificgene expression changes of Bmp and downstream of Bmp PCP genes and c) test the epistasis of the Bmp-PCP signaling axis on jaw development. In Specific Aim 2 we will use 4D-confocal analysis in control andethanol-treated Bmp and PCP mutants to quantify ethanol-induced disruptions to a) cell velocity coherence andpersistence of migration and resulting changes to size and shape of the anterior PE and b) actin polarization andcellular protrusion dynamics. In Specific Aim 3 we will a) quantify shape and polarity and b) analyze E-cadheringene expression as well as E-cadherin and PCP protein localization in anterior PE cells of control and ethanol-treated Bmp PCP and Bmp-PCP compound mutants. We will also c) quantify ethanol-induced jaw defects inBmp- and PCP-E-cadherin compound mutants. Overall this work will greatly advance our understanding of thecell behaviors and molecular mechanisms driving ethanol-induced structural malformations and provide concretesignatures to pursue predictive diagnostic and novel therapeutic approaches to FASD.

project_terms:
Actins;Adhesions;Adult;Anterior;Attenuated;Automobile Driving;Bone Morphogenetic Proteins;Cell Adhesion;Cell Polarity;Cell Shape;Cells;Child Health;Complex;Craniofacial Abnormalities;Defect;Development;Diagnostic;Dose;E-Cadherin;Embryo;Endoderm;Endoderm Cell;Ethanol;Etiology;Event;Face;Fetal Alcohol Spectrum Disorder;Fluorescent in Situ Hybridization;Gene Expression;Gene Expression Profile;Gene Proteins;Genes;Genetic;Genetic Epistasis;Human;Jaw;Link;Liver;Molecular;Morphogenesis;Mus;Mutation;Neural Crest;Pathway interactions;Pharyngeal structure;Phosphorylation;Process;Proteins;Shapes;Signal Pathway;Signal Transduction;Signaling Protein;Smad Proteins;Societies;Structural Congenital Anomalies;Structural defect;Testing;Therapeutic;Tissues;Work;Zebrafish;alcohol exposure;bone morphogenetic protein receptors;cell behavior;cell motility;confocal imaging;driving behavior;experimental study;genetic risk factor;in vivo;in vivo Model;insight;malformation;migration;mutant;novel therapeutic intervention;planar cell polarity;receptor;receptor expression;response;single-cell RNA sequencing

public_health_relevance:
Project NarrativeFetal Alcohol Spectrum Disorders (FASD) describe a continuum of ethanol-induced structural defects causingsevere impact both on child health and society in general. Craniofacial malformations are common in FASDyet we know little of the ethanol-sensitive cellular and molecular mechanisms driving facial formation. Ourproposal will conceptually and mechanistically advance our understanding of the ethanol-sensitive cellbehaviors and molecular mechanisms contributing to structural malformations and will provide a conceptualframework to pursue predictive diagnostic and therapeutic approaches to FASD.


application_id: 11087484
project_number: 5P50AA024337-10
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD
subproject_number: 5282
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The primary function of OMICS Core is to provide members of the University of Louisville Alcohol ResearchCenter (ULARC) with the expertise resources and facilities needed for metabolomic proteomic andbioinformatic analyses of biological samples collected to study nutrition gut flora/intestinal dysfunction andalcohol-induced organ injury and therapeutic interventions. OMICS Core personnel will assist with the designof sample collection protocols will drive the development and the execution of novel and robustchromatographic methods for sample separation and mass spectrometric methods for the analysis of proteinspeptides and metabolites with a goal of providing a greater understanding of the evolution of molecularmechanisms that correlate with or participate in liver dysfunction. OMICS Core will ensure uniformity andstandardization in sample preparation method development instrument performance data collection datareporting and data sharing. OMICS Core endeavors to contribute to the overall success and utility of theULARC and to enhance the infrastructure and the technical and academic capabilities of the institution as awhole. OMICS Core will also promote the education and training of the ULARC members with regards to thestate-of-the-art omics technologies. Furthermore OMICS Core will become an independent and self-supporting entity using a set comprehensive approaches that have been already been implemented and havedemonstrated their success in our current ULARC. The OMICS Core is projected to provide necessary andessential support to all ULARC projects.

project_terms:
Acetylation;Affinity;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Analytical Chemistry;Bacteria;Bilophila wadsworthia;Bioinformatics;Biological;Biometry;Broccoli - dietary;Butyrates;Cecum;Chromatography;Complex Mixtures;Consumption;Data Collection;Data Reporting;Development;Enhancers;Ensure;Epigenetic Process;Ethanol;FOXP3 gene;Family;Feces;Functional disorder;Ginger;Glutathione;Goals;Heavy Drinking;Human;Human Resources;IL17 gene;Immunoglobulin Class Switching;Individual;Inflammatory;Infrastructure;Institution;Intestines;Lactobacillus casei rhamnosus;Lipids;Liver;Liver Dysfunction;Mass Spectrum Analysis;Measures;Mediating;Mediator;Methods;Molecular Evolution;Monitor;Mus;Nutrition;Pathogenicity;Pathway interactions;Patients;Peptides;Performance;Phosphorylation;Plasma;Play;Post-Translational Protein Processing;Preparation;Probiotics;Production;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Reaction;Research;Research Personnel;Resolution;Resources;Role;STAT3 gene;Sampling;Science;Stable Isotope Labeling;Standardization;T-Lymphocyte;Techniques;Technology;Testing;Therapeutic Intervention;Time;Tissue Sample;Training and Education;Translational Research;Tryptophan;Universities;Variant;Volatile Fatty Acids;alcohol research;data sharing;design;efficacy evaluation;exosome;follow-up;gut dysbiosis;gut microbiota;inflammatory milieu;instrument;interleukin-22;lipid mediator;lipidomics;liver injury;member;metabolomics;method development;microbial;multidisciplinary;nanoparticle;novel;novel therapeutic intervention;organ injury;pathogenic bacteria;prevent;protective effect;sample collection;sex;stool sample;success;teratogenesis;transcription factor;treatment group


application_id: 11087482
project_number: 5P50AA024337-10
project_title: Probiotic-derived nano-particles in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD
subproject_number: 5281
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
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:
Probiotics have been used to prevent/treat alcoholic liver disease (ALD). Live probiotics need to colonize the gutto exert their function. Unfortunately underlying disease states provide an unfavorable environment for probioticbacterial gut colonization which diminishes probiotics function. In the last few years we showed that LGGculture supernatant (LGGs without live bacteria) was effective in the prevention of ALD in experimental modelsof acute and chronic alcohol exposure in mice. However how LGG supernatant exerts its therapeutic effects isnot fully understood. Exosomes are nanoparticles (NPs) derived from cell endocytosis which act as transmittersbetween cells. Recent studies show that bacteria both Gram-negative and Gram-positive produce NPs. TheNPs derived from bad bacteria have been demonstrated to be pathogenic. However good bacteria-probiotics-derived NPs have not been studied. Our preliminary study showed that administration of LGG-derivedexosome-like NPs (LDNPs) effectively reversed ALD in the binge-on-chronic alcohol exposure mouse modelsuggesting that probiotic LGGs may exert its function through LDNPs in ALD. Administration of LDNPs markedlyincreased intestinal AhR activity IL-22 and regenerating islet-derived 3 (Reg3)  and  expression which playa key role in maintaining gut microbiota homeostasis and preventing bacterial intestinal transcytosis. In additionLDNPs administration significantly increased intestinal epithelial cell (IEC) tight junctions and decreasedcirculating LPS concentration associated with upregulation of intestinal Nrf2 signaling which is known forprotecting intestinal barrier junctions against oxidative stress-induced damage by alcohol. Metabolomic analysisrevealed that LDNPs contain high levels of microbial metabolites of tryptophan which are AhR ligands indicatingLDNPs may activate intestinal AhR signaling. Furthermore we demonstrated that ginger exosome-likenanoparticles (GDNPs) are preferentially taken up by LGG suggesting that GDNP may serve as a prebiotic toenhance the effects of LGG. These preliminary studies provide the groundwork for our central hypothesis thatby activating intestinal AhR-Nrf2 signaling LDNPs increase intestinal expression of Il-22 Reg3 and tightjunctions and modulate gut microbiota homeostasis and enhance intestinal barrier function leading to thesuppression of ALD. We will test our hypothesis in following four specific aims: (1) Determine the role of bacteria-derived NPs in ALD; (2) Define the mechanisms of the beneficial effects of LDNPs in ALD; (3) Determine whetherGDNPs treatment enhances LDNP production and AhR agonist enrichment that lead to improved effects ofLDNPs against ALD; and (4) Evaluate the intestinal AhR-Nrf2 signaling in alcoholic hepatitis patients treated withLGG. Completion of this study is expected to significantly impact the development of LGG-based probiotictherapeutics in the treatment of alcohol-associated liver diseases.

project_terms:
Acute;Agonist;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Bilophila wadsworthia;Biological Markers;Cells;Chronic;Clinical;Development;Digestive System Disorders;Disease;Endocytosis;Environment;Epithelial Cells;Epithelium;Evaluation;Experimental Models;Functional disorder;Future;Ginger;Growth;Homeostasis;Intestines;Mediating;Mus;National Institute on Alcohol Abuse and Alcoholism;Natural regeneration;Nutrition;Outcome;Oxidative Stress Induction;Pathogenicity;Pathway interactions;Patients;Play;Prevention;Probiotics;Production;Receptor Signaling;Regenerating islet derived protein 3-Gamma;Role;Signal Transduction;Testing;Therapeutic Effect;Tight Junctions;Tryptophan;Upregulation;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;clinical application;disorder prevention;dysbiosis;exosome;gut colonization;gut inflammation;gut microbes;gut microbiota;improved;interleukin-22;intestinal barrier;intestinal epithelium;islet;metabolomics;microbial;mouse model;nanoparticle;organ injury;pathogenic bacteria;prebiotics;prevent;probiotic therapy;programs;protective effect;stool sample;transcytosis


application_id: 11087478
project_number: 5P50AA024337-10
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD
subproject_number: 5280
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
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: 2025-05-01
project_title:
Enhancer-mediated transcriptional dysregulation in neural crest cells and ethanol-induced teratogenesis

project_abstract:
Fetal Alcohol Spectrum Disorders (FASD) is among the most devastating consequences of the widespread useand abuse of alcohol. Growing evidence suggests that impairment of the differentiation migration and survivalof neural crest cells (NCCs) is a major component of the pathogenesis of FASD. However there is a fundamentalgap in understanding how ethanol leads to the dysregulation of gene expression and subsequently impairs NCCdevelopment in embryos. Enhancers are DNA elements that govern spatial and temporal regulation of geneexpression through its function as integrated transcriptional factor binding platforms. We have recentlydemonstrated that ethanol exposure resulted in a locus-specific reduction in enhancer activity across the genomein zebrafish embryos as indicated by lower levels of H3K27ac mark in ethanol-exposed embryos relative tocontrol. We termed these sites as the Ethanol-induced Variant Enhancer Loci (E-VELs). In addition ethanoltreatment reduced the activity of the selected enhancers in human NCCs (hNCCs). The objective of this proposalis to elucidate the mechanisms by which enhancers mediate ethanol-induced impairment of NCC developmentand teratogenesis and to establish epigenetic modulation of enhancer activity as a feasible approach forpreventing FASD. The central hypothesis of this project is that ethanol epigenetically modulates the activity ofthe selected enhancers and subsequently disrupts the expression of their cognate genes in NCCs leading tothe impairment of the differentiation migration and survival of NCCs and teratogenesis and that epigeneticmodulation of the activity of the selected enhancers and the expression of their cognate genes by sulforaphane(SFN) or broccoli-derived exosome-like nanoparticles (BELNs) can prevent ethanol-induced teratogenesis. Totest our hypothesis the following specific aims will be addressed: Aim 1: To identify the E-VELs that areassociated with aberrant expression of their cognate genes involved in NCC and craniofacial development inhNCCs and zebrafish embryos. Aim 2: To functionally validate the role of the selected E-VELs in ethanol-induceddysregulation of gene expression impairment of the differentiation migration and survival of NCCs and ethanol-induced teratogenesis. Aim 3: To elucidate the mechanisms by which ethanol epigenetically modulates theactivity of the selected E-VELs that modulate the expression of genes involved in the differentiation migrationand survival of NCCs. Aim 4: To test the hypothesis that epigenetic modulation of the activity of the selected E-VELs by SFN or BELNs represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis.The proposed work is innovative because this is the first study attempting to prevent FASD through the newlyrecognized role of enhancers in regulating gene expression and NCC development. It also represents the firstattempt to prevent FASD using edible plant-derived exosome-like nanoparticles. This study is also significantbecause the results from this study are expected to provide insights into the mechanisms by which enhancersmediate ethanol-induced teratogenesis and to yield enhancer-based strategies for the prevention of FASD.

project_terms:
Address;Alcohol abuse;Alcohols;Behavioral;Binding;Broccoli - dietary;Cell Physiology;Congenital Abnormality;DNA;Defect;Development;Disease;Edible Plants;Elements;Embryo;Embryonic Development;Enhancers;Epigenetic Process;Ethanol;Event;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Human;Impairment;Learning Disabilities;Mediating;Neural Crest Cell;Neuronal Dysfunction;Nutrition;Pathogenesis;Prevalence;Prevention;Prevention approach;Prevention strategy;Psyche structure;Regulation;Role;Site;Sulforaphane;Testing;Therapeutic;Variant;Work;Zebrafish;alcohol consumption during pregnancy;alcohol exposure;cell type;craniofacial development;embryonic alcohol exposure;exosome;innovation;insight;maternal alcohol use;migration;nanoparticle;novel therapeutic intervention;organ injury;prevent;programs;spatiotemporal;teratogenesis;transcription factor


application_id: 11087474
project_number: 5P50AA024337-10
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD
subproject_number: 5279
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
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: 2025-05-01
project_title:
Pathogenic Role of Loss of Butyrate Producing Bacteria in Immune Dysregulation and Development of Alcoholic Liver Disease (ALD)

project_abstract:
This project (Project 2) will define specific pathogenic features of alcohol-induced gut dysbiosis and investigateits causative role (and underlying mechanisms) in systemic/hepatic immune dysregulation in alcoholic liverdisease (ALD). Based on our compelling preliminary data from pre-clinical and clinical studies we hypothesizethat loss of butyrate producing bacteria is a significant pathogenic feature of gut dysbiosis in patients with ALDwhich plays a major role in developing a pro-inflammatory T cell-IL-17 milieu leading to pathogenic changes inthe gut-liver axis in ALD. This project will utilize a highly innovative animal model of human fecal microbiotatransplant (FMT) from alcoholic hepatitis patients into conventional mice that recapitulates key features ofhuman ALD to identify mechanisms and develop targeted therapeutic interventions. Specifically the projectwill test the efficacy of evidence-based nutritional therapeutic strategies that target gut dysbiosis namely (i)Tributyrin (Tb) a dietary butyrate pro-drug and known HDAC inhibitor and (ii) Faecalibacterium prausnitzi - amajor human butyrate producing probiotic. The proposal leverages existing resources of the NIH fundedAlcHepNet clinical consortium (U01AA026980) which include a large available cohort of ALD patients andcontrol subjects participant recruitment validated demographic and clinical data biospecimen and biomarkercollection and clinical expertise in liver diseases. This proposed study will provide new insights into themechanisms underlying ALD and identify new targets for ALD treatment thereby contributing to the ULARCprogram and theme of nutrition and alcohol-induced organ injury. The specific aims of the proposal are: AIM 1) Determine the qualitative and quantitative loss of butyrateproducing microbial communities as a defining pathogenic feature of alcohol-induced gut dysbiosis leading toimmune dysregulation represented by the activation of the proinflammatory T cell-IL-17 axis in patients withALD AIM 2) Determine the causative role of alcohol-induced loss of butyrate producing bacteria on theactivation of the proinflammatory T cell/IL-17 axis and neutrophil recruitment in hepatic inflammation/injury andAIM 3) Evaluate the efficacy of nutritional interventions targeting the alcohol-induced loss of enteric butyrateproducing bacteria and butyrate production in attenuating the pathogenic changes in the gut-liver axis in ALD.

project_terms:
Address;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Bacteria;Biological Markers;Butyrates;Clinical;Clinical Data;Clinical Research;Collection;Data;Development;Dietary Intervention;Dietary Supplementation;Disease Marker;Enteral;Exhibits;Fatty Liver;Funding;Hepatic;Histone Deacetylase Inhibitor;Human;IL17 gene;Immune;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Knowledge;Liver;Liver diseases;Mediating;Mus;Neutrophil Infiltration;Nutrition;Nutritional;Pathogenesis;Pathogenicity;Patient Recruitments;Patients;Play;Preclinical data;Preventive;Probiotics;Prodrugs;Production;Resources;Role;Severity of illness;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Transplantation;United States National Institutes of Health;cohort;dietary;dysbiosis;efficacy evaluation;efficacy testing;evidence base;fecal transplantation;gut bacteria;gut dysbiosis;gut-liver axis;human model;human study;immune activation;inflammatory milieu;innovation;insight;liver development;liver inflammation;liver injury;microbial;microbial community;mouse model;organ injury;preclinical study;prevent;problem drinker;programs;systemic inflammatory response;targeted treatment;therapeutic target;treatment strategy;tributyrin


application_id: 11087471
project_number: 5P50AA024337-10
project_title: Role of n3 PUFAs and inflammation-resolving lipid mediator RvD1 in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD
subproject_number: 5278
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
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:
Alcoholic liver disease (ALD) is a major and increasing health problem in the US (especially in Kentucky) andworldwide. In spite of the magnitude of this problem there is no FDA-approved therapy for any stage of ALD. Inaddition the mechanisms and regulators of the disease progression and severity are not well understood. Dietaryfats play an important interactive role with alcohol consumption in ALD pathogenesis however the role of n3PUFAs in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD in part vian3-PUFA-derived pro-resolving mediators which facilitate inflammation resolution improvement in the gut-liveraxis and subsequent attenuation of liver injury. We propose that resolvin D1 (RvD1) is a potent therapeuticagent in severe ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and topromote repair of hepatocellular damage in part via enhancement of pro-restorative macrophages. Wepostulate that compromised inflammation resolution due to impaired RvD1 production/signaling is one of thecritical nutritional contributing factors to the progressive ALD and severity of alcoholic hepatitis (AH) in humans.The Specific Aims of the proposal are: Aim 1. To test whether n3 PUFAs exert beneficial effects on EtOH-associated liver injury/inflammation by enhancing the effectiveness of inflammation resolution and byrepair of hepatocellular damage through increase in n3-PUFA-derived specialized pro-resolving mediatorspromoting(SPMs) and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling andreprogramming pro-inflammatory macrophages into a pro-restorative phenotype. Wild Type (WT) Fpr2-/-Neat1-/- and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in thisAim. We will also examine the therapeutic effectiveness of RvD1 utilizing a novel nanoparticle technology oftargeted RvD1 delivery examine the role n3-PUFAsto the liver with plant-derived edible exosomes. Aim 2. Toand RvD1 in maintaining gut barrier integrity and in the resolution of intestinal inflammation in experimental ALD.We will: i) test in vivo in animal models and in vitro in intestinal organoid culture whether n3 PUFA or RvD1improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whetherdisruption of the RvD1-FPR2 axis exacerbates while blocking Neat1 signaling attenuates intestinal inflammationand alterations in the gut barrier integrity; iii) test a novel therapeutic strategy of administering an engineeredbacteria strain to convert n6 to n3 PUFAs in the intestine and thus to attenuate gut barrier dysfunction in mice.In Aim 3 we seek to translate and extend our findings in animal models to human ALD. Utilizing de-identifiedhuman samples we will: i) determine effects of n3-PUFA dietary supplementation on plasma SPM levels markersof liver injury systemic inflammation and intestinal permeability in heavy drinking individuals; ii) examine plasmaSPM levels and SPM synthesis in whole blood and peripheral blood monocytes (PBMCs) obtained from AHpatients; and iii) test whether RvD1 improves phagocytosis/efferocytosis of PBMCs obtained from AH patients.

project_terms:
Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Chronic;Cytokine Signaling;Data;Development;Diet;Dietary Fats;Dietary Fatty Acid;Dietary Supplementation;Disease Progression;Down-Regulation;Effectiveness;Engineering;Ethanol;Experimental Animal Model;FAT gene;FDA approved;FPR2 gene;Functional disorder;Health;Heavy Drinking;Hepatic;Hepatocellular Damage;Homeostasis;Host Defense;Human;Immune;Immune response;Immunomodulators;Impairment;In Vitro;Individual;Inflammation;Inflammatory;Intestinal permeability;Intestines;Kentucky;Linoleic Acids;Liver;Macrophage;Mediating;Mediator;Microbe;Modeling;Molecular;Mus;Nuclear;Nutrition;Nutritional;Organoids;Pathogenesis;Patients;Phagocytosis;Phenotype;Plants;Plasma;Play;Production;Prognosis;Research;Resolution;Rodent;Role;Sampling;Severities;Severity of illness;Signal Transduction;Survivors;Technology;Testing;Therapeutic Agents;Tissues;Transcript;Transgenic Organisms;Translating;Whole Blood;attenuation;cytokine;exosome;gut inflammation;gut-liver axis;improved;in vivo evaluation;intestinal barrier;lipid mediator;liver inflammation;liver injury;monocyte;nanoparticle;novel;novel therapeutic intervention;organ injury;peripheral blood;preclinical study;receptor;repaired;systemic inflammatory response;therapeutic effectiveness;tissue repair


application_id: 11087469
project_number: 5P50AA024337-10
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD
subproject_number: 5277
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) is a multidisciplinary group ofinvestigators focusing on nutrition gut flora/intestinal dysfunction and alcohol-induced organ injuryand therapeutic interventions. The ULARC investigators come from 13 departments across 6 schools. TheAdministrative Core provides oversight and coordination to the ULARC. The Administrative Core supportsadministrative oversight a tissue handling technician and a biostatistician/bioinformatician. The PI will beassisted by an Associate Director the Steering and Program Advisory committees and a part-time assistant.The Specific Aims of the Administrative Core are to:1) continue the formal governance structure to provide coordination implementation direction and prioritizationof activities including budget issues and resolving any conflicts as they arise ensuring the quality of allfunctions and evaluation progress;2) provide a mechanism to replace any key individuals who may leave;3) provide biostatistical and bioinformatics support for investigators;4) provide chain of custody for tissue/sample handling and storage; and5) disseminate pertinent information to the scientific and lay community.All projects and cores will be using the Administrative Core.

project_terms:
Advisory Committees;Alcohol abuse;Alcohols;Area;Arts;Basic Science;Bioinformatics;Biometry;Budgets;Cancer Center;Clinical;Clinical Investigator;Clinical Treatment;Collaborations;Communities;Consultations;Country;Development;Discipline of Nursing;Education;Engineering;Ensure;Epigenetic Process;Evaluation;Functional disorder;Grant;Health Sciences;Individual;International;Intestines;Lead;Leadership;Medicine;Nutrition;Organ;Preventive;Proteomics;Public Health;Reporting;Research;Research Personnel;Research Proposals;Resources;Role;Sampling;Schools;Science;Social Work;Specialized Center;Standardization;Structure;System;Therapeutic Intervention;Time;Tissues;Universities;alcohol research;gut microbiota;high school;innovation;interest;intestinal barrier;medical schools;member;metabolomics;multidisciplinary;novel;organ injury;programs


application_id: 11087468
project_number: 5P50AA024337-10
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
program_official: MURRAY, GARY
project_start_date: 2016-05-15
project_end_date: 2027-04-30
study_section: ZAA1-DD(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) was created to serve as aregional/national resource to perform interdisciplinary collaborative research on the role of nutrition asa cofactor in alcohol induced organ injury and as a possible therapeutic intervention to prevent/treatthis organ injury. The nutrition and alcohol-induced organ injury theme of the center is unique amongalcohol centers. The approach is highly translational. Our investigators include faculty from 13 departmentsand 6 colleges. The Specific Aims of the ULARC are to:1) perform/facilitate interdisciplinary research on nutrition and alcohol-induced organ injury;2) serve as a regional/national resource for the study of nutrition and alcohol-induced organ injury;3) develop potential therapeutic targets/interventions for alcohol induced organ injury based on themechanistic research of the ULARC; and4) disseminate knowledge/interventions to the scientific and lay communities.We will explore interactions of nutrition and alcohol abuse in the development of alcohol-induced organdysfunction and we will evaluate diverse potential nutritional preventive/therapeutic interventions. Project 1(Kirpich/McClain) evaluates the role of dietary fat in ALD pathogenesis; Project 2 (Barve) evaluates alcohol-induced epigenetic alterations in the gut:liver axis. Project 3 (Chen) will elucidate the mechanisms by whichenhancers mediate ethanol-induced developmental impairment of neural crest cells and teratogenesis andunique exosome treatment for prevention of FASD. Project 4 (Feng) studies the beneficial effects of theprobiotic Lactobacillus rhamnosis GG (LGG)on the gut:liver axis in ALD. Together these projects form a cohesive and interactive approach to investigate the effects of nutrition andnutritional interventions on alcohol-induced organ injury.

project_terms:
Alcohol abuse;Alcoholic Liver Diseases;Alcohols;Brain;Broccoli - dietary;Butyrates;Cause of Death;Chronic;Collaborations;Communities;Country;Development;Dietary Fats;Dietary Intervention;Education;Enhancers;Epigenetic Process;Ethanol;FDA approved;Faculty;Feces;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Fostering;Functional disorder;Funding;Future;Goals;Grant;Health;Health Care Costs;Impairment;Individual;Industry;Injury;Institution;Interdisciplinary Study;Intervention;Intestines;Knowledge;Lactobacillus;Lipids;Mediating;Mediator;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Nutrition;Nutritional;Organ;Pathogenesis;Prevention;Prevention approach;Preventive;Probiotics;Productivity;Proteomics;Research;Research Personnel;Resources;Role;School Dentistry;Signal Transduction;Sulforaphane;Therapeutic Intervention;United States;United States National Institutes of Health;Universities;Volatile Fatty Acids;alcohol abuse therapy;alcohol exposure;alcohol intervention;alcohol research;alcohol use disorder;base;cofactor;college;exosome;gut bacteria;gut inflammation;gut-liver axis;high school;improved;intestinal barrier;liver inflammation;metabolome;metabolomics;mortality;mouse model;multidisciplinary;nanoparticle;new therapeutic target;novel;organ injury;prevent;teratogenesis;therapeutic effectiveness;therapeutic target

public_health_relevance:
Alcohol abuse exacts a major toll on health and health costs in the United States and is the 3rd leadingpreventable cause of death in the U.S. There is no FDA-approved therapy for most forms of alcohol-induced organ injury such as alcoholic liver disease. Our focus on nutrition and alcohol-induced organinjury should lead to new therapeutic targets new nutritional preventions/treatments and improvedmortality and morbidity.


application_id: 11086064
project_number: 5F31AA030934-03
administering_ic: NIAAA
award_notice_date: 2025-07-25
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: AA
serial_number: 030934
program_official: LIN, LI
project_start_date: 2023-07-01
project_end_date: 2026-06-30
study_section: ZAA1-GG(32)L
contact_pi_person_id: 78328369
contact_pi: WALTER, MARY NANCY
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_title:
The role of MKP-1/MAPK in hepatocytes and macrophages in alcohol-associated liver disease pathogenesis

project_abstract:
Project SummaryAlcohol-associated liver disease (ALD) is responsible for nearly half of all deaths from liver disease. Despitethe severity of this disease there remain no FDA-approved treatments for any stage of the diseasehighlighting the critical need to elucidate the underlying mechanisms of ALD progression to develop newtherapies. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is the archetypal member of the dual-specificity phosphatases with a pivotal role in organ inflammation and injury including in the liver. Earlier workshowed that decreased MKP-1 levels are associated with the activation of c-Jun N-terminal kinase (JNK)which triggers an apoptotic cascade leading to alcohol induced liver injury. However the exact mechanisms ofhow MKP-1 downregulation leads to hepatocyte injury and/or inflammation in ALD are known. Moreover therole of MKP-1 in macrophages and MAPK-driven inflammation in ALD has never been examined. Ourpreliminary studies show that MKP-1 deletion in hepatocytes augments alcohol-induced liver injury is a NIAAAchronic plus binge model of ALD. Data also suggest that MKP-1 deletion in hepatocytes sensitizes them toTNF induced toxicity. As an aspiring scientist whose goal is to pursue a career in alcohol-related multi-organpathology investigating new players in ALD pathogenesis would not only help fill this medical need but alsoserve as an excellent platform from which to learn how to become a successful scientist. With the help andsupervision of my mentors Dr. Gobejishvili (an expert in basic research on ALD) and Dr. McClain (an expert onclinical aspects of the disease) as well as several knowledgeable collaborators I will investigate the role ofalcohol-associated downregulation of MKP-1 in the pathogenesis of ALD. The first aim of this study is to furthercharacterize the role of MKP-1 deletion in hepatocytes using hepatocyte specific MKP-1 knpockout mice in twodifferent mouse models of ALD. I will isolate hepatocytes and immune cells from these models examine theeffect of MKP-1 deletion on pro-inflammatory chemokine production and immune cell phenotype and describechanges in hepatocyte and immune cell health and function. The second aim will determine the role of MKP-1specifically in macrophages using RAW 264.7 macrophage cell line primary Kupffer cells and macrophage-specific knockout mice. To complete this research I will follow a detailed training plan laid out for me by my co-mentors and pursue my career goals. These include among others continuing my didactic training in areasrelevant to my research gaining experience in new laboratory techniques developing effective written and oralcommunication skills and building a professional network of scientists. Collectively the training and researchproposed here will not only fill a significant need for the development of ALD treatments but will also foster mydevelopment from a young scientist to a successful independent investigator in the field of alcohol-inducedorgan disease.

project_terms:
Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Apoptotic;Area;Basic Science;Cell Count;Cell Line;Cell model;Cells;Cessation of life;Chronic;Cirrhosis;Clinical;Data;Development;Disease;Disease Progression;Down-Regulation;Endotoxins;Ethanol;FDA approved;Fostering;Galactosamine;Goals;Health;Hepatic;Hepatitis;Hepatocyte;Immune;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intestinal permeability;Investigation;Knockout Mice;Kupffer Cells;Laboratories;Learning;Liver;Liver diseases;LoxP-flanked allele;MAPK1 gene;MAPK8 gene;Macrophage;Mediating;Medical;Mentors;Mitogen-Activated Protein Kinases;Modeling;Morbidity - disease rate;Mus;Myeloid Cells;N-terminal;National Institute on Alcohol Abuse and Alcoholism;Organ;Pathogenesis;Pathology;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Play;Portal vein structure;Predisposition;Primary carcinoma of the liver cells;Production;Research;Research Personnel;Role;Scientist;Severity of illness;Signal Transduction;Specificity;Steatohepatitis;Supervision;TNF gene;Techniques;Testing;Tissues;Toxic effect;Training;Work;Writing;alcohol effect;alcohol exposure;career;career networking;chemokine;cytokine;experience;hepatocyte injury;in vivo;intrahepatic;liver inflammation;liver injury;member;microbial products;mortality;mouse model;new therapeutic target;novel;novel therapeutics;oral communication;p38 Mitogen Activated Protein Kinase;phosphatase-1 kinase;response;simple steatosis;skills;western diet

public_health_relevance:
Project NarrativeAlcohol-associated liver disease (ALD) is responsible for a significant proportion of liver disease deaths yetthere are no FDA-approved therapies for the treatment of any stage of its progression and the underlyingmechanisms of disease progression are still under investigation. Mitogen-activated protein kinase phosphatase1 (MKP-1) a key regulator of tissue inflammation and injury is downregulated in the livers of alcohol-fed miceand ethanol-exposed hepatocytes. Complete assessment of the role of decreased MKP-1 expression in bothhepatocytes and immune cells in the progression of ALD might lead to novel therapeutic targets for thetreatment of ALD.


application_id: 11085761
project_number: 3P20GM135004-05S1
project_title: Administrative Core
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
subproject_number: 7949
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
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
project_abstract:
The goal of the CCII COBRE is to establish a thematic multidisciplinary research center of excellence at the University of Louisville that focuses on improving our understanding of cancer immunology and developing novel immunotherapeutic approaches. Importantly with the recent clinical successes of immune checkpoint inhibitors and oncolytic viruses there is great interest and momentum in understanding the interaction between the host immune system and neoplastic cells. Our projects proposing basic immunology research coupled with translational and human specimen studies are expected to ultimately lead to entirely new immunotherapeutic approaches as well as strategies for overcoming resistance to existing agents. The Administrative Core (AC) will coordinate the professional activities of the more than 40 individuals who will constitute the new Center for Cancer Immunology and Immunotherapy (CCII). The AC will provide administrative fiscal and scientific oversight and planning for junior investigators mentors projects the research core a pilot program and advisory committees. In addition to governance functions the AC will provide key research and mentoring support. This will include the awarding of project grants assignment of mentors provision of a grant writing mentorship program biostatistics and bioinformatics support compliance and regulatory oversight mentoring of pilot projects and encouragement of diversity and inclusion. Internal advisors and an External Advisory Committee (EAC) that consists of five leading scientists in the CCII thematic area will guide the AC. The EAC will provide scientific guidance and constructive feedback regarding center/project progress and be involved in CCII strategic planning and in the selection of replacement and pilot projects. The two PIs of the overall CCII program will direct the AC with key support from two co-Is who have extensive experience administering multi- component grant programs and from two additional co-Is who are well qualified to oversee the essential biostatistics and bioinformatics support. Their efforts will supplement a mentoring program that is anchored by eight senior investigators who are experienced mentors and have been highly productive and well funded in the thematic area. The three specific aims of this Administrative Core that encompass all of these functions are to: (1) Establish procedures for CCII administration planning and decision-making; (2) Provide a mentorship program to accelerate the careers of the CCII junior investigators; and (3) Create a CCII pilot grant program that will stimulate new projects and collaborations. Innovative features of the AC are built on lessons learned from establishing other multidisciplinary thematic centers and include a shared governance approach that aims to ensure engagement of all participants and a holistic mentoring strategy that provides comprehensive guidance for our CCII junior investigators. By the end of the 5-year funding program we expect that 4-6 CCII junior investigators will have been awarded R01 grants and that many of these graduates will remain key members of this new COBRE focused on cancer immunology and immunotherapy.

project_terms:
Acceleration;Adoptive Cell Transfers;Advisory Committees;Applications Grants;Area;Award;Bacterial Infections;Basic Science;Bioinformatics;Biometry;Cancer Biology;Cancer Center;Cancer Patient;Centers of Research Excellence;Clinical;Clinical Research;Collaborations;Coupled;Credentialing;Decision Making;Education;Ensure;Evaluation;Feasibility Studies;Feedback;Feeling hopeless;Funding;Goals;Grant;Human;Human Resources;Immune checkpoint inhibitor;Immune mediated destruction;Immune response;Immune system;Immunology;Immunotherapeutic agent;Individual;Interdisciplinary Study;International;Leadership;Malignant Neoplasms;Mentors;Mentorship;Molecular;Molecular Profiling;Nobel Prize;Oncolytic viruses;Participant;Patients;Physicians;Pilot Projects;Prediction of Response to Therapy;Procedures;Productivity;Qualifying;Research;Research Personnel;Resistance;Role;Scientist;Specimen;Strategic Planning;Study Section;Testing;Training Programs;Translational Research;Treatment outcome;Tumor Escape;United States National Institutes of Health;Universities;Writing;cancer immunotherapeutics;cancer immunotherapy;career;diversity and inclusion;experience;improved;innovation;interest;meetings;member;multidisciplinary;neoplastic cell;next generation;novel;operation;programs;response;senior faculty;success;translational study;tumor;tumor immunology


application_id: 11085171
project_number: 5R01DK113625-08
project_title: Contributions of Hepatic and Intestinal Pathways to Cholesterol Excretion
administering_ic: NIDDK
award_notice_date: 2025-04-15
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 113625
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2017-09-13
project_end_date: 2027-03-31
study_section: Nutrition and Metabolism in Health and Disease Study Section[NMHD]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY 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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
7. Project SummaryReverse cholesterol transport (RCT) is the process by which excess cholesterol is eliminated from thebody. Disruptions in RCT contribute to a variety of metabolic diseases including atherosclerosis insulinresistance and non-alcoholic fatty liver disease (NAFLD). The ABCG5 ABCG8 (G5G8) steroltransporter facilitates sterol secretion in the hepatobiliary and transintestinal pathways. Our new dataindicate that G5G8 is indispensable in opposing dietary cholesterol accumulation however the relativecontribution of hepatic vs. intestinal G5G8 in opposition cholesterol accumulation is unknown. Despiteits discovery over 20 years ago little known about the post-translational regulation of the transporter.We've recently developed key biological reagents and approaches that will allow for the investigationof endogenous G5G8 post-transcriptional regulation. Preliminary experiments revealed severalsurprises. 1) G5G8 is localized to an intracellular compartment in vivo and in polarized hepatocytes. 2)G5G8 translocates to the apical domain in response to stimulation with the intestinal hormone FGF15/19in vivo. 3) G5G8 is degraded in lysosomes following heterodimer formation. We hypothesize thathepatic G5G8 is post-translationally regulated to promote biliary cholesterol secretion butdependent on intestinal G5G8 to prevent dietary cholesterol accumulation mechanisms that aredisrupted by clinical variants that contribute to MetS phenotypes. Aim I will determine molecularmechanisms of G5G8 post-translational regulation in vitro and in vivo. We will interrogate thebiosynthetic itinerary and steady state distribution of the G5G8 heterodimer in WIF-B polarizedhepatocytes. The sub-apically located structures in which it resides in unstimulated cells will beidentified. Apical translocation in response to stimuli of biliary cholesterol secretion (bile acidsFGF15/19 etc.) will be determined and results confirmed in vivo. These studies will be replicated withhuman G5G8 expressed in liver-specific G5G8-deficient mice. Aim II will determine the impact ofhepatic and intestinal G5G8 on cholesterol excretion. Control and mice and lacking G5G8 in liverintestine or both organs will be challenged with cholesterol-containing diets. Plasma and fecal sterolsand measures of RCT will be analyzed. Hepatic gene expression and metabolic phenotypes includinginsulin sensitivity and measures of NAFLD will be assessed. Aim III will investigate the impact of humanvariants of ABCG5 and ABCG8 on basal and bile acid-stimulated biliary cholesterol secretion usingnovel adenoassociated viral vectors and tissue-specific G5G8-deficieny mice. We will also investigatethe effect of these variants on the development of obesity-related phenotypes in response tocholesterol-containing diets.

project_terms:
Ablation;Alanine Transaminase;Apical;Atherosclerosis;Bile Acids;Bile fluid;Biliary;Biological;Cells;Cholesterol;Chronic;Clinical;Complex;Coupling;Data;Development;Diet;Dietary Cholesterol;Disease;Enzymes;Equilibrium;Excretory function;Fatty Liver;Fatty acid glycerol esters;Fibroblast Growth Factor;Gall Bladder Diseases;Gallbladder;Gene Expression;Glycosylated hemoglobin A;Hepatic;Hepatobiliary;Hepatocyte;High Density Lipoproteins;Homeostasis;Human;In Vitro;Inflammation;Insulin Resistance;Intestinal Hormones;Intestines;Investigation;Lipids;Liver;Lysosomes;Measures;Metabolic Diseases;Metabolic syndrome;Modeling;Molecular;Mus;Organ;Orthologous Gene;Pathway interactions;Phenotype;Phospholipids;Physiological;Plasma;Post-Transcriptional Regulation;Post-Translational Regulation;Predisposition;Process;Proteins;Publishing;Reagent;Recombinant Proteins;Regulation;Risk;Role;Signaling Molecule;Small Intestines;Sterols;Stimulus;Structure;Tissues;Triglycerides;Variant;absorption;adeno-associated viral vector;adenoviral mediated;cardiovascular risk factor;cholesterol absorption;cholesterol transporters;diet-induced obesity;dietary;experimental study;ezetimibe;glycemic control;improved;in vivo;inhibitor;insulin sensitivity;metabolic phenotype;non-alcoholic fatty liver disease;novel;obesity development;overexpression;prevent;response;reverse cholesterol transport;tool;transcriptome sequencing

public_health_relevance:
Project NarrativeDisruptions in biliary cholesterol secretion increases risk for chronic metabolic diseases includinginsulin resistance nonalcoholic fatty liver disease and atherosclerosis. This project investigates themechanisms by which the G5G8 cholesterol transporter is regulated and opposes metabolic disease.


application_id: 11084834
project_number: 5P20GM121327-08
project_title: Regulation of one-carbon metabolism and purine synthesis by YRDC in hepatocellular carcinoma
administering_ic: NIGMS
award_notice_date: 2023-12-20
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: GARTRELL, KYUNGSOOK
project_start_date: 2024-01-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3(C2)
subproject_number: 7998
contact_pi_person_id: 16489042
contact_pi: ALI, EUNUS
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
project_abstract:
Hepatocellular carcinoma (HCC) accounts for >80% of patients with liver cancer and is one of the leading causes of cancer-associated mortalities both worldwide and in the United States. Recent evidence highlights the involvement of YRDC (YrdC-threonylcarbamoyltransferase domain-containing protein) a tRNA modifying enzyme in tumor growth via N6-threonylcarbamoylation (t6A) of tRNA in various cancer types including HCC. Additionally YRDC has been shown to be overexpressed in different types of cancer and associated with chemotherapeutic drug resistance as well as poor prognosis in HCC patients. However the precise molecular mechanisms underlying YRDC overexpression in cancers and its involvement in the regulation of tumor metabolism remain unknown. The objective of our study is to define the mechanisms by which YRDC drives cellular growth and investigate the potential of targeting YRDC in cancers with a specific focus on HCC. Our preliminary data employing metabolomic and isotope tracing approaches have shown that YRDC can act as a novel regulator of one-carbon metabolism and purine synthesis in several cancer cells including HCC cells. We demonstrate that YRDC depletion reduces flux through one-carbon metabolism thereby restricting the availability of substrates for the synthesis of de novo purine nucleotides. In light of these findings this proposal focuses on studying YRDC and its impact on tumor metabolism using HCC as a model. We hypothesize that YRDC promotes tumor growth by activating one-carbon metabolism thereby stimulating de novo purine synthesis. Consequently targeting YRDC represents a potentially effective strategy against HCC. We will define the mechanisms underlying YRDC upregulation in HCC we will use isogenic cell settings deleted for the tumor suppressor P53 and expressing mutant KRAS and examine the role of the MAPK/ERK downstream of KRAS in the regulation of YRDC mRNA and protein levels (Aim1). Then we will determine the molecular mechanisms by which YRDC stimulates one-carbon metabolism and purine synthesis in HCC cells (Aim2). Finally we will examine the therapeutic potential of suppressing YRDC to improve HCC and/or sensitize HCC to chemotherapy (Aim3). Overall the proposal is significant because it will identify novel regulators of onecarbon metabolism and the de novo purine synthesis pathways clarify the tumor pro-growth function of YRDC and identify a novel drug target in HCC treatment. The project is highly innovative because to date YRDC has not been linked to the regulation of one-carbon metabolic pathway. The proposal will provide a stepping-stone to aid the applicant to establish an independent research career and the work performed under this award will be used to generate NIH R01 grant proposals.

project_terms:
Applications Grants;Award;Cancer Center;Cancer Etiology;Carbon;Cells;Data;Drug resistance;Enzymes;Growth;Isotopes;KRAS2 gene;Kentucky;Light;Link;MAP Kinase Gene;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Messenger RNA;Metabolic Pathway;Metabolism;Modeling;Molecular;Pathway interactions;Patients;Primary carcinoma of the liver cells;Prognosis;Protein Overexpression;Proteins;Purine Nucleotides;Purines;Regulation;Research;Role;TP53 gene;Therapeutic;Transfer RNA;Tumor Promotion;United States;United States National Institutes of Health;Universities;Up-Regulation;Work;cancer cell;cancer type;career;cell growth;chemotherapy;improved;innovation;metabolomics;mortality;mutant;new therapeutic target;novel;overexpression;tumor;tumor growth;tumor metabolism


application_id: 11084399
project_number: 5R01HL163712-03
project_title: Inflammatory Injury Caused by Silica Exposure
administering_ic: NHLBI
award_notice_date: 2025-05-31
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163712
program_official: VUGA, LOUIS J
project_start_date: 2023-05-01
project_end_date: 2027-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMore than 2 million people in the US are exposed to respirable crystalline silica at work. Inhalationof dust containing respirable crystalline silica causes silicosis which is characterized by chronicinflammation and pulmonary fibrosis. Silica exposure also increases the risk of developingautoimmune diseases and cancer. Silicosis patients have a median survival of 6 years afterdiagnosis. The pathophysiology of silicosis has not been fully understood. Currently there is noeffective treatment against this devastating disease. It has been reported that the dysregulationof alveolar macrophages plays an important role in the pathogenesis of silicosis. The depositionof fine silica particles in alveoli and the ingestion of silica particles by alveolar macrophages triggerpro-inflammatory and pro-fibrotic responses. However molecular mechanisms of thedysregulated alveolar macrophage responses remain elusive. Using a mouse model of silicosisour preliminary studies indicate that myeloid HDAC6 plays an essential role in the pathogenesisof silicosis. In the proposed studies we will test the hypothesis that myeloid HDAC6 is a keymediator of pro-inflammatory and pro-fibrotic responses in silicosis. We will investigate thespecific role of myeloid HDAC6 in silicosis and evaluate the therapeutic potential of HDAC6 as atarget to treat silicosis.

project_terms:
AKT1 gene;Acetylation;Alveolar Macrophages;Alveolus;Autoimmune Diseases;Binding;Cell Physiology;Chronic;Clinical Trials;Cytoplasm;Deacetylase;Deacetylation;Deposition;Diagnosis;Disease;Dust;Exposure to;Fibrosis;Functional disorder;Future;Genetic Transcription;HDAC6 gene;Inflammation;Inflammatory;Inflammatory Response;Ingestion;Inhalation;Injury;Leukocytes;Malignant Neoplasms;Mediating;Mediator;Microtubule Stabilization;Microtubules;Molecular;Myelogenous;Nuclear Translocation;Pathogenesis;Patients;Persons;Phenotype;Phosphorylation;Play;Production;Profibrotic signal;Pulmonary Fibrosis;Pulmonary Inflammation;Regulation;Reporting;Risk;Role;Signal Transduction;Silicon Dioxide;Silicosis;TNF gene;Testing;Therapeutic;Transforming Growth Factor beta;Tubulin;Work;effective therapy;mouse model;novel;particle;protective effect;protein function;response;therapeutic target;transcriptomics; Tubulin

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of HDAC6 in the pathogenesisof silicosis. The studies will validate the therapeutic potential of HDAC6 inhibition against silicosis. Theproposed studies will provide important information for future clinical trials.


application_id: 11083604
project_number: 5R01DK135885-03
administering_ic: NIDDK
award_notice_date: 2025-04-21
opportunity_number: PAS-20-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 135885
program_official: RAJAPAKSE, NISHADI
project_start_date: 2023-04-01
project_end_date: 2025-07-31
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
budget_start_date: 2025-04-01
project_title:
Older Adults Using Social Support to Improve Self-Care (OASIS): Adaption Implementation and Feasibility of Peer Support for Older Adults with T2DM in Appalachia

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;Health Care;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;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: 11083120
project_number: 5R01DE029498-05
project_title: Role of Notch-1/PLA2-IIA in oral dysbiosis inflammation and periodontal disease
administering_ic: NIDCR
award_notice_date: 2025-05-21
opportunity_number: PAR-19-172
application_type: 5
activity_code: R01
ic: DE
serial_number: 029498
program_official: CHANDER, PREETHI
project_start_date: 2021-08-01
project_end_date: 2027-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
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:
The mechanisms by which mucosal responses to the microbiota in the presence of specific pathogenic bacterialspecies (e.g. P. gingivalis-Pg) could abrogate the host-microbe symbiotic relationship leading to dysbiosis andinflammatory disease remain not fully understood. Our pioneering R21 studies demonstrated that Pg-inducedphospholipase A2 group IIA (PLA2-IIA) in a mechanism that involves activation of Notch-1 receptor (N1R) byPg gingipains modulates the antimicrobial properties of oral epithelial cells (OECs). This is consistent with invivo and clinical evidence supporting the potent (ng/mL) antimicrobial effects of PLA2-IIA. Noteworthy oralbacterial species exhibited differential antimicrobial susceptibility to PLA2-IIA. Moreover gingival PLA2-IIAexpression and N1R activation were elevated during initiation and progression of periodontal disease which wasconcurrent with oral dysbiosis in non-human primates. In agreement with these observations new preliminarystudies using mice models demonstrated increased gingival PLA2-IIA expression and N1R activation early afterPg infection. Remarkably the oral microbiome of transgenic mice overexpressing PLA2-IIA (PLA2-IIA-Tg)exhibited significant differences in the abundance of bacterial species (decreased Firmicutes and increasedProteobacteria) compared to their wild type co-caged littermates. Oral dysbiosis in PLA2-IIA-Tg mice wasassociated with changes in the gingival expression of genes involved in intracellular sensing (NOD2) classicalantimicrobial factors (S100a8/S100a9 hBD1) and M1/M2 macrophage chemokines. N1R is a critical modulatorof mucosal immunity; therefore the ability of Pg to activate N1R in OECs is an exciting and innovativeobservation. Preliminary data suggested that other OEC functions/responses (bacterial sensing apoptosis andautophagy) could involve Pg-induced N1R activation. Based on this evidence we hypothesize that activation ofNotch-1/PLA2-IIA pathway in gingival epithelial surfaces would be an innovative and plausible mechanism bywhich pathogens such as Pg could specifically enhance oral dysbiosis inflammation and periodontal disease. Totest this hypothesis we propose three specific aims: (i) To determine the role of PLA2-IIA in Pg-inducedoral dysbiosis inflammation and periodontal disease (ii) To determine the role of epithelialNotch-1 in Pg-induced PLA2-IIA and periodontitis and (iii) To identify and validate oralepithelial innate responses modulated by Pg through Notch-1 activation. To address theseknowledge gaps we will use the Pg-induced periodontitis oral gavage model in mouse strains with or without anatural PLA2-IIA mutation PLA2-IIA-Tg mice with their WT littermates epithelial-specific N1R deficient miceas well as OEC cultures to validate the role of this pathway in Pg-induced oral dysbiosis and periodontal disease.These findings will enable a better understanding of the cellular and molecular mechanisms that are specificallymodulated by pathogens to alter microbial communities at mucosal surfaces as well as contribute to the evidencefor future research designed to determine the role of N1R in oral health and other diseases (e.g. oral cancer).

project_terms:
Address;Adverse effects;Agreement;Animal Model;Anti-microbial susceptibility;Antimicrobial Effect;Apoptosis;Autophagocytosis;Bacteria;Cell Physiology;Cell Proliferation;Cells;Clinical;Complex;Data;Development;Disease;Eating;Ecology;Enzymes;Epithelial Cells;Epithelium;Event;Exhibits;Firmicutes;Gene Expression;Gingiva;Health;Human;Immune;In Vitro;Inbred BALB C Mice;Infection;Inflammation;Inflammatory;Knowledge;Lesion;Macrophage;Mediating;Microbe;Modeling;Molecular;Mouse Strains;Mucosal Immunity;Mucous Membrane;Mus;Mutation;Natural Immunity;Oral;Oral health;PLA2G2A gene;Pathogenicity;Pathway interactions;Periodontal Diseases;Periodontitis;Phospholipase A2;Play;Porphyromonas gingivalis;Property;Proteobacteria;Public Health;Receptor Activation;Reporting;Research;Research Design;Resistance;Role;Surface;Testing;Time;Transgenic Mice;Variant;adaptive immunity;antimicrobial;bone loss;chemokine;chronic infection;chronic inflammatory disease;dysbiosis;gingipain;in vivo;innovation;malignant mouth neoplasm;microbial;microbial community;microbiota;mouse model;nonhuman primate;notch protein;oral cavity epithelium;oral microbiome;oral pathogen;overexpression;pathogen;prevent;receptor;recruit;response

public_health_relevance:
This research is relevant to public health because it will identify a potential new molecular mechanism throughwhich pathogens like P. gingivalis could be specifically manipulating epithelial innate responses to alter normalhost-bacteria interactions at mucosal surfaces that will evolve to dysbiosis persistent infection and inflammatorydisease. Positive findings of these studies will provide new opportunities for the development of innovativeapproaches to prevent/treat periodontal disease and its potential adverse effects in systemic health.


application_id: 11083053
project_number: 5K23AA029198-05
project_title: Lactobacillus rhamnosus: A Novel Probiotic Therapy for treating Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2025-07-09
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: AA
serial_number: 029198
program_official: WANG, JOE
project_start_date: 2021-05-10
project_end_date: 2027-04-30
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 11616840
contact_pi: VATSALYA, VATSALYA
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:
This application is a proposal for a mentored clinical research award (K23) that will enable Dr. VatsalyaVatsalya to continue to develop his skills in clinical research; specifically identifying new therapeutic targets forthe treatment of patients with alcohol use disorder (AUD) and concomitant moderate alcohol associatedhepatitis (AH). AUD represents one of the leading causes of preventable deaths in the United States andefforts are in progress to identify new interventions. Emerging animal and human research suggest thatLactobacillus rhamnosus GG (LGG) a probiotic is involved in the restoration of a normal gut microbiomeattenuating gut dysfunction and lowering endotoxemia and inflammation. Dr. Vatsalyas overall goal is tocomplete mentored research and transition to independent research. He also plans to successfully obtain atenure-track faculty position that will allow him to fully establish his own independent research program. Dr.Vatsalyas training goals are to: (1) broaden his conceptual knowledge in researching theneuropharmacological mechanisms in AUD; (2) enhance his experience with human studies in the field of AUDand alcohol associated liver disease (ALD); (3) improve his methodological skills in order to conduct effectivelarge-scale trials; and (4) improve his grant- and publication-writing skills. These training goals will be achievedthrough: (a) the resources available at the University of Louisville; (b) the high quality of mentorship providedby his mentor and the mentor committee; (c) focused training and clinical experiences; and (d) the proposedresearch project. During the award period Dr. Vatsalyas goals are to: (1) complete the K23 research anddevelop preliminary data to conduct a larger bedside-to-bench study using the results and skills obtainedduring the K23 grant; and (2) apply for an NIAAA investigator-initiated (R01) grant based on the preliminaryoutcomes. Alcohol consumption is associated with altered microbiome and gut dysfunction increased gutpermeability systemic endotoxemia (gut-derived bacterial products in the circulation) and proinflammatoryactivity. The gut dysfunction observed with heavy drinking has also been associated with the development ofliver injury and inflammation observed in ALD. The research component of Dr. Vatsalyas application willinvestigate if LGG can restore normal gut function reduce gut permeability and proinflammatory activitythereby improving the symptomology of concomitant AUD and ALD. The proposed research project extendsDr. Vatsalyas previous work on the pharmacological treatment of AUD and on the role of LGG in mediating thegut-brain axis that could be expanded to identifying new interventional-mechanistic targets in AUD.

project_terms:
Abstinence;Adverse effects;Adverse event;Albumins;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Award;Behavior Therapy;Behavioral;Bilirubin;Biochemical Markers;Biochemistry;Biological Assay;Biological Markers;Blood;Brain;Chronic;Circulation;Clinical;Clinical Research;Complex;Data;Diagnosis;Dietary fiber fermentation;Disease;Disulfiram;Dopamine;Double-Blind Method;Endotoxemia;Enrollment;Equipment and supply inventories;FDA approved;Faculty;Frequencies;Functional disorder;Goals;Grant;Health;Health Care;Heavy Drinking;Hepatitis;Human;Inflammation;Inflammatory;Inflammatory Response;Intervention;Intestinal permeability;Knowledge;Lactobacillus casei rhamnosus;Lipopolysaccharides;Liver;Liver diseases;Measures;Mediating;Medical;Mentors;Mentorship;Methodology;Naltrexone;National Institute on Alcohol Abuse and Alcoholism;Neurotransmitters;Outcome;Pathway interactions;Patient Outcomes Assessments;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Placebos;Positioning Attribute;Probiotics;Prognostic Marker;Property;Psychological reinforcement;Public Health;Publications;Quality of life;Randomized;Regulation;Relapse;Reporting;Research;Research Personnel;Research Project Grants;Resources;Rewards;Role;Serotonin;Severities;Structure;Symptoms;Testing;Therapeutic;Training;Tryptophan;United States;Universities;Volatile Fatty Acids;Withdrawal;Woman;Work;Writing;alcohol use disorder;bench to bedside;candidate marker;chronic alcohol ingestion;comorbidity;craving;design;drinking;effective therapy;efficacy testing;efficacy validation;eligible participant;experience;gamma-Aminobutyric Acid;gut microbiome;gut microbiota;gut-brain axis;improved;liver development;liver inflammation;liver injury;men;metabolomics;microbiome alteration;neurobehavioral;neuroinflammation;new therapeutic target;novel;organ injury;preventable death;probiotic therapy;programs;response;restoration;skills;success;symptomatic improvement;tenure track;therapeutic target;treatment adherence;treatment comparison;treatment trial

public_health_relevance:
PROJECT NARRATIVEHeavy and chronic alcohol drinking is a major medical and public health problem that is frequently diagnosedas alcohol use disorder (AUD). Existing FDA approved treatment options for AUD have limited efficacy andadverse effects; thus alcohol associated organ injury especially liver injury is a commonly observedcomorbidity. This project may lead to the use of Lactobacillus rhamnosus GG (LGG) as a novel effectivetherapy for AUD and concomitant moderate alcohol associated hepatitis (AH).


application_id: 11083044
project_number: 5K23DA054309-03
administering_ic: NIDA
award_notice_date: 2025-05-15
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: DA
serial_number: 054309
program_official: LAO, GUIFANG
project_start_date: 2023-06-15
project_end_date: 2028-05-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 15234572
contact_pi: MEADOWS, AMY LYNN
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-06-01
project_title:
Improving Opioid Use Disorder Treatment Retention Outcomes Using Mindfulness in Childhood Trauma Survivors

project_abstract:
ABSTRACTThis Mentored Patient-Oriented Research Career Development Award (K23) application seeks support forresearch training to augment the candidates knowledge and skills in co-occurring childhood trauma and opioiduse disorder (OUD) in order to support her progress to become an independent investigator. During the awardthe candidate will develop and implement a research program related to technology-based mindfulnessinterventions and use of biomarkers to improve engagement in medication treatment for opioid-use disorder(MOUD) in those who have experienced childhood trauma. The central hypothesis is that changes in autonomicfunction and inflammation mediate the relationship between childhood trauma and poor treatment retention inMOUD and that mobile mindfulness training (mMT) is feasible in this population with potential benefits toemotional inflammatory and autonomic function. This proposal includes training activities to ensure Dr.Meadows achieves the following career goals: 1) Training in the discovery interpretation and assessment ofpotential biomarkers to assess the link between childhood trauma and outcomes 2) Advanced training in thedesign and implementation of clinical interventions and 3) Training in the analysis and interpretation of data.The mentorship team includes experts in the following areas of research: substance use disorders (Drs. Rushand Martin) intervention development (Dr. Rush) and advisors with expertise in the use of mobile mindfulnesstraining for substance use disorder (Dr. Reynolds) inflammatory biomarker evaluation (Dr. Moylan) heart ratevariability (Dr. Minassian) trauma treatment (Dr. Sprang) and advanced statistical modeling (Dr. McLouth). Dr.Meadows will apply the skills from the training to test the three specific aims: 1) Demonstrate baseline differencesin autonomic function inflammation and treatment engagement between those with a history of childhoodtrauma and those without childhood trauma or post-traumatic stress disorder enrolled in MOU 2) Implement andevaluate mMT in childhood trauma-exposed individuals enrolled in MOUD in order to a) demonstrate feasibilityand acceptability and b) estimate effect sizes for improvements in emotional health autonomic function andinflammation and 3) Assess whether mMT improves treatment engagement and retention in MOUD. Theproposed research is innovative because it will provide insight into the relationship between potential biomarkersand treatment engagement in MOUD. It is also highly significant because it focuses on a mobile intervention thatcan be readily adapted as an adjunct to existing treatment programs to improve outcomes. The research trainingplan mentorship and institutional support will facilitate Dr. Meadowss transition to becoming an independentphysician-scientist to better serve the needs of individuals with co-occurring childhood trauma exposure andsubstance use who are at the highest risk of treatment dropout and poor outcomes.

project_terms:
Adherence;Age;Applied Skills;Area;Autonomic nervous system;Award;Biological;Biological Markers;Buprenorphine;C-reactive protein;Chronic;Clinic;Clinical;Clinical Treatment;Cues;Data;Data Analyses;Dropout;Early treatment;Educational Intervention;Effectiveness;Emotional;Enrollment;Ensure;Exposure to;Goals;Health;Individual;Inflammation;Inflammatory;Informal Social Control;Institution;Interleukin-6;Intervention;K-Series Research Career Programs;Kentucky;Knowledge;Left;Link;Mediating;Mediator;Mentored Patient-Oriented Research Career Development Award;Mentorship;Mindfulness Training;National Institute of Drug Abuse;Nervous System Physiology;Opioid;Outcome;Pain;Parasympathetic Nervous System;Participant;Patient Self-Report;Patients;Pharmaceutical Preparations;Physicians;Physiological;Population;Post-Traumatic Stress Disorders;Recording of previous events;Recovery;Recurrence;Reporting;Research;Research Personnel;Research Support;Research Training;Risk;Risk Factors;Science;Scientist;Self-control as a personality trait;Serum;Signal Transduction;Statistical Models;Stress;Substance Use Disorder;Survivors;Sympathetic Nervous System;Technology;Testing;Training;Training Activity;Trauma;Treatment Factor;Treatment outcome;Universities;Work;acceptability and feasibility;addiction;adverse childhood events;biological systems;biomarker evaluation;biomarker identification;career;career development;clinical development;clinical implementation;comorbidity;craving;depressive symptoms;design;early childhood;experience;heart rate variability;high risk;improved;improved outcome;inflammatory marker;innovation;insight;methadone treatment;mindfulness;mindfulness intervention;novel;online delivery;opioid use;opioid use disorder;pediatric trauma;perceived stress;potential biomarker;predicting response;premature;programs;protective factors;psychologic;reduced substance use;relapse risk;return to use;skills;skills training;substance use;therapy development;trauma exposure;treatment adherence;treatment program;treatment response;treatment risk

public_health_relevance:
PROJECT NARRATIVEChildhood trauma survivors have higher rates of treatment dropout during medication treatment for opioid usedisorder (MOUD) with those who leave treatment early being at extremely high risk for recurrence of opioid usedisorder (OUD). Autonomic nervous system dysregulation and inflammation may mediate risk for dropout and/orreturn to use during MOUD in childhood trauma survivors but mindfulness interventions may normalizepsychological and physiological changes attributable to early childhood stress. The proposed project willimplement a research program to elucidate the interplay of biological and psychological risk and protectivefactors associated with treatment retention in individuals in MOUD to guide the development of clinicalinterventions improve treatment adherence and reduce the risks of OUD.


