# projects

application_id: 10914080
project_number: 5P42ES023716-08
project_title: Project 1 - Cardiometabolic Injury due to VOCs
administering_ic: NIEHS
award_notice_date: 2024-06-11
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2025-06-30
study_section: ZES1-LAT-S
subproject_number: 5053
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe overall goal of this project is to assess the impact of exposure to Superfund-relevant volatileorganic compounds (VOCs) on cardiometabolic disease the underlying conditions thatcontributes to diabetes cardiovascular and liver diseases. VOCs such as trichloroethylenebenzene acrolein formaldehyde xylene and butadiene are major chemicals of concern at mostSuperfund sites and extensive previous work suggests the exposure to VOC could have a varietyof adverse health effects. Nevertheless whether exposure to VOCs at levels relevant toneighborhood adjacent to Superfund sites could adversely affect cardiometabolic health remainsunknown. Our extensive studies with animal exposed to different VOCs suggest that chronicexposure to low dose VOCs could increase blood pressure inflict vascular injury accelerateatherosclerosis and induce liver disease. Nevertheless the cardiometabolic risk of VOCs hasnot been evaluated and longitudinal data to interrogate exposure-response relationships aremissing. Hence to assess CMD risk imposed by VOCs we will test the hypothesis that exposureto VOCs exacerbates/induces vascular and hepatic dysfunction leading to a cascade of eventsthat increase CMD risk. To assess the impact of VOC exposures we will examine 1200 residentsof Jefferson County including those who live in areas adjacent to Superfund sites such as LeesLane and Distiller Farm as well as high VOC emission such as the Rubbertown neighborhood.In each participant we will assess CMD risk by measuring arterial stiffness marker of hepatocytedeath as well as suite of biomarkers indicative of risk for diabetes cardiovascular and liverdiseases. To determine population-level VOC exposure and its relationship with CMD-relatedhospital admissions and mortality we will establish a network of VOC monitors to measure VOClevels throughout Jefferson County and monitor domestic wastewater for urinary VOCmetabolites. We will monitor wastewater every other month for 3 years and assess the extent towhich population-level exposure estimates reflect ambient air VOC levels and individual-levelexposure (Aim 1) and how these estimates relate to population-level and individual-level CMDrisk. To obtain longitudinal data we will examine CMD progression and determine theassociation between individual-level and community-level VOC exposures with vascular andhepatic function and other indices of cardiometabolic risk. This will help us in assessing how VOCexposure and/or residential proximity to Superfund sites affects the risk of CMD and thisexcessive risk differs from that imposed by background VOC exposures in urban neighborhood.We expect that completion of this project will lead to the development of quantitative risk modelsand rigorous estimates of the additional CMD risk attributable to residential VOC exposures.

project_terms:
Acceleration;Acrolein;Affect;Air;Animals;Area;Atherosclerosis;Benzene;Bile Acids;Biological Markers;Blood Platelets;Blood Pressure;Blood Vessels;Butadiene;Carcinogens;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Chronic;Collaborations;Communities;County;Data;Data Analyses;Development;Diabetes Mellitus;Disease Progression;Dose;Environmental Exposure;Enzymes;Event;Exposure to;Farm;Formaldehyde;Functional disorder;Goals;Hazardous Chemicals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Hospital Mortality;Hospitalization;Human;Individual;Injury;Insulin Resistance;Kentucky;Keratin;Lipids;Liquid substance;Liver;Liver diseases;Location;Measurement;Measures;Metabolic Diseases;Metabolism;MicroRNAs;Modeling;Monitor;Neighborhoods;Participant;Plasma;Population;Process;Risk;Serology;Serum;Steatohepatitis;Superfund;Target Populations;Testing;Toluene;Trichloroethylene;Variant;Vascular Diseases;Water;Work;Xylene;arterial stiffness;attributable risk;blood glucose regulation;blood pressure elevation;carcinogenicity;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;circulating biomarkers;cohort;data management;diabetes risk;disorder risk;exposed human population;fatty liver disease;indexing;land use;landfill;liver biopsy;monocyte;mortality;particle;primary endpoint;response;stem cells;superfund site;toxicant;urinary;vascular injury;volatile organic compound;wastewater monitoring

public_health_relevance:
NARRATIVEThis project is to identify assess and evaluate the potential health effects due to exposure to hazardouschemicals prevalent in urban neighborhoods and areas around Superfund sites.


application_id: 10914079
project_number: 5P42ES023716-08
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2024-06-11
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2025-06-30
study_section: ZES1-LAT-S(SF)
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (Overall)This proposal is to continue to grow and expand the University of Louisville Superfund Center established in2017. Currently the Center supports research on the cardiometabolic effects of volatile organic chemicals(VOCs) that are of high relevance to the Superfund Program. Center investigators conduct mode-of-actionresearch to unravel critical pathways of toxicity and to identify toxicological end-points (cardiometabolic changes)of chemicals (VOCs) found at Superfund and related sites. Using high throughput mass spectrometry and aninnovative suite of mechanism-based biomarkers animal experiments and human population studies Centerinvestigations have contributed to the discovery and validation of novel biomarkers of both exposure andcardiometabolic injury that would lay the foundation for future remediation strategies. These studies employstate-of-the-art tools to develop pollutant atmospheres for animal exposure and to measure unique and sensitivebiological endpoints reflective of cardiometabolic injury. In addition work supported by the Center is leading tothe development of new methods and devices for quantifying atmospheric levels of VOCs that employ advancedtechnologies and offer precise but low-cost measurements of hazardous waste sites. As before the majorobjectives of the Center are to conduct state-of-the-art research on the cardiometabolic toxicity of VOCs and todetermine how they affect cardiometabolic disease (CMD) prevalence and severity in exposed populations.These studies will be complemented by mode-of-action mechanistic studies in animals to identify the molecularand cellular mechanisms that contribute to VOC toxicity. The findings of these studies will continue to contributeto both the discovery and the validation of sensitive and robust biomarkers that could be used to assess theextent of exposure metabolism and toxicity. Center investigators are creating new technologies for detectingVOCs at low environmental levels to enable future exposure assessment activities. Senior Center memberseducate and train junior investigators graduate students and post-doctoral Fellows in the field of environmentalscience and promote relevant community awareness and participation to enhance mutual bidirectionalunderstanding of exposure risk and the health effects of exposure. The findings and discoveries of the Centerwill be transferred to affected communities end users in public and private sectors and other stakeholders. Forfuture use and analysis all samples of human and animal tissues and all data collected during Centerinvestigations will be stored in a computer-coded biorepository. Collectively expansion and growth of the Centeractivities will enhance its contribution and lead to rigorous evaluation and better understanding of the effects ofthese hazardous chemicals on obesity diabetes and cardiovascular disease.

project_terms:
Action Research;Advanced Development;Affect;Animal Experiments;Animal Model;Animals;Area;Atmosphere;Awareness;Biological;Biological Markers;COVID-19;Cardiology;Cardiometabolic Disease;Cardiovascular Diseases;Chemical Exposure;Chemicals;Chemistry;Communities;Community Outreach;Cost Measures;Critical Pathways;Data;Data Analyses;Data Storage and Retrieval;Decision Making;Development;Devices;Diabetes Mellitus;Disease Pathway;Education and Outreach;Ensure;Environment;Environmental Exposure;Environmental Science;Epidemiology;Etiology;Evaluation;Exposure to;Foundations;Funding;Future;Generations;Goals;Growth;Hazardous Chemicals;Hazardous Substances;Hazardous Waste Sites;Health;Heart Diseases;Hepatology;Human;Incidence;Industrialization;Injury;Investigation;Knowledge;Mass Spectrum Analysis;Measures;Membrane;Metabolism;Methods;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Population;Postdoctoral Fellow;Predisposition;Prevalence;Private Sector;Procedures;Process;Public Health;Public Sector;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Risk;Sampling;Science;Severities;Site;Superfund;Technology;Tissue Sample;Toxic effect;Toxicology;Training;Training Programs;Universities;Validation;Work;animal tissue;biobank;cardiometabolism;community engagement;computer code;data archive;data management;data sharing;detection method;education research;education resources;experience;exposed human population;fatty liver disease;graduate student;human population study;human tissue;innovation;interest;member;new epidemic;new technology;novel;novel marker;obesity development;outreach program;pollutant;programs;remediation;repository;resilience;response;self assembly;superfund chemical;superfund site;tool;translational medicine;volatile organic compound

public_health_relevance:
RELEVANCEThis proposal is to support research within the University of Louisville Superfund Center on the health effect ofhazardous Superfund chemicals. Continued work in this Center will help in further evaluating the health impactof several hazardous chemicals that are present in the environment and in understanding how exposure tochemicals could contribute to the risk and development of obesity diabetes and heart disease.


application_id: 10913638
project_number: 5R01EY035138-02
project_title: Dissecting the role of aggrecan and perineuronal nets in visual plasticity
administering_ic: NEI
award_notice_date: 2024-06-21
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: EY
serial_number: 035138
program_official: FLANDERS, MARTHA C
project_start_date: 2023-09-01
project_end_date: 2025-07-31
study_section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: QIU, SHENFENG
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryCritical periods are time windows during development when experience-dependent plasticity is most robust.The developing visual system in the premier model for studying how circuits modified by experience-dependentplasticity are consolidated when a critical period closes. This model is clinically relevant because the closure ofthe visual critical period is implicated in the pathophysiology of amblyopia a childhood visual disordercharacterized by deficits in spatial vision including poor visual acuity and impaired depth perception. Effectivetherapy is more difficult after the critical period closes because the brain is less plastic. In animal models ofamblyopia monocular deprivation (MD) causes lasting deficits in ocular dominance (OD) binocular depthperception and visual acuity. The closure of the critical period is coincident with the maturation of perineuronalnets in visual cortex but how these extracellular structures may limit plasticity is not understood. In the proposed research we will determine the role and cellular source of aggrecan a principalcomponent of perineuronal nets in closing the developmental critical period for plasticity in visual circuits. Ourhypothesis is that aggrecan operates outside of perineuronal nets to close the critical period. We will use acombination of behavioral assays of vision multi-unit electrophysiology calcium imaging in vivo and sliceelectrophysiology in vitro and genetic manipulations to determine how aggrecan regulates the plasticity of visualcircuits. This project will improve understanding of the mechanisms by which experience-dependent plasticity isrestricted in the maturing brain and may reveal new avenues for developing therapeutic approaches to treatdevelopmental visual disorders such as amblyopia and central visual impairment.

project_terms:
Adult;Affect;Alleles;Amblyopia;Animal Model;Behavioral Assay;Brain;Calcium;Childhood;Chondroitin ABC Lyase;Chondroitin Sulfate Proteoglycan;Depth Perception;Development;Disease;Disinhibition;Dissection;Electrophysiology (science);Enterobacteria phage P1 Cre recombinase;Enzymes;Equilibrium;Extracellular Structure;Eye;Functional disorder;Gene Expression;Genes;Genetic;Image;Impairment;In Vitro;Injections;Injury;Interneurons;Knowledge;Lazy Eyes;Measures;Mission;Modeling;Mus;Nerve Degeneration;Neuronal Plasticity;Neurons;Ocular Dominance;Parvalbumins;Population;Property;Public Health;Rattus;Recovery;Research;Role;Signal Pathway;Slice;Source;Stains;Study models;Synapses;Testing;Therapeutic;Therapeutic Intervention;Time;United States National Institutes of Health;Vision;Vision Disorders;Visual;Visual Acuity;Visual Cortex;Visual System;Visual impairment;aggrecan;area striata;autism spectrum disorder;brain circuitry;chondroitin sulfate glycosaminoglycan;clinically relevant;conditional mutant;critical developmental period;critical period;dark rearing;effective therapy;excitatory neuron;experience;experimental study;flexibility;genetic manipulation;improved;in vivo;in vivo calcium imaging;monocular deprivation;neural circuit;neuronal excitability;neurotransmission;progenitor;response;selective expression;spatial vision;targeted treatment;visual plasticity

public_health_relevance:
Project NarrativeAbnormal vision during a childhood critical period can cause amblyopia also known as lazy eye a disordercomprising several deficits in spatial vision including poor acuity and/or impaired depth perception. The proposedresearch is relevant to public health because knowledge of the signaling pathways that limit flexibility with neuralcircuitry sufficient to restore acuity and eye dominance will improve our understanding of targets for therapeuticintervention. The proposed research is relevant to the mission of the NEI/NIH to increase understanding of thecritical period in order to determine how experience-dependent plasticity alters connectivity in the developingvisual system.


application_id: 10913431
project_number: 5R01AA028447-04
project_title: Impaired Risk Awareness during Intoxication in Recidivist DUI Offenders
administering_ic: NIAAA
award_notice_date: 2024-06-24
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: AA
serial_number: 028447
program_official: CASTLE, I-JEN
project_start_date: 2021-09-20
project_end_date: 2026-06-30
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTAlcohol-related traffic fatality and injury continue to be a major public health problem in the United States.Driving under the influence (DUI) remains one of the most frequently repeated offenses with over one-third ofoffenders being charged with a second DUI offense within five years. Prevention programs involve motivationalinterviewing and education with emphasis on increasing the offenders perceptions of the risks associated withalcohol use (i.e. increasing risk awareness). Our laboratory research has examined acute responses toalcohol in DUI offenders and showed they display heightened impulsivity and reduced perceptions ofimpairment. This suggests a lack of risk awareness in the intoxicated state when critical decisions are madeabout whether or not to drive. This 4-year R01 proposal builds on this evidence by testing the efficacy offeedback-based training to increase DUI offenders perceptions of risk associated with alcohol use. DUIoffenders will undergo experiential feedback-based training in which they are administered controlled doses ofalcohol and receive structured feedback and training to accurately appraise the behavioral impairing effects ofthe dose and accurately estimate their breath alcohol concentration. The research tests the hypothesis that thistraining will increase risk awareness among DUI offenders during intoxication as evident by reduceddisinhibiting and risk-taking effects in response to alcohol. Our evidence for atypical reactions to alcohol amongDUI offenders truly breaks new ground and identifies promising treatment targets for new interventions toreduce recidivism. Testing the efficacy of this experiential-based feedback approach represents a logical nextstep that advances the field by building upon the basic science to date.

project_terms:
Acute;Address;Alcohol consumption;Alcoholic Intoxication;Alcohols;Automobile Driving;Awareness;Basic Science;Behavior;Behavioral;Behavioral Mechanisms;Blood alcohol level measurement;Characteristics;Charge;Coupled;Decision Making;Dedications;Disinhibition;Dose;Economics;Education;Expectancy;Feedback;Impairment;Impulsivity;Individual;Injury;Intervention;Intoxication;Investigation;Laboratories;Laboratory Research;Laboratory Study;Mindfulness Training;Outcome;Pattern;Perception;Pharmaceutical Preparations;Prevention;Prevention program;Public Health;Publishing;Reaction;Reporting;Research;Resources;Risk;Risk Taking;Role;Self-control as a personality trait;Structure;Testing;Time;Training;United States;alcohol effect;alcohol response;behavioral impairment;binge drinking;breath alcohol measurement;drinking;driving behavior;driving under influence;efficacy testing;hazardous drinking;improved;innovation;motivational enhancement therapy;novel therapeutic intervention;offender;prevent;programs;recidivism;reduced alcohol use;response;risk perception;sobriety;success;trait impulsivity;treatment program

public_health_relevance:
Driving under the influence (DUI) of alcohol remains one of the most frequently repeated offenses with overone-third of offenders being charged with a second DUI offense within five years. Our research suggests thatoffenders awareness of risks associated alcohol use is diminished particularly in the intoxicated state whendecisions are made to drive. The proposed research aims to reduce recidivism in offenders using experientialfeedback and mindfulness-based approaches to enhance their risk awareness during states of intoxication thatpose risk for DUI.


application_id: 10912467
project_number: 5R01AA030485-03
administering_ic: NIAAA
award_notice_date: 2024-07-24
opportunity_number: RFA-AA-21-016
application_type: 5
activity_code: R01
ic: AA
serial_number: 030485
program_official: PERRUCCIO, ELIZABETH M
project_start_date: 2022-09-10
project_end_date: 2027-07-31
study_section: ZAA1-DD(17)V
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: HARRIS, LESLEY BETH;KERR, JELANI
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-08-01
project_title:
Alcohol Misuse Gut Microbial Dysbiosis and PrEP Care Continuum: Application and Efficacy of SBIRT Intervention

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

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

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


application_id: 10912096
project_number: 1R56DK136728-01
administering_ic: NIDDK
award_notice_date: 2023-09-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R56
ic: DK
serial_number: 136728
program_official: SHEA-DONOHUE, TEREZ
project_start_date: 2023-09-20
project_end_date: 2026-08-31
contact_pi_person_id: 12197847
contact_pi: ALAM, M. ASHFAQUL
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: 2023-09-20
budget_end_date: 2026-08-31
project_title:
Impact of dysbiotic and symbiotic catabolism of luminal amino acids on intestinal epithelial barrier function and inflammation

project_abstract:
Over 3 million adults in the U.S. suffer from inflammatory bowel diseases (IBD) which encompasses Crohnsdisease (CD) and ulcerative colitis (UC). IBD is characterized by dysbiotic gut microbiota compromised epithelialbarrier function chronic intestinal inflammation and increased mucosal cytokines. Epithelial barrier function isregulated by a series of intercellular junctions that encompass the tight junction (TJ) adherens junction anddesmosomes. Disruption of the critical epithelial barrier allows access of luminal contents to immunologicallyprivileged compartments thereby contributing to IBD pathogenesis. The dysbiotic gut microbiota-inducedmucosal inflammation perturbs intercellular junctions and epithelial homeostatic properties thereby resulting ina compromised epithelial barrier. However our knowledge of the molecular basis of commensal-stimulatedintercellular junction proteins function epithelial homeostasis and restoration of the compromised epithelialbarrier during intestinal inflammation is very limited. Thus the overall goals of this proposal are to identifymechanisms by which specific commensal bacteria and bacterial metabolic products regulate functions ofintercellular junction proteins and protect from epithelial barrier compromise and injury. Our preliminary datadetermined that the symbiotic Bacteroides uniformis predominantly catabolizes arginine to produce polyaminespermidine which promotes a healthy barrier. In contrast dysbiotic Proteobacterial species E. coli predominantlycatabolizes lysine to synthesize polyamine cadaverine which impairs gut permeability. Bacterial polyamines arealiphatic amines that regulate multiple cellular processes. Based on our preliminary data we hypothesize thatmicrobial polyamines regulate epithelial barrier functions by activating TRPV and regulating TJ SUMOylation apost-translational modification of claudin and ZO proteins in the gut epithelial barrier. Polyamines can activateTransient Receptor Potential Receptors (TRPVs) to regulate cellular functions. In Aim 1 we will dissect thesymbiotic polyamine-activated TRPV1 and dysbiotic cadaverine-elicited TRPV3-mediated TJ regulatoryprocesses. In Aim 2 we will elucidate microbial polyamine-driven SUMOylation of TJ proteins eventuating inthe perturbed barrier function. Finally in Aim 3 we will determine the impact of small molecules and luminalmetabolites which inhibit cadaverine synthesizing enzymes of the dysbiotic gut bacteria and thereby dampenintestinal inflammation. This project is both conceptually and technically innovative. It will employ the creativeuse of Trpv1 and Trpv3 knockout mice and a novel pathogen-specific antibacterial agent. The investigation ofthe effects of gut bacterially produced polyamines on epithelial TRPV and TJ SUMOylation approach is novel.Completion of these studies will provide clear insights into the molecular basis of intestinal epithelial barrierregulation by commensals amino acid catabolism and engender new ideas and proof-of-principle of exploitingcommensal bacterial metabolites to develop therapeutics for IBD and other gastrointestinal diseases a highNIDDK research priority.

project_terms:
6-Aminocaproic Acid;Adherens Junction;Adult;Agmatine;Amines;Amino Acids;Anti-Bacterial Agents;Arginine;Attention;Bacteria;Bacteroides;Cadaverine;Carboxy-Lyases;Catabolism;Cell membrane;Cell physiology;Cells;Cellular biology;Chronic;Colon;Creativeness;Crohn's disease;Data;Desmosomes;Disease;Ensure;Enterocytes;Enzymes;Epithelial Attachment;Epithelial Cells;Epithelium;Escherichia coli;Gastrointestinal Diseases;Germ-Free;Goals;Health;Homeostasis;Immune;Immunologics;Impairment;Inflammation;Inflammatory Bowel Diseases;Injury;Intercellular Junctions;Interleukin-10;Intestinal Mucosa;Intestinal permeability;Intestines;Investigation;Knockout Mice;Knowledge;Link;Lysine;Mediating;Metabolic;Molecular;Mucositis;Mucous Membrane;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Neurons;Oxidative Stress;Pathogenesis;Pathway interactions;Perception;Permeability;Polyamines;Post-Translational Protein Processing;Process;Property;Proteins;Proteobacteria;Putrescine;Regulation;Research Priority;Role;Series;Shotguns;Spermidine;Spermine;Sumoylation Pathway;TRPV1 gene;Testing;Therapeutic;Tight Junctions;Ulcerative Colitis;Vanilloid;commensal bacteria;cytokine;design;dysbiosis;emerging pathogen;extracellular;gastrointestinal epithelium;gut bacteria;gut inflammation;gut microbes;gut microbiota;improved;in vitro Assay;innovation;insight;intestinal barrier;intestinal epithelium;mass spectrometric imaging;member;metabolomics;microbial;microbiota;microbiota metabolites;mutant;novel;novel therapeutic intervention;pathobiont;protein function;receptor;restoration;small molecule;small molecule inhibitor;success;symbiont

public_health_relevance:
Project NarrativeCommensal microbial metabolites are important in intestinal mucosa during health and disease. However ourknowledge of the molecular basis of commensal-stimulated intercellular junction protein function and restorationof the compromised epithelial barrier during intestinal inflammation is very limited. Leveraging the metabolomicstudies this project is designed to investigate how microbiota-produced polyamines regulate the polyamine-sensing receptors on colonic epithelial cells & modulate epithelial tight junctions paracellular permeability &intestinal inflammation.

study_section:
Digestive System Host Defense, Microbial Interactions and Immune and Inflammatory Disease Study Section[DHMI]


application_id: 10912050
project_number: 5R21AG080859-02
project_title: 4D Flow MRI in Assessment of True Severe Low-Gradient Aortic Stenosis
administering_ic: NIA
award_notice_date: 2024-06-11
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AG
serial_number: 080859
program_official: TSAP, LEONID V
project_start_date: 2023-09-01
project_end_date: 2027-05-31
study_section: Clinical Translational Imaging Science Study Section[CTIS]
contact_pi_person_id: 1880208
contact_pi: AMINI, AMIR A
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Degenerative aortic stenosis is a progressive valvular heart disease affecting the aging population and whenhemodynamically significant is associated with serious adverse outcomes such as heart failure syncope anddeath. Although symptomatic classical severe aortic stenosis (AS) wherein aortic valve anatomical or effectivearea is  1.0 2 and mean gradient  40 mmHg raises no diagnostic dilemma patients with low gradient aorticstenosis (i.e. mean gradient < 40 mmHg) that may be severe (i.e. aortic valve area  1.0 2) remain achallenge for determining the true severity of aortic stenosis and present a significant unmet clinical need. Thediscordance between aortic valve area of  1.0 2 and mean gradient < 40 mmHg is encountered in as manyas 30 to 40% of patients with aortic valve area  1.0 2 by transthoracic echocardiography (TTE). In patientswith these discordant findings the true severity is uncertain and have led to the use of dobutamine stressechocardiography (DSE). Based on DSE one can classify the potentially severe low-gradient subjects into 4distinct subgroups a) Low gradient severe aortic stenosis (LGS): aortic valve area of  1.0 2 and a meangradient of  40 mmHg with DSE. b) Low gradient pseudo-severe aortic stenosis (LGPS): aortic valve area of >1.0 2 and a mean gradient of < 40 mmHg with DSE. c) Low gradient indeterminate aortic stenosis severity(LGI): aortic valve area of  1.0 2 and a mean gradient of < 40 mmHg with DSE. d) Finally aortic valve areaof > 1.0 2 and a mean gradient of  40 mmHg with DSE are classified as moderate or less severe aorticstenosis (LSA). Nearly one-third of patients classified as LGS are classified as LGPS with DSE (6). Furthercompounding the concern in patients classified as LGPS LGI LSA is that they often manifest with symptomspotentially attributable to severe AS suggesting an initial misclassification perhaps due to measurement errors.Compared to echo with MRI the velocities can be measured in all 3D directions and due to its tomographicnature no geometric assumptions are required. The hypothesis of the study is that our planned CMR methodswhich we will develop based on previous work will be able to better stratify these AS subjects. Our specific aimsare: 1) We will develop efficient rest and dobutamine stress 4D Spiral flow imaging protocols based on k-spacedependent respiratory gating. 2) We have recently developed a Deep Learning framework which based onComputational Fluid Dynamics (CFD) simulations of training data learns to directly map velocities to pressures.This will be adapted to measure the transvalvular pressure gradients (TVPG) in human subjects and validated.3) In 40 subjects with potentially severe low gradient AS (10 in each of the LGS LGPS LGI LSA) a TTE studyand a CMR study will be performed both at rest and under dobutamine stress. To validate TVPG will bemeasured with cath in a group with n=10 of moderate AS (MAS) subjects undergoing cath for other purposes.This group will also undergo TTE and CMR studies. Subjects with severe AS were not selected for cath for safetyreasons. Classification across modalities flow velocity pressure and orifice area will be statistically correlated.

project_terms:
3-Dimensional;4D MRI;Adopted;Affect;Anatomy;Aortic Diseases;Aortic Valve Stenosis;Area;Breathing;Catheterization;Cessation of life;Chest;Chronic;Classification;Clinical;Correlation Studies;Diagnostic;Diagnostic Procedure;Dobutamine;Dobutamine Stress Echocardiography;Doppler Echocardiography;Drops;Echocardiography;Enrollment;Equation;Goals;Heart;Heart Valve Diseases;Heart failure;Image;Learning;Left Ventricular Ejection Fraction;Liquid substance;Magnetic Resonance Imaging;Maps;Measurement;Measures;Methods;Modality;Morphologic artifacts;Nature;Noise;Operative Surgical Procedures;Patients;Protocols documentation;Rest;Risk;Safety;Scanning;Severities;Severity of illness;Stratification;Stress;Subgroup;Survival Rate;Symptoms;Syncope;Therapeutic Embolization;Work;adverse outcome;aging population;anatomic imaging;aortic valve;aortic valve disorder;aortic valve replacement;data space;deep learning;hemodynamics;human subject;imaging modality;improved;pressure;respiratory;simulation;tomography;training data;ultrasound

public_health_relevance:
Aortic Stenosis (AS) is a significant disease of the aortic valve of the heart which is chronicprogressive and has a 2-year survival rate of 50% in symptomatic patients who are untreated. Inas many as 30-40% of subjects with low gradient but potentially severe AS current diagnosticmethods are discordant and inconclusive. The proposal will develop new MRI methods forimproved stratification of these subjects.


application_id: 10912006
project_number: 5R01AG072797-04
project_title: Novel precision medicine approach to treatment of osteoporosis based on bone turnover
administering_ic: NIA
award_notice_date: 2024-08-28
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: AG
serial_number: 072797
program_official: NELLISSERY, MAGGIE JACOB
project_start_date: 2021-09-30
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-S(02)M]
contact_pi_person_id: 7705149
contact_pi: RAO, MADHUMATHI
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
1. Project Summary/AbstractOsteoporosis is a health problem of major proportions. It affects more than 40 million Americans and results inmore than 2 million fractures annually among Medicare patients alone. Hospital admissions for osteoporoticfractures exceed those of heart attacks strokes and breast cancer combined. Osteoporosis is commonlyconsidered a disease associated with menopause. This estrogen deficiency related bone loss is characterizedby high bone turnover with increased resorption without commensurate changes in bone formation. It is incontrast to age-related bone loss which starts as early as in the fourth decade of life and continues withincreasing age. Age-related bone loss is usually associated with lower bone turnover and decreased boneformation is the main abnormality. Current therapies do not address age-related bone loss and the special needsof the age-related osteoporosis population is currently ignored. This is to a great degree due to difficultiesassociated with the bone biopsy necessary for determination of bone turnover status. Thus the current standardof care relies on starting with an antiresorber which is less effective in age-related osteoporosis and in factimpedes the effectiveness in this population of the appropriate anabolic medication.Our study seeks to achieve two specific aims: Aim 1) to establish a novel precision medicine approach totreatment of age-related osteoporosis based on recognition of low bone turnover and initial treatment withanabolics and Aim 2) to find a non-invasive method for diagnosing low bone turnover in osteoporotic patientsby measurements of serum carboxylated osteocalcin (1-43/49) with validation via the gold standard bonebiopsy and histomorphometry.Our approach will be to enroll female patients who have been diagnosed with osteoporosis in a prospectiveproof of concept study. Patients will undergo bone biopsy and blood draws at baseline. Bone turnover status willbe assessed employing histomorphometry. In addition blood levels of carboxylated osteocalcin (1-43/49) will bemeasured in order to determine their validity - alone or in combination with other bone markers - for diagnosinglow bone turnover prevailing in age-related bone loss.Patients will be grouped according to turnover status. Low-turnover patients will be randomized (1:1) either totreatment with the anabolic teriparatide (Group 1) or with the standard of care antiresorber alendronate (Group2) for one year. In order to provide the necessary comparison group for the non-invasive assessment of turnovernormal-high turnover patients (Group 3) will be treated with standard of care alendronate for one year. At baselineand at one-year bone mineral density measurements will be performed by DXA and 1-year changes in BMD willbe compared between groups. Our central hypothesis is that low turnover age-related osteoporosis needs to bediagnosed and treated differently from estrogen deficiency related osteoporosis. The results will provide aparadigm shift in the treatment of osteoporosis.

project_terms:
Achievement;Adult;Affect;Age;Age-Related Bone Loss;Age-Related Osteoporosis;Alendronate;American;Anabolic Agents;Biological Assay;Biopsy;Blood;Bone Density;Bone Resorption;Bone marrow biopsy;Complement;Data;Diagnosis;Disease;Dual-Energy X-Ray Absorptiometry;Effectiveness;Elderly;Enrollment;Estrogen deficiency;Familiarity;Forteo;Fracture;Health;Hematologist;Histology;Hospitalization;Life;Malignant Breast Neoplasm;Measurement;Measures;Medicare;Menopause;Methods;Myocardial Infarction;Osteocalcin;Osteogenesis;Osteoporosis;Osteoporotic;Outcome;Patients;Pharmaceutical Preparations;Physicians;Population;Quality of life;Randomized;Regimen;Serum;Societies;Special needs;Stroke;Techniques;Testing;Therapeutic;Training;Treatment Protocols;Validation;Woman;age related;aging population;bisphosphonate;bone;bone loss;bone mass;bone turnover;burden of illness;carboxylate;comparison group;design;improved;individualized medicine;mortality;normal aging;novel;osteoporosis with pathological fracture;personalized approach;precision medicine;prospective;standard of care;success;tool;women patients

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


application_id: 10911994
project_number: 5R35ES028373-08
project_title: Environmental Liver Disease
administering_ic: NIEHS
award_notice_date: 2024-08-16
opportunity_number: RFA-ES-16-008
application_type: 5
activity_code: R35
ic: ES
serial_number: 028373
program_official: SCHUG, THADDEUS
project_start_date: 2017-09-15
project_end_date: 2026-08-31
study_section: ZES1-LWJ-K(R)
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Liver disease is a major global health problem. Fatty liver disease or excess accumulation of lipids inhepatocytes affects more than 25% of the worldwide adult population but children and adolescents may alsobe affected. Chronic liver disease may progress to cirrhosis and liver cancer resulting in liver-related death ortransplantation. Liver disease also impacts the development of diabetes and cardiovascular disease. Liverdiseases may be caused or influenced by exposures to environmental chemicals but this is an understudiedarea. To address these problems this project establishes a major integrative and collaborative researchprogram the Environmental Liver Disease Revolutionizing Innovative Visionary Environmental Health ResearchProgram (ELD-RIVER). ELD-RIVER will have a transformative impact in the field. The project investigates two broad scientificthemes: (i) the impact of endocrine and metabolism disrupting chemicals (EDCs/MDCs) in fatty liver diseaseand (ii) other liver diseases (such as liver cancer) associated with chemical exposures. The ELD-RIVER takes abroad integrative scientific approach by investigating relevant chemicals; nutrient:chemical interactions; bothanimal models and human subjects; and both sexes through state-of-the-art methods including multi-omics.EDC/MDC exposures may also impact liver disease through their effects on obesity and diabetes. Thus obesityand diabetes endpoints will also be evaluated. While the specific projects are expected to evolve over time the initial work focusses on exposures topolychlorinated biphenyls and vinyl chloride. Both of these chemicals currently rank in the top five in the Agencyfor Toxic Substances and Disease Registry (ATSDR) Substance Priority List. ELD-RIVER strictly adheres to theprinciples of scientific rigor and reproducibility and data transparency and availability. ELD-RIVER leveragesexisting collaborations between multiple organizations including academia government agencies industry andscientific/medical societies. The vision is for ELD-RIVER to become the global hub for environmental liverdisease research. To accomplish its translational mission the program integrates the work of basic scientistsepidemiologists and physicians. The project will also develop diagnostic biomarkers new treatments practiceguidelines and it has the potential to impact policy change. Along the way unique institutional education/trainingresources will be utilized so that ELD-RIVER will help produce the next generation of environmental healthscientists. The work proposed is relevant to Strategic Plan of the National Institute of Environmental HealthSciences (Themes 1 2 and 5 and Goals 1 4 7 and 8).

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

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


application_id: 10911156
project_number: 5K01CA251487-05
project_title: Promoting Cervical Cancer Screening among African American and Sub-Saharan African Immigrant women
administering_ic: NCI
award_notice_date: 2024-08-07
opportunity_number: PAR-18-365
application_type: 5
activity_code: K01
ic: CA
serial_number: 251487
program_official: WALI, ANIL
project_start_date: 2020-09-02
project_end_date: 2026-08-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 14387971
contact_pi: ADEGBOYEGA, ADEBOLA O
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe highest incidence rates of cervical cancer (CC) are in sub-Saharan Africa South Central Asia and SouthAmerica. In the United States (U.S.) CC ranks 14th in frequency. However in certain populations and geographicareas of the U.S. CC incidence and death rates are significantly higher due in part to racial and ethnic disparitiesin access utilization and quality of care all of which contribute to worse health outcomes. Black womenexperience a disparate burden of CC incidence and mortality having a higher risk of being diagnosed with anddying from CC than non-Hispanic White women. Appropriate and timely CC screening is a key factor inprevention. Leveraging the positive benefits of CC screening may reduce the CC disparate burden amongBlacks. Research studies typically treat Blacks as a homogeneous group despite differences within thispopulation. To begin to address a gap in the literature within the scope of a career development award thisstudy focuses specifically on two subgroups of Black women - African Americans (AA) and Sub-Saharan Africanimmigrants (SAI) given that there is paucity of research with SAI despite known cancer related disparities amongSAI women. To promote screening for these underserved minority women we will conduct research to betterunderstand factors that influence engagement in cancer screening practices and willingness to conduct HPVself-sampling in which women self-collect samples for HPV testing using a swab brush or lavage. Guided by thefindings we will develop and pilot test an innovative tailored intervention incorporating HPV self-sampling withpeer-delivered education. The specific aims are to (1) examine general awareness and cultural factors relatedto cancer control and prevention among AA and SAIs; (2) examine the socioecological barriers and facilitators toCC screening with HPV self-sampling to tailor an evidenced based cervical health promotion program in theseunderserved subgroups; and (3) assess feasibility acceptability and preliminary efficacy of the intervention. Theintervention entitled Health is Wealth: A Cervical Health Program will be pilot tested with 30 AA and 30 SAIwomen aged 30 to 65 years using a quasi-experimental design. These aims will also support the candidatescareer goal of developing an independent and extramurally funded program of research to promote cancercontrol and prevention for minority women. To further support this goal a mentored career development planconsisting of training in mixed methods adaptation and development of behavioral interventions randomizedclinical trial design and research team management is proposed. The rich research environment at theUniversity of Kentucky and the expertise of the mentoring team will provide the supplemental resources andsupport needed for the candidate to successfully complete the proposed research and training plans. As suchthis K01 award will provide the training mentoring and research experiences needed for the candidate tosuccessfully compete for a R01-level CC screening intervention study and expedite her career development.

project_terms:
Address;Africa South of the Sahara;African;African American;African American Women;African American population;Awareness;Behavior Therapy;Belief;Black Populations;Cancer Burden;Cancer Control;Cancer Etiology;Central Asia;Cervical;Cervical Cancer Screening;Clinic Visits;Clinical Trials Design;Collection;Consent;Cross-Sectional Studies;Data;Death Rate;Developing Countries;Development;Development Plans;Diagnosis;Disparate;Disparity;Education;Emotional;Environment;Evidence based intervention;Extramural Activities;Frequencies;Fright;Funding;Future;Geographic Locations;Goals;Gynecologic;Health;Health Promotion;Health behavior;Health education;Healthcare Systems;Human Papillomavirus;Human papilloma virus infection;Immigrant;Incidence;Individual;Intervention;Intervention Studies;K-Series Research Career Programs;Kentucky;Knowledge;Lavage;Lesion;Literature;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentored Research Scientist Development Award;Mentors;Methods;Minority;Minority Women;Modality;Modeling;Not Hispanic or Latino;Outcome Measure;Pattern;Physicians;Population;Population Heterogeneity;Population Study;Preventative vaccination;Prevention;Privatization;Quality of Care;Quasi-experiment;Research;Research Personnel;Resources;Role;Sampling;Screening for cancer;Screening procedure;Self Efficacy;Sensitivity and Specificity;South America;Structure;Subgroup;Swab;Testing;Training;Treatment Efficacy;Underserved Population;United States;Universities;Visit;Vulnerable Populations;White Women;Woman;Women's mortality;access disparities;aged;anti-cancer research;behavior change;behavior influence;black men;black subgroup;black women;cancer health disparity;cancer prevention;career;career development;cost;detection method;ethnic disparity;evidence base;experience;health belief;health care availability;health knowledge;high risk;high risk population;innovation;intervention effect;mortality;peer;pilot test;poor health outcome;prevent;programs;racial disparity;racial population;randomized clinical trials;recruit;research study;satisfaction;screening;screening participation;skills;social;social cognitive theory;underserved minority;willingness

public_health_relevance:
PROJECT NARRATIVEDespite the availability of screening tools that can prevent cervical cancer Black women are burdened by highcervical cancer incidence and mortality. This project seeks to enhance cervical cancer screening among Blackwomen African Americans and sub-Saharan African immigrants by tailoring and pilot testing an evidence-basedintervention incorporating HPV self-sampling and peer-delivered education to promote cervical cancerscreening.


application_id: 10910356
project_number: 3R01AI145910-05S1
project_title: Dysregulation of maternal immunity during pregnancy by pregravid obesity
administering_ic: NIAID
award_notice_date: 2023-08-31
opportunity_number: RFA-AI-18-023
application_type: 3
activity_code: R01
ic: AI
serial_number: 145910
suffix: S1
program_official: PRABHUDAS, MERCY R
project_start_date: 2019-09-01
project_end_date: 2025-08-31
study_section: ZAI1-NVM-I(M1)
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
project_abstract:
Successful pregnancy requires carefully coordinated changes in the immune system that facilitate placentationpromote fetal tolerance and growth and induce labor. Deviations from this tightly regulated pregnancyimmunological clock can lead to as pre-eclampsia and complications during labor. The rates of obesity amongstwomen of childbearing age have increased at an alarming rate making it one of the most common comorbiditiesduring pregnancy. Previously published studies and our preliminary data indicate an enhancement of monocyteresponse to LPS between 12 and 37 weeks of gestation Importantly our preliminary analyses indicate thatmaternal pregravid body mass index (BMI) >30 abrogates this pregnancy-associated monocyte activation. Thisobservation provides a potential explanation for the increased susceptibility to infections and poor wound healingoutcomes observed in obese pregnant women. We hypothesize that chronic low grade inflammationinduced by pregravid obesity disrupts the gestational age dependent monocyte activation skewing themto an immunotolerant phenotype. Additionally given that macrophages in the decidua are recruited fromcirculating monocytes we will investigate the burden of obesity on phenotype and function of decidualmacrophages. We further hypothesize that pregravid obesity results in a hyper-inflammatory phenotypewithin decidual macrophages. We will employ a multi-dimensional approach to test these hypotheses. Thenovelty of this application lies in the systems biology approach that integrates phenotypic functional andgenomic readouts longitudinally in peripheral blood and at term in the placenta. Completion of the proposedexperiments will reveal the molecular mechanisms that explain progressive changes in monocyte activation overthe course of healthy pregnancy and how that is disrupted with obesity.

project_terms:
37 weeks gestation;Address;Biology;Birth;Blood;Blood specimen;Body mass index;Categories;Cell physiology;Cells;Cesarean section;Chronic;Data;Decidua;Dendritic Cells;Development;Dimensions;Epigenetic Process;Equilibrium;Exhibits;Female of child bearing age;Fetal Growth;Frequencies;Functional disorder;Genetic Transcription;Genomics;Gestational Age;Gestational Diabetes;Gravid;Growth;Growth and Development function;Health;Heterogeneity;Homeostasis;Host Defense;Immune;Immune system;Immunologics;Immunology;Impaired wound healing;Impairment;Induced Labor;Infection;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Innate Immune System;Investigation;Labor Complications;Laboratories;Ligands;Link;Macrophage;Macrophage Activation;Maintenance;Maternal-Fetal Exchange;Maternal-fetal medicine;Maternally-Acquired Immunity;Metabolic;Metabolism;Modeling;Molecular;Natural Killer Cells;Obesity;Outcome;Phagocytes;Phenotype;Placenta;Placentation;Play;Positioning Attribute;Pre-Eclampsia;Predisposition;Pregnancy;Pregnant Women;Premature Birth;Publishing;Risk;Role;Sampling;Statistical Models;Surgical Wound Infection;Systems Biology;Testing;Thinness;Third Pregnancy Trimester;Time;Tissues;Villous;Woman;adverse outcome;adverse pregnancy outcome;age related;antimicrobial;cell type;comorbidity;epidemiology study;epigenome;experimental study;fetal;healthy pregnancy;insight;intraamniotic infection;maternal outcome;monocyte;next generation sequencing;novel;obese mothers;peripheral blood;pregnancy hypertension;prepregnancy obesity;recruit;response;surgical risk;wound healing

public_health_relevance:
NARRATIVEPre-pregnancy obesity is associated with significant adverse health outcomes for the mother including increasedrisk of gestational diabetes and hypertension preeclampsia and infection. Recent studies from our laboratoryrevealed significant changes in immune cell function in blood samples collected from obese women at week 37of gestation. Since immune cells play a critical role in anti-microbial defense as well as the development ofchronic inflammation this application will carry out an in-depth investigation of maternal pre-pregnancy obesity-driven changes in the functional transcriptional and epigenetic landscape of blood immune cells.


application_id: 10910204
project_number: 5UC7AI180309-02
project_title: UofL RBL BSL3 Facility Management Maintenance and Operations Core
administering_ic: NIAID
award_notice_date: 2024-08-05
opportunity_number: RFA-AI-22-075
application_type: 5
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: ZAI1-SJ-W
subproject_number: 9957
contact_pi_person_id: 79041956
contact_pi: STEFFEN, MARLENE CLARKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY: Facility Management Maintenance and Operations (FMMO) CoreThe Center for Predictive Medicine (CPM) Regional Biocontainment Lab at the University of Louisville wasdesigned and constructed following established guidelines to provide a safe facility for the trained and qualifiedpersonnel to work with hazardous pathogens while protecting themselves the community and environment. Inorder to assure that the structure and specialized content within hold up to the exceptional standards over theyears a highly skilled and dedicated team of individuals from all walks of life e.g. project management technicaltrades biosafety animal welfare security business services information technology and senior scientificprofessionals to name a few must combine their expertise to reach this goal. The CPM Facility OperationsManager is paramount in the success of the management maintenance and operations 24/7/365. Theestablished activities processes and workflows are based on risk assessment and communicated to allstakeholders. Preventive maintenance is the strategy employed to make certain preparedness is the foundationfor fulfilling the CPM mission. Each facet (management maintenance and operations) is essential to thereliability longevity and purpose set forth in 2009 and have an impeccable record to affirm its efficacy.In addition personnel must be familiar with the standard operating procedures safety protocols security accessmeasures emergency procedures BSL-3/ABSL-3 practices and are trained and educated annually to reviewrefresh and reinforce the basis of proper steps to safely complete their assigned tasks.Collaboration and communication with law enforcement Homeland Security FBI public health agenciesgovernment entities university and local subject matter experts other groups in the NBL/RBL Networkinspectors and service technicians all enhance the outcome.Based on our historical successes the contributions (impact commitment involvement dedication) of theFMMO Core provide the necessary assets for our expert scientists to be at the leading edge of infectiousdiseases research and readiness to respond for another pandemic.

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


application_id: 10910200
project_number: 5UC7AI180309-02
project_title: UofL RBL Operations Workforce Development and Pandemic Preparedness Research
administering_ic: NIAID
award_notice_date: 2024-08-05
opportunity_number: RFA-AI-22-075
application_type: 5
activity_code: UC7
ic: AI
serial_number: 180309
program_official: DIAZ SAN SEGUNDO, FAYNA C
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: ZAI1-SJ-W(S1)
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY (OVERALL):The University of Louisville Regional Biocontainment Laboratory (RBL) is operated by the University Center forPredictive Medicine for Biodefense and Emerging Infectious Diseases (CPM). The RBL is a regional resourcethat facilitates translational research to develop diagnostics prognostics therapeutics and vaccines to mitigatebiodefense and emerging infectious disease threats. Our Center operates the only BSL-3 and ABSL-3 facilitiescurrently operating in the Commonwealth of Kentucky. The CPM mandate is to prepare for and respond to publichealth emergencies such as the COVID-19 pandemic.The broad long-range objectives and goals of the University of Louisville (UofL) CPM RBL are:1. To offer state-of-the-art research services to the regional and national biomedical research community to learn from past pandemics and biological warfare experiences and effectively predict and mitigate future emerging infectious disease threats.2. To manage maintain and operate the UofL RBL to serve the national and regional need for biocontainment facilities suitable for research on Risk Group 3 pathogens and other biothreats.3. To follow a philosophy of continuous improvement in BSL-3 and ABSL-3 work practices and to ensure that all personnel who need to access BSL-3 and ABSL-3 containment laboratories are appropriately trained and prepared to serve the national and regional need for biocontainment research professionals.To achieve these aims we propose to establish three collaborative Cores. The Facilities ManagementMaintenance and Operations Core (FMMO Core) is responsible for ensuring that the facility is always availableto meet the research and emergency preparedness mission of the RBL. The BSL-3 Practices and WorkforceDevelopment Core (BSL-3PWD Core) formalizes our mentor-mentee training plan to ensure our laboratory isstaffed with BSL-3 research professionals who are proficient at biocontainment research professionals. This coreresponds to the reality that response to rapidly emerging public health emergencies like COVID-19 is limited bythe number of available BSL-3 trained and experienced research professionals. Our Pandemic Preparednessand Response Integrated Research Core (PaPR Core) responds to the substantially increased requests for ourBSL-3 research services by organizing an integrated full-service BSL-3 research support function to supportinvestigator needs. These cores will work in unison to achieve the CPM mission: to prepare for and respond topublic health emergencies like the COVID-19 pandemic.

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

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


application_id: 10910037
project_number: 5R01AI142841-07
project_title: Maternal obesity and neonatal innate immunity
administering_ic: NIAID
award_notice_date: 2024-08-22
opportunity_number: PAR-20-298
application_type: 5
activity_code: R01
ic: AI
serial_number: 142841
program_official: PRABHUDAS, MERCY R
project_start_date: 2018-09-24
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-V(56)R]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: VARLAMOV, OLEG
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The developing fetal immune system is exquisitely sensitive to signals from the maternalenvironment. Maternal pre-pregnancy (pregravid) obesity has emerged as one of the mostconsequential regulators of fetal health. Data from clinical and animal model studiesdemonstrated increased susceptibility to microbial infection as well as a higher incidence ofinflammatory disorders and auto-immune diseases with maternal obesity. This dichotomy isillustrated by splenocytes generating dampened inflammatory responses to LPS stimulation whilegut resident immune cells generate exaggerated ones. Similarly pregravid obesity resulted inlower expression of inflammatory genes in umbilical cord blood monocytes at rest but followingdifferentiation into macrophages expression of inflammatory genes was significantly increased.These observations strongly suggest that pregravid obesity disrupts the development andmaturation of the fetal immune system and differentially impacts circulating monocytesand tissue resident macrophages (TRMs). However the molecular underpinnings of thisdysregulation by maternal obesity remain poorly understood due to the difficulty of obtaining termfetal tissues and of controlling for multiple maternal variables that modulate fetal immunity. Thusin this application we will leverage the rhesus macaque model to interrogate multiple fetalcompartments within the same subject to address this knowledge gap. Immune ontogeny occursvia 3 different waves starting with yolk sac transitioning to fetal liver and finally the bone marrow.TRMs are derived primarily from yolk sac and fetal liver while circulating monocytes are derivedfrom bone marrow. We recently reported that pregravid obesity is associated with low gradeinflammation that is further compounded by pregnancy. Thus we postulate that exposure to lowgrade maternal inflammation leads to training of TRMs while heightened maternal inflammatoryenvironment in late gestation leads to tolerance of bone marrow derived monocytes. Thereforethis application will test the central hypothesis that pregravid obesity results in differentialrewiring of TRMs and circulating monocytes wherein TRMs are poised to generate aheightened inflammatory response while circulating monocytes display a stuntedresponse. The novelty of this application lies in the systems biology approach integratingmaternal clinical metadata with genomic and functional readouts obtained in multiple immunecompartments in the same animal. Completion of the proposed experiments will reveal themolecular mechanisms that result in altered fetal macrophage and monocyte functions thusinforming the potential development of early interventions.

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

public_health_relevance:
NARRATIVEPre-pregnancy maternal obesity is associated with significant adverse health outcomes for the offspring includingincreased risk of severe neonatal infections and developing chronic diseases such as asthma and cardiovasculardisease which suggests a dysregulated immune system. Recent studies from our laboratory revealed significantchanges in umbilical cord blood immune cells from babies born to obese mothers but the impact of maternalobesity on fetal immune cells remains poorly defined/understood. This application will carry out an in-depthinvestigation of maternal pre-pregnancy obesity-driven changes to the fetal immune cell populations andfunctions to contribute to the fundamental knowledge of the immune system development and identify potentialinterventions to address fetal immune dysregulations.


application_id: 10909931
project_number: 5R24AI138963-07
administering_ic: NIAID
award_notice_date: 2024-08-12
opportunity_number: PAR-20-063
application_type: 5
activity_code: R24
ic: AI
serial_number: 138963
program_official: BREEN, JOSEPH J
project_start_date: 2018-07-23
project_end_date: 2027-08-31
study_section: ZAI1-SB-I(M1)
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: SMITH, MELISSA LAIRD
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-01
project_title:
An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

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

project_terms:
2019-nCoV;Adaptive Immune System;Adult;Antibodies;Antibody Repertoire;Antibody Response;Antibody-mediated protection;Area;Autoimmunity;Award;B-Lymphocytes;Basic Science;Biomedical Research;Brazil;Catalogs;Clinical;Collaborations;Collection;Communities;Complex;Data;Data Set;Databases;Deposition;Development;Disease;Ensure;European;Genbank;Gene Expression Regulation;General Practitioners;Genes;Genetic;Genetic Diseases;Genetic Polymorphism;Genetic Variation;Genome;Genomics;Genotype;Genotype-Tissue Expression Project;Germ Lines;Germ-Line Mutation;HIV;Haplotypes;Health;Human;Human Genome;Human Resources;IGL@ gene cluster;Immune;Immunogenetics;Immunogenomics;Immunoglobulin A;Immunoglobulin G;Immunoglobulin Genes;Immunoglobulin M;Immunoglobulins;Immunologic Receptors;Immunology;Individual;Infection;International;Investigation;Knowledge;Light;Link;Malignant Neoplasms;Methods;Modeling;Nucleotides;Oceania;Outcome;Population;Population Heterogeneity;Positioning Attribute;Quantitative Trait Loci;Research;Resources;Rheumatic Heart Disease;Role;Sampling;Single Nucleotide Polymorphism;South African;Summary Reports;Uganda;Underrepresented Populations;V(D)J Recombination;Variant;analysis pipeline;cohort;data access;database of Genotypes and Phenotypes;dbSNP;design;ethnic diversity;frontier;genetic association;genome browser;genome resource;genomic data;high standard;immunoglobulin light chain locus;improved;novel;precision medicine;reference genome;response;tool;vaccine response

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


application_id: 10909249
project_number: 5R33DA049130-05
project_title: Glutamergic Mechanisms in Opioid and Cocaine Co-Use
administering_ic: NIDA
award_notice_date: 2024-08-20
opportunity_number: PAR-18-084
application_type: 5
activity_code: R33
ic: DA
serial_number: 049130
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2020-09-30
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-X(03)M]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: STOOPS, WILLIAM WALTON
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Opioid use disorder (OUD) is a leading public health crisis in the United States. Individuals with opioid usedisorder frequently use other substances including cocaine. Past year opioid withdrawal was associated with 4times greater odds of current cocaine use which may represent an attempt to ameliorate opioid withdrawaleffects but also increases overdose risk as evidenced by preclinical and clinical findings. Approved OUDpharmacotherapies are modestly effective but these medications are not indicated for treating cocaine co-usehighlighting the need for a novel intervention approach to improve outcomes in co-morbid OUD and cocaine usedisorder. Mechanistically drug-motivated behaviors are regulated by glutamate signaling within corticostriatalcircuitry. Both opioid and cocaine self-administration (SA) down-regulate the glial glutamate transporter (GLT-1) and alter synaptic plasticity measured as changes in dendritic spines and AMPA-to-NMDA current ratios(A/N) within the nucleus accumbens core (NAcore). Thus glutamatergic plasticity is a conserved neuralmechanism underlying drug motivation in both opioid and cocaine use. The combined effects of opioid andcocaine co-use on glutamatergic systems however are unknown. n-Acetylcysteine (NAC) has showntranslational promise for treating multiple drug use disorders including cocaine and opioids. NAC is capable ofrestoring glutamatergic alterations induced by either drug alone likely by increasing glutamate clearance fromthe synapse following drug use through upregulation of GLT-1. Clinically we have shown that NAC reduces theincentive salience of cocaine-related stimuli which controls drug seeking. As well others have shown that NACnormalizes glutamate function in cocaine-dependent individuals. Whether NAC reduces drug intake and reversesglutamatergic alterations induced by co-use of opioids and cocaine is unknown. The work proposed here willbegin to fill those crucial knowledge gaps. Our overarching hypotheses are that (1) persistent brain glutamatechanges induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence andwithdrawal and (2) that NAC will ameliorate glutamatergic dysregulation and thus will reduce both oxycodoneand cocaine use. We propose a two phase translational project supported by the R21/R33 mechanism. In thefirst phase (R21) we will characterize NAcore glutamatergic signaling in opioid and cocaine co-use as a neuralbiomarker for pharmacotherapeutic targeting with NAC using preclinical laboratory methods. Upon meeting themilestones set forth for the R21 we will conduct the second phase (R33) in which we will determine the influenceof NAC on glutamate function and reinforcing effects of cocaine in co-morbid opioid and cocaine use disorderusing human laboratory methods. The milestones completed during this translational project will elucidateglutamatergic dysregulation underlying opioid and cocaine co-use laying the groundwork for effectivepharmacotherapeutic treatment for this pattern of polysubstance abuse through targeting glutamate signaling.

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

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


application_id: 10907434
project_number: 5R01AA030756-02
administering_ic: NIAAA
award_notice_date: 2024-05-15
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: 2024-06-01
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 prevention;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: 10907197
project_number: 1R13CA290978-01
project_title: 23rd Midwest DNA Repair Symposium
administering_ic: NCI
award_notice_date: 2024-04-25
opportunity_number: PA-21-151
application_type: 1
activity_code: R13
ic: CA
serial_number: 290978
program_official: SHARMAN, ANU
project_start_date: 2024-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZCA1 PCRB-9 (J1)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe 23rd Midwest DNA Repair Symposium (MDRS) will take place in Louisville KY on June 1-2 2024 atthe Health Science Campus of the University of Louisville. The MDRS started in 1999 at the University ofMichigan  Ann Arbor and has met at various universities in the Midwest every year since then except fora 3-year hiatus imposed by the COVID19 pandemic. The Midwest DNA Repair Symposium was originallyconceived as a forum to bring together DNA repair researchers from the Midwestern region on an annualbasis to discuss ongoing research to stimulate collaborations and to interact with leading DNA repairresearchers in an informal atmosphere. In 2024 we will have 3 eminent DNA repair researchers as keynotespeakers continuing the history of leading researchers gladly accepting the invitation. Additional goals ofthe MDRS include making the cost of attending the symposium as inexpensive as possible and to provideearly stage investigators postdoctoral fellows and graduate students priority in presenting their work inoral and poster sessions. DNA repair is a fundamental cellular process critical to maintenance of genomeintegrity and human health. DNA repair dysfunction has been linked with many inherited diseases as wellas chronic diseases such as cancer neurodegeneration cardiovascular disease and aging. Theorganizers are pleased that this symposia series has been very successful and has seen significantincrease in attendance the past several years. One key to the success has been to keep the costs ofattendance low. This low cost has been possible because the organizers for each year held the symposiumat their home institutions and have secured both intramural and extramural funding to cover some of themajor expenses. Especially in times of restricted research funding the MDRS is one quality conference towhich PIs have been able to bring their students and post-doctoral fellows to interact with leading scientistsin the field and to present their work among peers. To celebrate its 25th anniversary the MDRS is returningto Louisville for the third time in 2024. The three principal goals of the MDRS are: 1) to provide a venue forscientists mainly but not exclusively from the Midwestern States to present and discuss current researchin the field of DNA damage repair and mutagenesis and to provide opportunities to foster scientificcollaborations. (2) To provide students postdoctoral fellows and early stage investigators the opportunityto present their work to peers and to interact with leaders in the field. (3) To provide an exceptional valueof these symposia by keeping them affordable.

project_terms:
Aging;Anniversary;COVID-19 pandemic;Cardiovascular Diseases;Cardiovascular system;Cell Physiology;Chronic;Chronic Disease;Collaborations;DNA Damage;DNA Repair;Development;Extramural Activities;Fostering;Functional disorder;Funding;Goals;Health;Health Sciences;Hereditary Disease;Home;Human;Institution;Link;Maintenance;Malignant Neoplasms;Michigan;Midwestern United States;Mutagenesis;Nerve Degeneration;Neurodegenerative Disorders;Oral;Participant;Postdoctoral Fellow;Prevention;Recording of previous events;Research;Research Personnel;Scientist;Secure;Series;Students;Time;Universities;Work;cost;genome integrity;graduate student;human disease;informal atmosphere;meetings;peer;posters;repaired;success;symposium

public_health_relevance:
Project NarrativeDNA damage contributes to the development and progression of chronic human disease including cancercardiovascular neurodegenerative diseases and aging. DNA repair is an essential cellular processes thatremoves the DNA damage and efficient DNA repair is essential to prevention of these chronic diseases.This symposium will bring together DNA repair researchers to discuss their newest research to exchangeideas and to develop new collaborations.


application_id: 10906432
project_number: 2R13DC016831-07
project_title: International Society for Neurogastronomy Symposium
administering_ic: NIDCD
award_notice_date: 2024-03-18
opportunity_number: PA-21-151
application_type: 2
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2029-02-28
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
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:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is still a relatively new society whose composition of scientists cliniciansnutritionists agricultural experts food service professionals and chefs naturallypredisposes it to focus on translational issues fundamental to how the chemical sensesimpact human health. The first two specific objectives are to provide a venue andopportunity that brings these groups together and facilitates the synergies that arise whendistinctly different fields interact productively. The third specific objective is to attractstimulate and promote the careers of the young scientists that are the future of the field ofneurogastronomy. The fourth specific objective is to do outreach that serves health andculinary professionals by informing them about the impact that smell and taste has upondiet nutrition and the growing health problems of obesity-related diseases. The fifthspecific objective is to ensure that this new field embraces a culture of diversity weavingthis principle into its early development by recruiting persons of diverse backgrounds to theconference.

project_terms:
Agriculture;Area;Brain;Chemicals;Clinical;Communication;Consumption;Development;Diet;Diet Habits;Disabled Persons;Disparity population;Eating;Ensure;Environment;Equation;Equilibrium;Event;Faculty;Food;Food Industry;Food Services;Formulated Food;Fostering;Funding;Future;Goals;Grant;Health;Health Promotion;Human;International;Knowledge;Life;Mission;Neurosciences;Nutritional;Nutritionist;Obesity associated disease;Pathway interactions;Perception;Persons;Policies;Productivity;Quality of life;Recruitment Activity;Rewards;Science;Scientist;Sensory;Smell Perception;Societies;Stimulus;Structure;Taste Perception;Training;Underrepresented Populations;Veterans;Work;career;design;drinking;food consumption;food preparation;improved;interest;meetings;member;multisensory;nutrition;outreach;preference;recruit;sensory integration;sensory neuroscience;social;sound;symposium;synergism

public_health_relevance:
PROJECT NARRATIVEA major part of the mission of the International Society of Neurogastronomy (ISN) is topromote the study of flavor and its use to enhance the quality of human life channeling ourgrowing knowledge of neurogastronomy and chemosensory science into translationalaction needed to overcome the ways in which flavor preferences can contribute tounhealthy eating habits. ISN promotes cooperation between scientists and foodprofessionals towards altering the balance of this equation in our culture. ISNs annualmeeting provides an important mechanism for facilitating the interactions betweenchemosensory scientists neuroscientists clinicians nutritional scientists agriculturalscientists and food professionals needed to develop strategies for using flavor properly -strategies that are both practical and scientifically sound.


application_id: 10906103
project_number: 5R21AI178798-02
project_title: HMPV/RSV co-infection: effects on replication and viral spread
administering_ic: NIAID
award_notice_date: 2024-07-30
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 178798
program_official: KIM, SONNIE
project_start_date: 2023-08-11
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-IMII-U(01)]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
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:
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are important respiratory viruses whichcause significant morbidity and mortality particularly in pediatric elderly and immunocompromised patients.Sensitive molecular techniques show that patients with respiratory infections are frequently infected with morethan one viral pathogen. In the case of RSV and HMPV co-infections while some studies found no or limitedimpact of co-infection other research strongly indicates that RSV-HMPV co-infection has a deleterious effect onthe course of disease and severity of symptoms. However few studies have examined the molecular details ofco-infection by these two important pathogens. Thus the impact of RSV/HMPV co-infections remains a criticalarea for continued study but relatively little is known about the mechanisms by which co-infections may affectthe steps of the viral lifecycle. Viral interference through triggering of innate immunity and also competition forcellular resources have been studied for their roles in co-infection and very recent work suggests that hybridviral particles can form between influenza and RSV. Our preliminary studies of HMPV/RSV co-infectiondemonstrate that inclusion bodies (IBs) which are key regions for viral transcription and replication can containboth RSV and HMPV genomes in co-infected cells indicating a shared replication compartment. Our overallhypothesis is that HMPV/RSV co-infection affects both virus replication and virus spread. To test this we willpursue two Specific Aims using a range of experimental approaches and the wealth of reagents we have createdfor the examination of pneumovirus infection. First we will dissect the effect of HMPV/RSV co-infection on IBformation dynamics and viral replication including careful analysis of IBs over the course of infection andanalysis of viral transcription and replication at the global and single cell level. Second we will determine theeffect of HMPV/RSV co-infection on potential formation of functional hybrid virus particles. In addition we willexamine whether a unique pathway for cell-to-cell spread which we have characterized for HMPV is also utilizedby RSV during co-infection. These important experiments will elucidate new molecular consequences of viral co-infection providing insight that may inform studies of additional respiratory viruses and lead to new ways totarget respiratory virus infections.

project_terms:
Affect;Area;Binding;Body Size;Cells;Clinical;Complex;Disease;Event;Filament;Fluorescent in Situ Hybridization;Foundations;Genetic Materials;Genetic Transcription;Genome;Genomics;Glycoproteins;Human;Human Metapneumovirus;Hybrids;Immunocompromised Host;Inclusion Bodies;Individual;Infection;Influenza;Innate Immune Response;Joints;Life Cycle Stages;Location;Messenger RNA;Molecular;Morbidity - disease rate;Natural Immunity;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Phase;Physiological;Pneumovirus;Pneumovirus Infections;Proteins;Public Health;Reagent;Reporting;Research;Resources;Respiratory System;Respiratory Tract Infections;Respiratory syncytial virus;Role;Severities;Site;Symptoms;System;Techniques;Testing;Time;Viral;Viral Interference;Virion;Virus;Virus Diseases;Virus Replication;Work;co-infection;experimental study;genetic element;influenzavirus;insight;joint formation;mathematical model;mortality;neutralizing antibody;new therapeutic target;novel;older patient;particle;pathogen;pathogenic virus;pediatric patients;receptor binding;respiratory examination;respiratory infection virus;respiratory virus;single cell technology;superresolution microscopy;viral RNA

public_health_relevance:
Patients with respiratory infections are frequently found to have more than one virus but theimpact of viral co-infection remains poorly understood. This work will examine the interactionsbetween respiratory syncytial virus and human metapneumovirus during infection of the samecell particularly focusing on key steps in the viral life cycle. These studies will provide molecularinsights that will also inform examination of other respiratory virus co-infection and may lead tonovel therapeutic targets and treatment options.


application_id: 10905412
project_number: 1R01AG084180-01A1
project_title: Impacting Inflammation through Mechanistic Target of Rapamycin (imTOR)
administering_ic: NIA
award_notice_date: 2024-08-30
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 084180
suffix: A1
program_official: TILAHUN, MULUALEM ENYEW
project_start_date: 2024-09-01
project_end_date: 2028-05-31
study_section: Special Emphasis Panel[ZRG1 EMS-D (02)]
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Inflammatory diseases limit healthspan defined as the length of ones life spent in good health. We propose anancillary study to an NIA-funded trial U01AG076941 (EVERLAST) that we call Impacting inflammation throughmechanistic Target Of Rapamycin (imTOR). The EVERLAST parent trial will test the ability of low/intermittentdoses of the rapamycin analogue everolimus to selectively inhibit mTORC1 but not mTORC2 and thusimprove multiple indicators of healthspan while avoiding the undesirable side-effects of rapamycin. Analysis ofimmune cells as major sources of mTOR-regulated inflammation coupled with analysis in the context of parenttrial outcomes would significantly enhance the value of EVERLAST without changing subject burden. imTORthus responds to NOT-AG-23-020 Maximizing the Scientific Value of Secondary Analysis of Existing Cohortsand Datasets in Order to Address Research Gaps and Foster Additional Opportunities in Aging Research.EVERLAST is enrolling middle-aged to older adults who are generally healthy but are overweight/obese andinsulin resistant to take placebo or everolimus daily (0.5mg) or everolimus once weekly (5mg) for 24 wks.EVERLAST will determine the impact of this intervention on fundamental hallmarks of aging including changesin metabolism muscle function brain health senescence and frailty. imTOR will expand the scope ofEVERLAST beyond flu vaccine-generated immune responses by quantitating the impact of everolimus onchronic inflammation a key cause of age-related health declines generated mainly by immune cells. imTORwill focus mainly on CD4+ T cells based on our data showing these cells are dominant sources of inflammationin healthy and obesity-associated aging. imTOR is designed to test the overall hypothesis that everolimuslowers the risk of age-related health problems by reducing chronic inflammation through mechanisms thatinclude improved bioenergetics and redox balance in immune cells. We will complement primary focus on Tcells with analyses of myeloid cells the latter a secondary source of systemic inflammation. Mechanisticinsights into everolimus action on immune cells will be analyzed relative to changes in hallmarks of agingcollected for EVERLAST. We will compare mitochondrial outcomes between immune cells and skeletal muscleto challenge the assumption of similar everolimus impacts on distinct tissue types. Parallel ex vivomanipulations will establish cause/effect relationships amongst everolimus mTORC1/2 function cellphysiology cytokine profiles and the frequency of polyfunctional T cells a newly appreciated modulator ofinflammatory disease. Success with the proposed project coupled with EVERLAST outcomes will determinesafety and efficacy of everolimus for promoting healthspan in our ever-aging population.

project_terms:
Address;Age of Onset;Aging;Ancillary Study;Animals;Bioenergetics;Blood;CCI-779;CD4 Positive T Lymphocytes;Cardiac;Cell Physiology;Cells;Chronic;Clinical Trials;Cognition;Cognitive;Compensation;Complement;Complex;Confocal Microscopy;Coupled;Data;Data Set;Disease;Dose;Effectiveness;Enrollment;Equilibrium;FRAP1 gene;Fostering;Frequencies;Funding;Health;Human;Immune;Immune response;Immunosuppression;In Vitro;Infection;Inflammaging;Inflammation;Inflammatory;Institution;Insulin Resistance;Intervention;Lead;Length;Life;Link;Lysosomes;Mediator;Metabolic;Metabolism;Mitochondria;Muscle function;Myeloid Cells;Obesity;Outcome;Outcome Study;Overweight;Oxidation-Reduction;Parents;Pathway interactions;Persons;Pharmaceutical Preparations;Placebos;Positioning Attribute;Process;Production;Proteomics;Regimen;Research;Resources;Risk;Risk Management;SDZ RAD;Safety;Sampling;Shipping;Signal Transduction;Sirolimus;Skeletal Muscle;Source;T-Lymphocyte;Testing;Tissues;Weight;age related;age related decline;age-related disease;aging biomarker;aging population;aging related;animal data;brain health;clinical practice;cohort;cytokine;design;drug action;extend lifespan;frailty;gain of function;geroprotector;hallmarks of aging;healthspan;healthy aging;immunoregulation;improved;influenza virus vaccine;inhibitor;innovation;insight;intervention effect;lens;loss of function;middle age;mitochondrial metabolism;muscle aging;older adult;pharmacologic;predictive modeling;prevent;secondary analysis;senescence;side effect;success;systemic inflammatory response;vaccine response

public_health_relevance:
Numerous studies support the premise that inflammation rises in aging. Drugs with immunomodulatory actionssuch as mechanistic Target of Rapamycin (mTOR) inhibitors may promote healthspan the length of ones lifespent in good health especially if given prior to onset of age-related declines. We will analyze deidentifiedsamples from an NIA-funded clinical trial to test the possibility that the mTORC inhibitor everolimus is a safeand effective option to ameliorate age-related inflammation and sequelae thereof.


application_id: 10905368
project_number: 1R36MH136807-01
project_title: Real-Time Monitoring of Relapse in Eating Disorders
administering_ic: NIMH
award_notice_date: 2024-06-20
opportunity_number: PAR-22-172
application_type: 1
activity_code: R36
ic: MH
serial_number: 136807
program_official: AVENILLA, FRANK R
project_start_date: 2024-07-01
project_end_date: 2025-05-31
study_section: Special Emphasis Panel[ZRG1 F02A-W (20)]
contact_pi_person_id: 77952578
contact_pi: HUNT, ROWAN
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Eating disorders (EDs) are severe mental illnesses with high mortality1 few effective treatments24 andhigh relapse rates.5 Current evidence-based treatments for EDs often result in only 50% of individuals reachingfull remission of their symptoms.4 Further even among those who do recover many relapse. Up to 50% ofthose who recover experience a relapse after treatment about 25% of individuals go on to experience asevere and persistent course of illness.513 Despite these high rates of relapse the past decades of researchhave culminated in very little improvement to prevent relapse within the EDs. To date we still know very littleabout why relapse occurs; in part because ED relapse has been studied primarily as an outcome (i.e.relapsed or not) rather than a dynamic process can be intervened upon.914 Reconceptualizing and studyingED relapse as a dynamic process will aid the identification of mechanisms of relapse and inform thedevelopment and refinement of interventions and relapse prevention efforts. A well-established model ofrelapse in substance use disorders (i.e. the cognitive behavioral relapse model; CBRM)15 can inform the initialformation of a similar model in EDs. With research design informed by the CBRM the proposed study will usemicro-longitudinal (i.e. ecological momentary assessment) and longitudinal (i.e. 3-month follow-up) methodsto capture lapses and relapse among those with EDs. The use of theory-driven fine-grained assessment willmove the field toward the elucidation of distal and proximal mechanisms of relapse as it unfolds in real-time.First we will capture the presence and dynamics of lapses (i.e. momentary engagement in ED behaviors) andwhether features of lapses (e.g. frequency time between lapses) predict eventual relapse (Aim 1). The CBRMspecifies that both tonic processes (i.e. stable chronic factors) and phasic responses (i.e. immediateprecipitants) increase the risk for relapse. As such we will test the associations between tonic processes andthe propensity for lapsing (i.e. higher urge valence and stability and lower urge variability; Aim 2). Additionallywe will use generalized estimating equation models to examine whether each proposed phasic response (e.g.affect emotion regulation skill use) predicts a lapse at the next survey (Aim 3). Lastly the CBRM posits thathigh-risk situations increase the likelihood of an individual lapsing. This study will aid in the initial identificationof said high-risk situations in EDs by using mixed-method (i.e. qualitative and quantitative) analyses to explorecontextual factors contributing to individuals reported lapses (Exploratory Aim 4). Overall the proposedproject will implement advanced statistics and micro- and macro-longitudinal design to provide aninitial mechanistic understanding of relapse as it occurs in the EDs. Findings from this study willinform the refinement of relapse prevention interventions and just-in-time adaptive interventions andultimately promote lasting long-term recovery for those with this impairing and persistent disorder.

project_terms:
Address;Adopted;Affect;Aftercare;Ambulatory Care;Behavior Disorders;Behavioral;Caring;Chronic;Cognitive;Cognitive Therapy;DOOR (deafness-onychodystrophy-osteodystrophy-retardation) syndrome;Data;Day Care;Dedications;Development;Dictionary;Disease;Disease remission;Distal;Eating Disorders;Ecological momentary assessment;Equation;Event;Evidence based treatment;Expectancy;Frequencies;Goals;Grain;Grant;Impairment;Individual;Inpatients;Intervention;Interview;Lead;Life;Literature;Measurement;Measures;Mental Depression;Mental disorders;Methodology;Methods;Modeling;Outcome;Participant;Patients;Phase;Prevention;Process;Psychiatry;Recovery;Recurrence;Relapse;Reporting;Research;Research Design;Research Personnel;Residential Treatment;Risk Factors;Role;Schizophrenia;Specific qualifier value;Substance Use Disorder;Suicide attempt;Surveys;Symptoms;Testing;Text;Time;Variant;adaptive intervention;cognitive enhancement;comorbidity;contextual factors;cost;design;effective therapy;efficacious treatment;emotion regulation;experience;follow-up;high risk;improved;intervention refinement;long term recovery;longitudinal design;medical complication;mortality;negative affect;preventive intervention;psychosocial;real time monitoring;relapse prediction;relapse prevention;relapse risk;response;severe mental illness;skills;social culture;statistics;substance use;suicidal risk;sustained recovery;theories;trait

public_health_relevance:
Project Narrative Eating disorders are an impairing and deadly psychiatric disorder with high rates of relapse. There is aneed to improve our understanding of relapse to inform the design of more efficacious treatments and relapseprevention efforts; however current research is limited by examining relapse as an outcome longitudinally (i.e.across 1 year) rather than a process that unfold through moment-to-moment choices engagement in EDbehavior (i.e. lapses). The current study  informed by existing theory of relapse borrowed from substance usedisorders15  will capture the process at the momentary level with the ultimate goal of identifying mechanismsof relapse that can be addressed through existing and new treatments.


application_id: 10904873
project_number: 5U24DA058961-02
project_title: The University of Kentucky Racial Equity Initiative Coordinating Center
administering_ic: NIDA
award_notice_date: 2024-06-27
opportunity_number: RFA-DA-23-025
application_type: 5
activity_code: U24
ic: DA
serial_number: 058961
program_official: GOLDSTEIN, AMY B
project_start_date: 2023-08-15
project_end_date: 2025-06-30
study_section: ZDA1-TXT-E(M1)R
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY The overarching goal of the University of Kentucky Racial Equity Initiative CoordinatingCenter (UK-REI-CC) is to focus on collectivism and elevate the resilience of People of Color andIndigenous (POCI) communities through supporting REI grantees to conduct culturally relevantbest practice community engaged substance use research. UK-REI-CC will draw from theRadical Healing in Communities of Color6 a strength-based framework to coordinate projectsfrom both Highly Resourced Institutions (HRIs) and Limited Resourced Institutions (LRIs). TheUK-REI-CC is led by a PI and faculty with established collaborations and extensive experiencefocused on community-engagement drug treatment HIV randomized controlled trialsimplementation science pharmacology and justice-involvement. In collaboration with the NIDASteering Committee and expert panel UK-REI-CC will complete the following aims: 1) Todevelop and support a learning community through networking & training among REI grantees.UK REI-CC will organize and convene a kick-off annual meetings and monthly meetings of REIgrantees. Using Pure network mapping system7 REI grantees and community partners willaccess investigators and their worldwide networks. UK-REI-CC will conduct a bi-annual needsassessment convene workgroups devise quarterly trainings develop a speaker series andhost networking events encouraging collectivism and highlighting assets among the REIinstitutions. 2) To enhance REI projects by providing research resources focused on communityengagement. UK REI-CC will provide technical assistance and consultations focused onelevating the voices of marginalized communities. The center will provide quarterly trainings toREI project sites and resources focused on building and strengthening academic-communitypartnerships. 3) To optimize data collection and analyses by the REI community. UsingTableau UK-REI-CC will host an interactive dashboard illustrating progress for REI projects.The center will provide consultation on devising research questions culturally appropriatemeasures recruitment and retention strategies qualitative and quantitative data analyses andincorporating community partners in data analyses. 4) To facilitate broad and accessiblecommunication and dissemination of REI project findings for end users. UK REI-CC will developonline resources to share press releases publications and research presentations. In additionthe UK-REI-CC will leverage our expertise in culturally tailoring messaging to ensureaccessibility for all communities participating in the research. Taken together these activitieswill enhance the capacity for REI projects to conduct impactful substance use research.

project_terms:
Acceleration;Affect;Black American;Collaborations;Color;Communication;Communities;Community Participation;Consultations;Data;Data Analyses;Data Collection;Ensure;Ethnic Origin;Event;Faculty;Goals;HIV;Hospitals;Indigenous;Indigenous American;Inequity;Institution;Intervention;Justice;Kentucky;Limited English Proficiency;Maps;Measures;Modeling;National Institute of Drug Abuse;Needs Assessment;Pharmacology;Pharmacotherapy;Positioning Attribute;Press Releases;Publications;Qualifying;Race;Racial Equity;Randomized Controlled Trials;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Series;Site;Substance Use Disorder;System;Testing;Training;Trauma;Universities;Voice;Work;community academic partnership;community engaged research;community engagement;community partners;dashboard;diversity and inclusion;experience;forgetting;healing;implementation science;indigenous community;innovation;learning community;marginalized community;meetings;member;novel;online resource;overdose death;people of color;recruit;resilience;retention rate;rural setting;social media;structural determinants;substance use;synergism;tailored messaging;urban setting;webinar

public_health_relevance:
Project Title: The University of Kentucky Racial Equity Initiative Coordinating Center (UK-REI-CC)Project Narrative: The UK-REI-CC is an innovative coordinating center model centering collectivism andemphasizing the resilience of racial and ethnic marginalized communities. The UK-REI-CC will enhance andsupport the NIDA REI projects by providing resources for networking and training conducting community-engaged research data collection and analyses and communication and dissemination. Completing theobjectives of the UK-REI-CC will result in accelerating the high impact work of the NIDA Racial Equity Initiative.


application_id: 10903086
project_number: 4R00AA030627-03
project_title: Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH
administering_ic: NIAAA
award_notice_date: 2023-12-18
opportunity_number: PAR-21-271
application_type: 4
activity_code: R00
ic: AA
serial_number: 030627
program_official: LIN, LI
project_start_date: 2022-09-21
project_end_date: 2026-11-30
study_section: NSS
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract:Alcohol-associated hepatitis (AH) is a clinical manifestation of alcohol-associated liver disease (ALD) that has avery poor prognosis. Current treatments are ineffective and liver transplantation is the only long-term solution.The liver has the unique ability to regenerate post-injury but in ALD/AH this process becomes compromised.Mitochondria dysfunction is a hallmark of ALD and AH that can contribute to compromised liver regeneration.Mitochondria enriched with cardiolipin maintain the energy requirements (e.g. ATP) necessary for hepatocyteproliferation and liver regeneration. Preliminary data demonstrate that hepatic cardiolipin synthesis iscompromised in clinical AH and experimental AH. Cardiolipin is required to maintain mitochondrial bioenergeticsand undergoes oxidation and depletion in ALD compromising liver regeneration. However treatment withcardiolipin or elamipretide (drug that prevents cardiolipin oxidation) can restore hepatocyte mitochondrial functionand proliferation. The aim of this study is to determine if cardiolipin supplementation and preservation willpromote liver regeneration via maintenance of ATP synthesis and prevention of hepatocyte apoptosis alleviatinghepatic insufficiency in AH. This study uses pre-clinical animal models and human in vitro models of AH toassess the treatment efficacy of cardiolipin supplementation and preservation. Aim 1 will determine if mice withcardiolipin deficient hepatocytes have compromised liver regeneration due to loss of mitochondrial ATPsynthesis in a model of AH. Aim 2 will test whether treatment with cardiolipin and elamipretide will enhancehepatic mitochondrial function liver regeneration and proliferating hepatocyte populations in an experimentalanimal model of AH. Aim 3 will identify cardiolipin species in human AH liver and plasma and assess their effecton hepatocyte proliferation and inflammatory responses in immune cells. The K99-phase (Aim 1) will providetraining in assaying liver regeneration and mitochondrial function sc-RNASeq analysis and use of a mousedeficient in hepatocyte cardiolipin. This MOSAIC K99/R00 proposal will provide the training necessary (K99) tobuild a solid research foundation providing a pathway to independence as an independent researcher in the fieldof ALD and liver regeneration (R00). Findings from this study will identify a therapeutic strategy to treat AH viaenhanced liver regeneration which could replace the only long-term treatment alternative liver transplantation.

project_terms:
ATP Synthesis Pathway;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Animal Model;Animals;Apoptosis;Binding;Bioenergetics;Biogenesis;Biological Assay;Biological Markers;Cardiolipins;Cells;Cessation of life;Clinical;Clinical Trials;Culture Media;Data;Death Rate;Dextrins;Dose;Enzymes;Ethanol;Euthanasia;Evaluation;Experimental Animal Model;Foundations;Galactosamine;Genes;Genus Hippocampus;Hepatic;Hepatic Insufficiency;Hepatitis;Hepatocyte;Human;Immune;Impairment;In Vitro;Inflammation;Inflammatory Response;Injections;Injury;Lead;Lipids;Liver;Liver Mitochondria;Liver Regeneration;Liver diseases;LoxP-flanked allele;Maintenance;Maltose;Measurement;Mediating;Mitochondria;Mitochondrial Myopathies;Modeling;Mus;Natural regeneration;Oxidative Phosphorylation;Partial Hepatectomy;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase;Phospholipids;Plasma;Population;Prevention;Process;Prognosis;Proliferating;Proliferation Marker;Proteins;Regimen;Research;Research Personnel;Respiratory Chain;Rodent;Role;Safety;Sampling;Solid;Sorting;Structure;Supplementation;TNF gene;Tail;Testing;Therapeutic;Training;Translations;Treatment Efficacy;Veins;Vesicle;Viral;Viral Genome;alternative treatment;chronic liver disease;cytochrome c;cytokine;disorder control;feeding;hepatocyte injury;improved;in vitro Model;ineffective therapies;lipidomics;liver cell proliferation;liver function;liver transplantation;male;mitochondrial dysfunction;mitochondrial membrane;novel;oxidation;particle;patient prognosis;pharmacologic;pre-clinical;preclinical study;preservation;prevent;problem drinker;response;restoration;single-cell RNA sequencing;therapeutically effective;treatment arm;treatment strategy

public_health_relevance:
Project Narrative:This study will aim to exploit the livers ability to regenerate in order to reverse alcohol-induced liver damagecommon in alcoholic-associated liver disease (ALD) and alcohol-associated hepatitis (AH). Specifically the studywill determine whether preservation and/or supplementation of hepatic cardiolipin promotes liver regeneration inALD/AH via multiple models (animal in vitro and human samples). Findings from this pre-clinical study will leadto the evaluation of the safety dose tolerance and efficacy of cardiolipin lipid vesicles and elamipretide as atreatment strategy for ALD/AH in clinical trials.


application_id: 10900959
project_number: 1F31AG087618-01
project_title: Using the gut microbiome to treat disuse atrophy in aging.
administering_ic: NIA
award_notice_date: 2024-07-05
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: AG
serial_number: 087618
program_official: BOYCE, AMANDA T
project_start_date: 2024-12-01
project_end_date: 2027-11-30
study_section: Special Emphasis Panel[ZRG1 F10B-Q (20)]
contact_pi_person_id: 79109124
contact_pi: BURKE, BENJAMIN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe age-related loss of skeletal muscle mass and function has considerable effects on autonomy quality oflife and disease prognosis. These negative outcomes can be exacerbated by diseases or treatments thatinduce immobilization. Older adults are especially susceptible to immobilization-induced losses in muscle sizeand function experiencing larger decrements and impaired rehabilitation in these measures compared to theiryoung counterparts. Recent findings from our lab have shown how gut microbiome interventions can reducethe level of atrophy induced via immobilization supporting an emerging body of literature linking the gutmicrobiome to the regulation of muscle mass and function. However little research has sought to exploit thegut microbiome to maintain muscle mass during periods of immobilization in older adults a populationespecially susceptible to the negative health effects of disuse. The proposed project will explore the effectsof gut microbiome interventions on skeletal muscle size and function during immobilization andrecovery in aged mice. Our preliminary data suggest that the transfer of cecal contents from exercise-trainedmice to mice undergoing hindlimb immobilization is sufficient to attenuate muscle atrophy. Throughmetabolomic analyses we identified candidate metabolites potentially responsible for the positive effects of thegut microbiome on muscle atrophy. In subsequent experiments I found promising evidence that theadministration of these candidate metabolites reduces muscle atrophy during hindlimb immobilization.However these findings were in young mice and must be confirmed in aged mice. Based on our preliminaryfindings I hypothesize aged mice receiving cecal transfers from exercise-trained mice or candidatemetabolites will have reduced muscle atrophy preserved muscle function and enhanced recovery. Totest this hypothesis I will transfer the cecal contents from young exercise-trained or sedentary mice into agedmice during periods of immobilization and recovery (Aim 1). I will conduct another set of experiments in whichcandidate metabolites responsible for the retention of muscle mass will be administered to aged mice duringperiods of immobilization and recovery (Aim 2). Collectively these experiments will allow me to determine theeffectiveness of the gut microbiome in 1) attenuating muscle loss 2) preserving muscle function and 3)enhancing muscle recovery during/following immobilization. This proposed research not only elucidatesmechanisms whereby the gut microbiome regulates aging skeletal muscle but also has the potentialfor extensive clinical impact potentially implicating pharmaceutical targets relevant to treating muscleatrophy in an aged population. Through this award I will receive excellent training in immunohistochemistryfluorescent microscopy western blot analysis muscle function measurement microbiology massspectrometry and bioinformatics as well as oral and written communication skills.

project_terms:
Accidents;Affect;Age;Aging;Area;Atrophic;Attenuated;Award;Bioinformatics;Clinical;Communication;Data;Development;Discipline;Disease;Disuse Atrophy;Elderly;Exercise;Experimental Designs;Faculty;Fellowship;Flexor;Gait;Goals;Growth;Health;Hindlimb;Hindlimb Suspension;Hospitalization;Immobilization;Immunohistochemistry;Impairment;Injury;Limb structure;Link;Literature;Maintenance;Mass Spectrum Analysis;Measurement;Measures;Mentorship;Microbiology;Microscopy;Modeling;Mus;Muscle;Muscle function;Muscular Atrophy;Older Population;Oral;Outcome;Pathway interactions;Patients;Pharmacologic Substance;Population;Postdoctoral Fellow;Predisposition;Quality of life;Recovery;Regulation;Rehabilitation therapy;Research;Risk;Role;Skeletal Muscle;Succinates;System;Testing;Therapeutic Intervention;Training;Universities;Western Blotting;Work;Writing;age group;age related;aging population;attenuation;candidate identification;disease prognosis;drug candidate;effectiveness evaluation;exercise training;experience;experimental study;functional decline;gut microbiome;member;metabolomics;microbial;microbiome therapeutics;muscle form;muscle strength;novel therapeutics;old mice;older adult;preservation;prevent;protective effect;sedentary;skeletal muscle wasting;skeletal preservation;skills;tenure track

public_health_relevance:
PROJECT NARRATIVESkeletal muscle atrophy caused by inactivity/disuse affects young and old individuals alike; however the fullrecovery of muscle mass and function is compromised in the elderly. The purpose of this proposal is todetermine if substances made by the gut microbiome are able to prevent muscle atrophy during limbimmobilization and enhance the recovery of muscle size and strength after disuse.


application_id: 10900873
project_number: 1F32AR083259-01A1
administering_ic: NIAMS
award_notice_date: 2024-04-15
opportunity_number: PA-21-048
application_type: 1
activity_code: F32
ic: AR
serial_number: 083259
suffix: A1
program_official: BELKIN, ALEXEY
project_start_date: 2024-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1 F10B-Q (20)]
contact_pi_person_id: 11434627
contact_pi: ALLEN, ROBYN S.
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
A multispecies system for elucidating proliferative control mechanisms during mammalian skin and musculoskeletal regeneration

project_abstract:
Abstract While antifibrotic therapies continue to advance they fall short when treating large or chronic wounds.Essential to developing new regenerative strategies is a comprehensive understanding of how cell proliferationis activated maintained and eventually terminated to accurately restore missing tissue. The objective of thisproposal is to determine the cell autonomous mechanisms that permit and control proliferation during complextissue regeneration in highly regenerative mammals (spiny mice and rabbits). Spiny mice are unique amongrodents in their ability to regenerate complex skin and musculoskeletal tissues and as such they represent apromising model for pinpointing molecular and cellular mechanisms that prevent regeneration in humans.Fascinatingly primary dermal fibroblasts from spiny mice and rabbits maintain proliferation in the face of reactiveoxygen species gamma irradiation and contact inhibition. These same conditions induce senescence orquiescence in primary dermal fibroblasts from poorly regenerative mammals (lab mice and rats). This proposaluses cells from these species to identify how identical signals trigger regeneration in some species and scarringin others. Further this proposal utilizes spiny mouse ear pinna regeneration a highly reproducible and tractablemodel of mammalian skin and musculoskeletal regeneration to further explore pro-regenerative signals in vivo.In Aim 1 I will examine how stress signals are differentially transduced by cells to determine how fibroblastsfrom highly regenerative mammals maintain proliferation in senescence inducing conditions in vitro. I will thenuse spiny mouse ear pinna regeneration to determine how this differential stress transduction leads to activationand maintenance of regenerative response following injury in vivo. In Aim 2 I will identify the mechanisms thatpermit primary fibroblasts from spiny mice and rabbits to proliferate at very high cell densities in vitro. I will thenuse spiny mouse ear pinna regeneration to determine how these mechanisms regulate proliferation and tissuesize in vivo. I hypothesize that cells from highly regenerative mammals differentially activate signaling pathwaysthat facilitate cell cycle progression in response to stress and maintain this activity in excess of inhibitory signalsthat terminate proliferation in non-regenerative mammals. These studies will generate RNA-seq datasets andidentify candidate genes that will drive discovery in the field and form a basis for my own independent research.By studying proliferative control during regeneration we can build a blueprint for the recapitulation ofregeneration in human medicine.

project_terms:
Adult;Candidate Disease Gene;Cell Cycle;Cell Cycle Progression;Cell Cycle Proteins;Cell Cycle Regulation;Cell Density;Cell Proliferation;Cells;Cicatrix;Complex;Contact Inhibition;Data;Data Set;Defect;Dependovirus;Dermal;Ear;Equilibrium;Exposure to;Fibroblasts;Fibrosis;Gene Activation;Gene Expression;Genes;Gerbils;Growth;Healthcare Industry;Human;In Vitro;Injury;Lentivirus;Long term disability;Maintenance;Mammals;Medicine;Modeling;Molecular;Mus;Musculoskeletal;Natural regeneration;Oryctolagus cuniculus;Outcome;Oxidative Stress;Pathway interactions;Phenotype;Physiological;Process;Proliferating;Proteins;Psychological Stress;Rattus;Reactive Oxygen Species;Regenerative Medicine;Regenerative response;Regulation;Reproducibility;Research;Resistance;Resolution;Rodent;Role;Screening procedure;Signal Pathway;Signal Transduction;Skin;Stress;System;Testing;Tissues;Work;antifibrotic treatment;candidate identification;cellular transduction;chronic wound;density;experimental study;external ear auricle;fascinate;gamma irradiation;high throughput screening;in vitro Assay;in vivo;innovation;insight;knock-down;model building;non-healing wounds;novel;novel strategies;organ injury;organ repair;prevent;programs;regenerative;regenerative approach;regenerative therapy;repaired;response;response to injury;screening;senescence;sensor;skills;skin regeneration;skin wound;small hairpin RNA;targeted treatment;tissue regeneration;tool;transcriptome sequencing

public_health_relevance:
Project NarrativeSkin and musculoskeletal regenerative therapies for large and chronic wounds are limited by an incompleteunderstanding of proliferative regulation. This proposal investigates how highly regenerative mammals activateand maintain cell proliferation in the face of inhibitory conditions to drive regeneration. This work will generatenovel targets for regenerative therapies and high throughput screening tools for evaluating phenotypesassociated with regenerative ability.


application_id: 10900020
project_number: 1F31HL170558-01A1
project_title: The myosin super-relaxed state and human dilated cardiomyopathy
administering_ic: NHLBI
award_notice_date: 2024-03-01
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: HL
serial_number: 170558
suffix: A1
program_official: CHEON, YEWON
project_start_date: 2024-04-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1 F10A-K (20)]
contact_pi_person_id: 78299799
contact_pi: WELLETTE-HUNSUCKER, AUSTIN
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 Dilated cardiomyopathies are a frequent cause of heart failure worldwide characterized by reducedsystolic function and left ventricular dilation. Dilated cardiomyopathy has been linked to various causes includingviral infections drug abuse endocrine dysfunction and genetic mutations. Reduced effective myocardialcontractility presents as a symptom early in disease progression of dilated cardiomyopathy. Studying themolecular basis of decreased contractility by investigating the myosin motors that power contractions can provideimportant insight and allow testing of potential therapeutic modulation. Current therapeutics for dilatedcardiomyopathy (e.g. ACE inhibitors -blockers etc.) target symptoms but do not attenuate the underlyingsource of contractile dysfunction. At the molecular level force generation in cardiac muscle is determined by thenumber of myosin motors that bind to the actin thin-filament during the systolic rise of calcium. Once myosinmotors bind myosins hydrolyze ATP and undergo conformational steps to generate force. Recent attention hasfocused on the myosin biochemical super-relaxed state an energy-conserving auto-inhibited state of cardiacmyosin that determines the proportion of myosin motors available. Thus the amount of myosin motors in thesuper-relaxed state modulates the magnitude of myosin motors available to generate sarcomere power uponactivation. The stability of the super-relaxed state can be modulated by phosphorylation of regulatory light chainand myosin binding protein C. Additionally as force increases stress on the thick filament rises resulting in therelease of myosin heads allowing greater force production. A decrease in available myosin motors as a resultof a shift towards the super-relaxed state is a potential mechanism of systolic dysfunction in human dilatedcardiomyopathy and has yet to be fully investigated. Therefore our central hypothesis is that depressedcontractile force in dilated cardiomyopathy results from increased myosins in the super-relaxed state (Aim 1)mediated by depressed regulatory protein phosphorylation (Aim 2) which may be able to be reversed with theuse of myosin activators (Aim 3). To test our hypothesis we will utilize the fluorescent ATP pulse-chasetechnique to quantify the proportion of myosins in the super-relaxed state and test the effects of myosin activatorsat short and long sarcomere lengths. Also using Phos-TagTM western blotting we will measure thephosphorylation status of regulatory proteins. This proposal will provide novel insight into the effects of myosinactivators on the super-relaxed state demonstrate fundamental aspects of myosin biochemical states and theirrole in the molecular basis of human dilated cardiomyopathy.

project_terms:
Actins;Adrenergic Agents;Adrenergic beta-Antagonists;Angiotensin-Converting Enzyme Inhibitors;Attention;Binding;Biochemical;Biochemistry;Biological Assay;Calcium;Cardiac;Cardiac Myosins;Control Groups;Coupled;DNA Sequence Alteration;Depressed mood;Dilated Cardiomyopathy;Disease;Disease Progression;Doctor of Philosophy;Drug abuse;Endocrine;Enzymes;Equilibrium;Event;Exhibits;Functional disorder;Generations;Goals;Heart;Heart failure;Human;Investigation;Ischemia;Left;Length;Link;Measures;Mediating;Molecular;Molecular Conformation;Motor;Myocardial;Myocardium;Myosin ATPase;Myosin Regulatory Light Chains;NADH;Patients;Permeability;Phosphorylation;Physiologic pulse;Prevalence;Principal Investigator;Production;Protein Dephosphorylation;Proteins;Pump;Regulation;Relaxation;Role;Sampling;Sarcomeres;Signal Transduction;Signaling Protein;Source;Stress;Sturnus vulgaris;Symptoms;Techniques;Testing;Therapeutic;Thick Filament;Thin Filament;Training;Translational Research;Transplantation;Ventricular;Virus Diseases;Western Blotting;Work;canine model;experimental study;gel electrophoresis;genetic regulatory protein;insight;meter;myosin-binding protein C;novel;prevent

public_health_relevance:
Project NarrativeDilated cardiomyopathy is a common cause of heart failure that is associated with reduced cardiac contractility.This project tests the hypothesis that the contractile dysfunction results from the myosin motors being shiftedtowards a super-relaxed state where they cannot contribute to force-generation.


application_id: 10899959
project_number: 1P50MD019476-01
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2024-07-13
opportunity_number: RFA-MD-23-011
application_type: 1
activity_code: P50
ic: MD
serial_number: 019476
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: Special Emphasis Panel[ZMD1 ML (J1)]
subproject_number: 5091
contact_pi_person_id: 10552456
contact_pi: WILLIAMS, LOVORIA B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY COMMUNITY ENGAGEMENT AND DEVELOPMENT CORE (CEDC)The Community Engagement and Dissemination Core of University of Kentucky (UK) ASCEND (AchievingSuccess in Community-Engaged research to elimiNate Disparities) provides a critical and integral componentof UK ASCENDs objective to advance health equity by promoting community-engaged research (CER)success among early-stage investigators (ESIs) from diverse backgrounds through the ASCEND ScholarsProgram (ASP) a novel and comprehensive CER Training Program followed by a rigorous CER Pilot Program;and bi-directional engagement with community stakeholders through a Community Advisory Board (CAB).Fostering such research success through community engagement is critical everywhere and particularly inKentucky recently ranked as #50 in national health standing with the nations highest cancer mortality andamong the highest rates of other diseases that commonly affect health disparities populations. The mission ofthe CEDC is to ensure that these ESIs ASCEND Scholars form and sustain productive researchcollaborations and engage in impactful dissemination activities with diverse community stakeholders. TheCEDC is led by experienced NIH-funded community-engaged health equity researchers and supported bystrong and enduring community and institutional partnerships. The CEDC has the following aims: (1) Cultivatebidirectional interactions between ESIs and community stakeholders to stimulate research collaborations andparticipatory planning processes and (2) Disseminate research findings to a broad range of audiences toensure translation of research results into sustainable community-level and system-level changes that advancehealth equity. These aims will be achieved by leveraging existing and developing new institution-wideresources coordinating interactions with a CAB to facilitate equitable and sustainable relationships withcommunity stakeholders and collaborating with the other UK ASCEND Cores. The CEDC will achieve bi-directional interaction between ESIs and community stakeholders by managing a central Resource Catalogthat supports CER infrastructure developing a Research Dissemination Toolkit and Individualized CER Plansand hosting an annual community-researcher summit. The dissemination and translation aim will be achievedby the provision and exchange of evidence-based health information and ESI research findings through UKsCommunity Health Worker Program and the creation of a Sustainability Planning Guide. The CEDC constitutesa critical resource interwoven throughout UK ASCEND. Such bi-directional collaboration enhances thelikelihood of achieving UK ASCENDs outcomes ESI CER career development community engagement andESI research success. The CEDC will promote the integration and authentic engagement of communityperspectives into ESIs CER training and pilot projects critical to overcoming significant health disparities andadvancing health equity.

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


application_id: 10899958
project_number: 1P50MD019476-01
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2024-07-13
opportunity_number: RFA-MD-23-011
application_type: 1
activity_code: P50
ic: MD
serial_number: 019476
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: Special Emphasis Panel[ZMD1 ML (J1)]
subproject_number: 5090
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY- INVESTIGATOR DEVELOPMENT COREThe Investigator Development Core (IDC) of UK ASCEND proudly proposes the ASCEND Scholar Program(ASP) comprised of two transformative and linked opportunities to advance health equity by promotingcommunity-engaged research (CER) success among ESIs from diverse backgrounds. The ASP strategy wasinfluenced by two national evidence-based programs UK institutional data and a career development modelimplemented in three UK ESI cohorts. Sixteen ESIs over four cohorts will be selected to become ASCENDScholars and engage in a three-component CER Training Program followed by an opportunity to deploy theirskills through the CER Pilot Program. The CER Training Program includes multilevel mentorship scientific andsocial networking and professional enrichment followed by the CER Pilot Program. UK ASCENDs CER PilotProgram will provide the preliminary studies necessary for highly competitive NIH grant applications. To ensurea pathway for continued inclusive research excellence we also will offer CER Pilot Projects to eightpostdoctoral fellows in the first and fifth years of the award. Throughout the ASP and in conjunction with theCommunity Engagement and Dissemination Core ESIs will authentically interact with community stakeholdersto successfully undertake research that appropriately and impactfully addresses health disparities. The IDChas the following aims: (1) Embed diverse health equity research-focused ESIs into the three-component CERtraining program and (2) Implement a rigorous CER pilot project program that leads to collaborative andsustainable interactions with community stakeholders and the successful dissemination of scholarly productsincluding publications presentations and grant submissions leading to research success. The IDC benefitsfrom strong leadership provided by Dr. Kevin Pearson a senior-level NIH-funded translational researcher whocurrently serves as Assistant Dean for Inclusive Research in the UK College of Medicine Career DevelopmentLeader for an NIH-funded environmental health center and Director of the UK COBRE pilot program and Dr.Shyanika Rose an early-mid career community-engaged health equity researcher who serves as a near-peermentor chairs the Research Committee for the Center for Health Equity Transformation (CHET) and leadsCHETs Health Equity Grant Programs. Our diverse experienced and complementary leadershipteam will work to promote excellence in community-engaged health equity research through mentorshipnetworking and professional enrichment followed by a CER pilot project that will serve as preliminary studiesfor publications presentations and subsequent NIH grant submissions. Our long-term objective is to increasethe critical mass of early-stage investigators from diverse backgrounds exceptionally capable of undertakingtransformative CER that achieves health equity.

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


application_id: 10899957
project_number: 1P50MD019476-01
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2024-07-13
opportunity_number: RFA-MD-23-011
application_type: 1
activity_code: P50
ic: MD
serial_number: 019476
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: Special Emphasis Panel[ZMD1 ML (J1)]
subproject_number: 5089
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY ADMINISTRATIVE COREThe Administrative Core of University of Kentucky (UK) ASCEND (Achieving Success in Community-Engagedresearch to elimiNate Disparities) provides strategic leadership for program oversight management andevaluation of the proposed activities. The Core also provides governance cross-core collaboration andcommunication fiscal management and institutional coordination to achieve our objective of advancing healthequity by promoting community-engaged research (CER) success among ESIs from diverse backgroundsthrough the ASCEND Scholars Program (ASP) which consist of two transformative and linked opportunities:(1) the CER Training Program and (2) the CER Pilot Program with bi-directional engagement with communitystakeholders through a Community Advisory Board (CAB). Motivated by the disproportionate health disparitiesexperienced by underserved rural (particularly Appalachian) Black Hispanic and socioeconomicallydisadvantaged populations living in Kentucky - a state ranked among the worst in overall health- the UKASCEND Administrative Core will provide the scientific and strategic direction for our proposed NIMHD Centerof Excellence. This Core is led by two Co-Directors who are also multiple principal investigators who havesuccessfully collaborated on grant applications leadership initiatives and a recent health equity cluster hires ofunderrepresented minority ESIs. Housed in the Center for Health Equity Transformation (CHET) and incollaboration with the UK Center for Clinical and Translational Research (CCTS) and other institutionalstrengths we will embed diverse ESIs within the rich research environments of institutionally-designatedResearch Priority Areas (RPAs). These RPAs address the most significant health disparities (cancerneurological disorders substance use disorders cardiovascular disease diabetes/obesity) with a sixth RPAaddressing diversity and inclusion. The Administrative Core aims to: (1) Provide scientific leadership andgovernance fiscal and regulatory management effective communication strategies and cross-sectorcollaboration for all programmatic activities consistent with NIH protocols and equitable and sustainablecommunity partnerships and (2) Continuously examine UK ASCEND's performance and progress through thesystematic deployment of formative and summative evaluation approaches using optimal measures evaluationscience standards and community engagement principles. Our three primary outcomes include: ESI CERcareer development community engagement and ESI research success. The Administrative Core will serveas the nexus for all UK ASCEND communication meetings financial management regulatory activitiesinteractions with the NIH and evaluation activities ever mindful of our key objective-- to advance health equityby attaining success in community-engaged health equity research among diverse early-stage investigators.

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


application_id: 10899956
project_number: 1P50MD019476-01
project_title: UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities)
administering_ic: NIMHD
award_notice_date: 2024-07-13
opportunity_number: RFA-MD-23-011
application_type: 1
activity_code: P50
ic: MD
serial_number: 019476
program_official: STINSON, NATHANIEL
project_start_date: 2024-07-13
project_end_date: 2029-01-31
study_section: Special Emphasis Panel[ZMD1 ML (J1)]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: CONWELL, DARWIN LEWIS;WILLIAMS, LOVORIA B
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY OVERALLThe University of Kentucky (UK) will establish Achieving Success in Community-Engaged research to elimiNateDisparities (UK ASCEND) driven by one overarching objective--advancing health equity by promotingcommunity-engaged research (CER) success among ESIs from diverse backgrounds. We propose thecomprehensive ASCEND Scholars Program (ASP) a CER Training Program followed by a robust CER PilotProgram infused with bi-directional engagement with community stakeholders. Compelled to overcome theextreme health disparities experienced by Kentuckys rural (particularly Appalachian) Black Hispanic andsocioeconomically disadvantaged populations the proposed Center of Excellence in Investigator Development andCommunity Engagement is led by multiple principal investigators with complementary expertise and experiencescaffolded by a well-resourced and committed university structure and leadership and centered within longstandingcommunity partnerships. Housed in UKs preeminent health equity research and training center the Center forHealth Equity Transformation (CHET) UK ASCEND proposes the following aims: (1): Coordinate bold andeffective scientific leadership and governance fiscal and regulatory management communication anddissemination strategies and evaluation to assess key outcomes on CER training and success (AdministrativeCore). (2): Cultivate community-engaged health equity research success among diverse early stage investigators(ESIs) by immersing them into a productive research career advancement program the ASCEND ScholarsProgram consisting of a three-component CER Training Program followed by an opportunity to deploy those skillsthrough a CER Pilot Program within an environment of strong community partnerships and institutional strengths(Investigator Development Core); (3): Catalyze and sustain long-standing bidirectional community stakeholder-ESIresearch partnerships and translate findings into sustainable community and system-level changes that advancehealth equity (Community Engagement and Dissemination Core). We will focus on three outcomes: ESI CERcareer development community engagement and ESI research success. Informed by the NIMHD ResearchFramework and the Institutional Model for Faculty Diversity Framework UK ASCEND takes a comprehensiveorientation to mitigating health disparities by fostering authentic exchanges among community stakeholdersresearchers providers and policymakers. UK ASCEND has the motivation vision and capacity to contribute toremediating the nations worst health disparities by providing comprehensive rigorous and inclusive CER trainingessential for impactful scientific discovery.

project_terms:
Address;Appalachian Region;Area;Black race;Cardiovascular Diseases;Career Mobility;Communication;Communities;Development;Diabetes Mellitus;Disadvantaged;Economically Deprived Population;Environment;Evaluation;Faculty;Fostering;Grant;Health equity research;Hispanic;Institution;Intervention;Kentucky;Leadership;Malignant Neoplasms;Mission;Modeling;Motivation;National Institute on Minority Health and Health Disparities;Nervous System Disorder;Obesity;Outcome;Policy Maker;Positioning Attribute;Principal Investigator;Productivity;Provider;Reduce health disparities;Research;Research Personnel;Research Priority;Research Training;Resources;Rural;Scholars Program;Science;Scientist;Specialized Center;Structure;Substance Use Disorder;System;Talents;Training;Training Programs;Translating;Translational Research;Universities;Vision;career development;clinical center;collaborative environment;community advisory board;community engaged research;community engagement;community partnership;community setting;design;disparity elimination;dissemination strategy;diversity and inclusion;experience;health disparity;health equity;health equity promotion;health inequalities;innovation;pilot test;programs;remediation;scaffold;skill acquisition;skills;socioeconomic disadvantage;success

public_health_relevance:
PROJECT NARRATIVEDriven to overcome the extreme health disparities experienced by Kentuckys rural (particularly Appalachian)Black Hispanic and socioeconomically disadvantaged populations the University of Kentucky (UK) proudlyproposes UK ASCEND (Achieving Success in Community-Engaged research to elimiNate Disparities). UKASCEND will cultivate health equity and community-engaged research (CER) success among early stageinvestigators (ESIs) from diverse backgrounds by implementing and evaluating the innovative ASCENDScholars Program (ASP). Housed in the Center for Health Equity Transformation and leveraging UKs rich andcollaborative community partnerships and institutional strengths the ASPs strategically designedcomprehensive CER Training Program leads directly into a CER Pilot Program that will provide the skillsdevelopment bi-directional engagement with community stakeholders and preliminary studies needed tofoster research independence and advance health equity.


application_id: 10899797
project_number: 3R01DA046526-05S1
project_title: Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
administering_ic: NIDA
award_notice_date: 2023-08-10
opportunity_number: PA-18-060
application_type: 3
activity_code: R01
ic: DA
serial_number: 046526
suffix: S1
program_official: NAIR, SUNILA GOPI
project_start_date: 2020-09-01
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a significant burden to public health. Nicotine an active alkaloid intobacco is responsible for addiction to tobacco-containing products such as cigars cigarettes and vaporizedliquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surgein popularity of nicotine-containing e-cigarettes there is a great need for innovative research on theneurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brainregions associated with drug reward especially within the nucleus accumbens core (NAcore). NAcoreglutamatergic mechanisms are involved in nicotine relapse including rapid transient potentiation of synapticstrength (t-SP; measured as increased AMPA to NMDA ratios) and accompanying glutamate receptor changes.Due to the cue dependency of smoking behavior exposure to nicotine-associated cues is a risk factor for relapse.We and others recently found that N-acetylcysteine (NAC) an antioxidant and anti-inflammatory currently underinvestigation as an addiction therapeutic appears to inhibit nicotine cue-associated t-SP and restore glialglutamate transport (GLT-1). As well preliminary data collected during an R00 award period indicate that NAcoreGLT-1 restoration is necessary for NAC to reduce nicotine seeking and NAC inhibits expression of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) within the NAcore. TNF activates nuclear factor-kappa B (NF-B) signaling and regulates learning memory and synaptic plasticity. Thus in Aim 1 we proposeto characterize the role of NF-B signaling in nicotine self-administration and cued nicotine seeking. As well thisaim will determine if TNF signaling impacts t-SP during cued nicotine relapse and if a monoclonal antibodyagainst TNF can inhibit these aberrant processes. Importantly TNF monoclonal antibodies are used clinicallyfor autoimmune disorders and are known to inhibit TNF from binding to its receptor. Aim 2 will then determinethe role of microglia in t-SP and nicotine seeking using chemogenetics. Interestingly we have found that GLT-1expression rapidly increases along with t-SP during cued nicotine seeking. It is unclear however if this isregulated by neuroinflammation and accompanied by astrocyte and microglial migration to the synapse duringnicotine seeking. Therefore in Aim 3 we propose to bi-directionally control microglia using chemogenetics todetermine their ability to gate NAcore astrocyte-synaptic contact during nicotine seeking. In conclusion findingsfrom these investigations will uncover an active dynamic role of neuroinflammatory signaling in nicotine self-administration and cue-driven nicotine relapse-associated synaptic plasticity and broaden the scope of ourcurrent understanding of neurobiological mechanisms underlying nicotine addiction.

project_terms:
Abstinence;Acetylcysteine;Alkaloids;Anti-Inflammatory Agents;Antioxidants;Astrocytes;Attenuated;Autoimmune Diseases;Award;Binding;Blood brain barrier dysfunction;Brain;Brain region;Cause of Death;Cells;Chemosensitization;Chronic;Cigar;Cigarette;Clinical;Cocaine;Complex;Cues;Data;Development;Electronic cigarette;Electrophysiology (science);FDA approved;Gene Transfer;Genetic;Glean;Glutamate Receptor;Glutamate Transporter;Glutamates;Health;Immunohistochemistry;Individual;Inflammatory;Intervention;Investigation;Knowledge;Label;Learning;Measures;Mediating;Membrane;Memory;Microglia;Monoclonal Antibodies;Morphology;N-Methylaspartate;Neurobiology;Neuroimmunomodulation;Neurons;Nicotine;Nicotine Dependence;Nicotine Withdrawal;Nuclear;Nucleus Accumbens;Outcome;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Phosphotransferases;Pre-Clinical Model;Process;Public Health;Relapse;Research;Rewards;Rheumatoid Arthritis;Risk Factors;Role;Signal Induction;Signal Transduction;Smoker;Smoking;Smoking Behavior;Synapses;Synaptic plasticity;TNF gene;Techniques;Testing;Therapeutic;Time;Tobacco;Tobacco use;Viral;Visualization;Western Blotting;Withdrawal;addiction;cell motility;craving;cytokine;designer receptors exclusively activated by designer drugs;drug abstinence;drug reward;electronic liquid;glutamatergic signaling;innovation;insight;migration;neurobiological mechanism;neuroinflammation;neuronal circuitry;neuroprotection;nicotine abuse;nicotine cue;nicotine exposure;nicotine seeking behavior;nicotine self-administration;nicotine use;novel;novel strategies;novel therapeutics;prevent;receptor;response;restoration;selective expression;small molecule;smoking abstinence;smoking addiction;smoking cessation;tool;vaping

public_health_relevance:
PROJECT NARRATIVENicotine addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability evenafter extended drug abstinence. The proposed research has the potential to reveal novel neuroimmunologicalmechanisms of nicotine addiction which could contribute to the development of novel therapeutic options aimedat reversing nicotine-induced alterations in the brain and promoting nicotine use cessation.


application_id: 10897994
project_number: 5K12DA035150-13
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2024-08-07
opportunity_number: RFA-OD-21-006
application_type: 5
activity_code: K12
ic: DA
serial_number: 035150
program_official: FALCON-MORALES, EDGARDO
project_start_date: 2022-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1-PSE-W(50)]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentuckys (UK) BIRCWH program is built around three pillars: mentoringinterdisciplinary research and career development. Given the significant health challenges inKentucky we focus on three areas of important health disparity for Appalachian Kentuckians: 1)substance use 2) violence against women and 3) lifespan changes in health with aging. UKBIRCWH objectives are: 1) to provide the environment mentorship and facilities to enhancethe ability of BIRCWH scholars to compete for NIH research grants in diverse areas of womenshealth research 2) to deepen our understanding of the unique role of sex and gender in themanifestation of health and disease 3) to develop and implement new communication andsocial networking technologies to address sex and gender differences and improve womenshealth 4) to personalize prevention diagnostics and therapeutics to address health disparities5) to stimulate new collaborations in focused interdisciplinary and interactive research areasthat are essential for uncovering sex and gender differences and improving womens health; and6) to use a thematic multidisciplinary focus as a platform for enhancing translational researchbetween basic clinical and public health scientists. Our formal framework for growing the nextgeneration of womens health and sex differences researchers includes a mentoring team foreach Scholar composed of: 1) experienced faculty members (Mentors) and 2) a former BIRCWHscholar (Coach). This mentoring team will collectively provide in-depth research experiencesand didactic training to assistant professor tenure-track faculty. Career development will alsoinclude mechanisms for accountability for manuscript submissions workshops on grantdevelopment and aspects of academic development such as personnel management negotiationskills self-care and promotion. UK BIRCWH Scholar appointments will be 2 years for PhD and3 years for MD scholars. Based on our prior experience we anticipate training 8 scholars over 5years of funding. Outcomes: Since 2000 40 Scholars have completed BIRCWH training (17MDs 23 PhDs) who have produced 1712 peer-reviewed publications secured $41636782 inNIH funding as PI and $239982415 as Co-I or PI from other external sources. UK has retained57% of our BIRCWH graduates who continue active research programs and support BIRCWHas Coaches and Mentors. Given this success why should UKs BIRCWH funding continue?Succinctly Kentuckys need continues. Our rates of substance use violence and chronic disease(3 foci) are among this nations highest. With BIRCWH funding we can support those who willaddress the health inequities Kentuckians and others across the nation still face.

project_terms:
Accountability;Address;Aging;Appalachian Region;Appointment;Area;Chronic Disease;Clinical;Collaborations;Communication;Development;Diagnostic;Disease;Doctor of Philosophy;Educational workshop;Environment;Face;Faculty;Funding;Gender;Grant;Health;Interdisciplinary Study;Kentucky;Manuscripts;Mediation;Mentors;Mentorship;Outcome;Peer Review;Personnel Management;Public Health;Publications;Research;Research Personnel;Research Project Grants;Role;Scientist;Secure;Self Care;Sex Differences;Social Network;Source;Technology;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;Violence;Women's Health;career development;experience;gender difference;health difference;health disparity;health inequalities;improved;individualized prevention;life span;member;multidisciplinary;next generation;professor;programs;research and development;sex;skills;substance use;success;tenure track;violence against women

public_health_relevance:
NARRATIVE:Finding and addressing sex and gender differences in effective health care research and treatment are criticalactions toward the goal of improving the health and wellbeing of all Americans. To achieve this goal the UKBIRCWH seeks to continue training and supporting our next generation of academic researchers to recognizesex and gender differences in conditions that disproportionately affect Kentuckians. In this training andmentoring program for emerging researchers we focus on 3 health concerns that disproportionately affectAppalachian Kentuckians: Substance use violence against women and lifespan changes.


application_id: 10897799
project_number: 5U18FD007318-04
administering_ic: FDA
award_notice_date: 2024-07-31
opportunity_number: PAR-20-132
application_type: 5
activity_code: U18
ic: FD
serial_number: 007318
program_official: BHATTACHARYYA, SOMA
project_start_date: 2021-07-01
project_end_date: 2025-09-30
study_section: ZFD1-SRC(99)
contact_pi_person_id: 14147267
contact_pi: HARRISON, GLEN ALAN
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-07-01
project_title:
The University of Kentucky Division of Regulatory Services (UKDRS) continued development of a risk-based Animal Feed Inspection Program

project_abstract:
Project SummaryThe University of Kentucky Division of Regulatory Services (UKDRS) achieved fullimplementation and conformance to the Animal Feed Regulatory Program Standards(AFRPS) in August of 2019. Moving forward UKDRS requests continued fundingsupport to continue full conformance with the AFRPS to maintain an integrated animalfeed safety system and to advance the cooperative agreement with FDA. It is the goalof the UKDRS to be an effective component of an integrated animal feed safety systemwithin the United States. Multiple activities will be supported through this projectincluding continued funding for our AFRPS Coordinator training travel feed samplingactivity conducting complaint investigations and conducting animal feed manufacturerinspections.

public_health_relevance:
Project Narrative:The University of Kentucky Division of Regulatory Services (UKDRS) achieved fullimplementation and conformance to the Animal Feed Regulatory Program Standards(AFRPS) in August of 2019. Moving forward UKDRS requests continued fundingsupport to continue full conformance with the AFRPS to maintain an integrated animalfeed safety system and to advance the cooperative agreement with FDA. It is the goalof the UKDRS to be an effective component of an integrated animal feed safety systemwithin the United States. Multiple activities will be supported through this projectincluding continued funding for our AFRPS Coordinator training travel feed samplingactivity conducting complaint investigations and conducting animal feed manufacturerinspections.


application_id: 10897081
project_number: 5P01AG078116-03
project_title: Project 4 - Astrocytic KATP channels in LATE+HS
administering_ic: NIA
award_notice_date: 2024-06-26
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7475
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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 4 SUMMARY/ABSTRACTAn astrocyte mechanism will be targeted with the goal of preventing a common subtype of dementia. Limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (HS) pathology arepresent at autopsy in approximately 25% of Alzheimers-type dementia cases. Notably a specific ABCC9gene variant is associated with increased risk of developing LATE+HS. ABCC9 encodes a protein that servesas a metabolic sensor linking brain hypoxia and stress to changes in intracellular calcium and blood flow.We hypothesize that dysregulation of ABCC9 in astrocytes causes or exacerbates LATE+HS via impairedcerebrovascular function hypometabolism (with ionic dyshomeostasis) and neuronal hyperexcitabilityaligning perfectly with themes of this P01. These astrocyte mechanisms can be targeted by a well-tolerateddrug (nicorandil) that has been shown to be clinically safe and effective with high potential public healthimpact. The research will be conducted with the following Specific Aims: Aim 1: Characterize ABCC9/SUR2transcripts and proteins in human astrocytes. We will test the hypothesis that the ABCC9 genetic variantassociated with LATE+HS risk is also associated with decreased ABCC9 expression in astrocytes. AstrocyteABCC9 transcripts are mostly unknown. In human samples we will evaluate the repertoire of mRNAtranscripts and splicing in astrocytes. We will characterize ABCC9 gene expression with RNA-Seq dataacross cell types. In genotyped human brains from Core C (LATE+HS and controls) we will evaluate ABCC9proteins immunohistochemically and we will explore Sur2 expression in mouse models. Aim 2: Test thehypothesis that modulation of astrocytic ABCC9//KATP leads to improved neurovascular and metabolicfunction in LATE+HS model mice. The novel (TetR-TDP) mouse an excellent animal model that has provenhippocampal cell loss astrocytosis TDP-43 proteinopathy and memory impairment will be used to test theimpact of astrocyte specific ABCC9 upregulation on neurovascular function (multiphoton to look atneurovascular coupling and vessel leakiness; MRI to look at cerebral blood flow and other endpoints). Theimpact of astrocyte specific upregulation of SUR2B on brain metabolism will also be tested (glutamate uptakein astrocytes; Ca2+ dynamics [GCaMP]; and MRS to characterize brain metabolites). Aim 3: Test thehypothesis that pharmacological modulation with nicorandil (a KATP channel agonist well-tolerated in oralpreparations) leads to improved neuronal and astrocyte function and neurobehavioral assessment outcomesin TetR-TDP mice. These outcomes will include readouts of neurobehavioral parameters (RAWM and Y-maze) and other endpoints including electrophysiological assessments in astrocytes. Follow-up assessmentswill include detailed neuropathology (astrocytosis HS TDP-43 proteinopathy and small vessel morphology).In summary while studying the mechanisms of astrocyte metabolic and neurovascular pathophysiology inLATE+HS we hope to test a novel therapeutic strategy.

project_terms:
Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Animal Model;Animals;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Binding;Blood Vessels;Blood flow;Brain;Brain Hypoxia;CRSP3 gene;Calcium;Cerebrovascular Circulation;Cerebrum;Clinical;Collaborations;Data;Dementia;Disease;Dose;EEF1A2 gene;Elderly;Electrophysiology (science);Evaluation;Functional disorder;Gene Expression;Genes;Genetic Variation;Genotype;Glutamates;Goals;Human;Image;Immunohistochemistry;Impairment;Ischemic Preconditioning;Knowledge;Link;Magnetic Resonance Imaging;Measures;Memory impairment;Messenger RNA;Metabolic;Methods;Microscopy;Modeling;Morphology;Mus;Nerve Degeneration;Neurons;Nicorandil;Oral;Outcome;Outcome Assessment;Pathologic;Pathology;Persons;Pharmaceutical Preparations;Physiology;Play;Potassium Channel;Preparation;Proteins;Public Health;RNA Splicing;Reporting;Research;Resources;Risk;Role;Sampling;Signal Transduction;Slice;Stress;Testing;Transcript;Up-Regulation;Western Blotting;biological adaptation to stress;brain metabolism;cell type;cerebrovascular;data management;disorder control;drinking water;follow up assessment;genetic variant;gliovascular;hippocampal cell loss;hippocampal sclerosis;improved;in vivo;limbic-predominant age-related TDP-43 encephalopathy;member;mouse model;multi-photon;multidisciplinary;neurobehavioral;neurobehavioral test;neuropathology;neurovascular;neurovascular coupling;novel;novel therapeutic intervention;pharmacologic;prevent;protein TDP-43;sensor;single-cell RNA sequencing;skills;sulfonylurea receptor;transcriptome sequencing;two-photon;uptake


application_id: 10897080
project_number: 5P01AG078116-03
project_title: Project 3 - Astrocytic glutamate dysregulation in AD and VCID
administering_ic: NIA
award_notice_date: 2024-06-26
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7473
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT 3  ABSTRACT SUMMARYIn alignment with the overall P01Strategies for targeting Astrocyte Reactivity in AD and ADRD Project 3 willtarget the astrocyte glutamate transporter EAAT2/Glt-1 (gene name SLC1A2) and assess the impact oncerebrovascular function metabolism and neural network activity in Alzheimers disease (AD) and relateddementias (ADRD). We and other groups have shown that SLC1A2 levels are reduced in AD and ADRD achange that is recapitulated in many AD and ADRD mouse models. SLC1A2 is well known to guard againstexcitotoxic damage to synapses by minimizing synaptic glutamate spillover. This mechanism has been studiedin many different disease models. However much less is known about whether SLC1A2 similarly preventsglutamate from adversely affecting astrocyte endfeet and cerebrovessels which are widely known to undergodysfunction in AD and ADRD. SLC1A2 is also well known to drive the production of lactate a key componentof the astrocyte-neuron lactate shuttle. Nonetheless few studies have investigated the possibility that loss ofSLC1A2 in reactive astrocytes impairs lactate shuttling leading to hypometabolism (another well-characterizedpathology in AD and ADRD). We hypothesize that the loss of SLC1A2 is a key loss of function phenotypeof reactive astrocytes that underlies impaired cerebro-vascular function/integrity hypometabolism and disruptedneural network activity in AD and ADRD. We will test this hypothesis across three Aims using two astrocyte-targeting approaches: a restoration approach where we use AAV-Gfa2 to overexpress SLC1A2 in astrocytesof a comorbid A/vascular model (5xFAD mice with hyperhomocystenemia) and a knockdown approach wherewe will use AAV-GfaP-Cre to knock-down astrocytic SLC1A2 in FLOX-SLC1A2 mice. Aim 1 will determine theimpact of SLC1A2 modulation on astrocyte Ca2+ signaling endfeet and BBB integrity cerebral blood flow andneurovascular coupling using two photon (2P) imaging in awake mice and MRI (in anesthetized mice). Aim 2will determine the impact of SLC1A2 modulation on lactate and glucose signaling in awake mice usingmicroelectrode arrays. And Aim 3 will test the effects of SLC1A2 modulation on neuronal network fidelity andsynaptic function and plasticity using either 2P imaging of awake mice or electrophysiology on in situ brain slices.Points of interaction: All functional outcomes are assessed in our Animal Vascular-Metabolic-Neural Networkcore (Core B). Interrelationships between different astrocyte pathways (MMP9 modulation /Project 1 Insulinreceptor modulation/Project 2 and KATP modulation/Project 4) will be assessed as a function of AD and ADRDcomorbidities through the shared use of postmortem tissue across projects (cerebrovascular pathology/Project1 amyloid pathology/Project 2 amyloid+vascular pathology/Project 3 LATE + hippocampal sclerosispathology/Project 4). Similar interrelationships will be assessed across comorbidities in shared postmortemhuman biospecimens (Core C Human Consultation-Biosamples-Biomarkers). All data will flow into our DataManagement and Biostatistics Core (Core D) for analysis of endpoint measures both within and across projects.

project_terms:
Address;Affect;Alzheimer's Disease;Alzheimer's disease related dementia;Amyloid;Amyloid beta-Protein;Anesthesia procedures;Animals;Astrocytes;Attention;Autopsy;Biochemical;Biological Markers;Biostatistics Core;Blood Vessels;Blood flow;Brain;Cerebrovascular Circulation;Cerebrovascular Disorders;Collaborations;Consultations;Data;Dementia;Electrophysiology (science);Endothelial Cells;Enterobacteria phage P1 Cre recombinase;Enzymes;Functional disorder;Genes;Glucose;Glucose Transporter;Glutamate Transporter;Glutamates;Human;Hyperhomocysteinemia;Image;Impairment;In Situ;Individual;Insulin Receptor;Intervention;Knowledge;Lactate Transporter;MMP9 gene;Magnetic Resonance Imaging;Measures;Metabolic;Metabolic dysfunction;Metabolism;Microelectrodes;Microvascular Dysfunction;Modeling;Mus;Names;Neurons;Outcome Assessment;Pathology;Pathway interactions;Phenotype;Production;Property;Proteins;Receptor Signaling;Rest;Role;Signal Transduction;Slice;Synapses;Synaptic plasticity;Testing;Tissues;Vibrissae;Work;amyloid pathology;awake;barrel cortex;calmodulin-dependent protein kinase II;cerebrovascular;cerebrovascular pathology;comorbidity;data management;disease model;excitotoxicity;extracellular;functional outcomes;hippocampal sclerosis;human tissue;knock-down;loss of function;mouse model;network dysfunction;neural network;neuroinflammation;neurotoxicity;neurovascular coupling;neurovascular unit;novel therapeutic intervention;overexpression;prevent;restoration;synaptic function;two-photon;vascular cognitive impairment and dementia;vector


application_id: 10897079
project_number: 5P01AG078116-03
project_title: Project 2 - Astrocytic insulin signaling and AD
administering_ic: NIA
award_notice_date: 2024-06-26
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7470
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
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 2  ABSTRACT/SUMMARYIn alignment with the overall proposal and goal of this P01 Strategies for Targeting Astrocyte Reactivity in ADand ADRDwe believe astrocytes can be targeted to impact a multitude of functions known to be dysregulatedin Alzheimers disease (AD) and AD-related dementias (ADRD) because of their close physical proximity to othercell types and essential role in brain metabolism. It is our intention to use an astrocyte-centric approach todiscover new pathways and signals previously uncharacterized in vivo in order to better address future therapiestargeting the health of astrocytes in AD. Here we will test the hypothesis that elevating insulin signalingspecifically in astrocytes in mouse models of AD-like pathology will normalize cerebrovascular metabolicand neuronal Ca2+ network changes commonly associated with AD and ADRD. We will combine our expertiseusing intranasal insulin (INI) delivery in combination with two-photon (2P) microscopy in the 5xFAD mouse modelof AD-like pathology to investigate astrocyte-specific overexpression and knockdown of insulin receptors (IR) inthe brain and will characterize the impact of this manipulation on: (Aim 1) neurovascular unit (NVU) functionusing red blood cell flow measures; (Aim 2) astrocytic and neuronal bioenergetics using fluorescent measuresof ATP/ADP ratios glucose imaging using 2-NBDG and glucose and lactate levels using multi-electrode arrays(MEAs); and (Aim 3) neuronal/ astrocytic Ca2+ networks using GCaMP6 fluorescent measures of Ca2+. Resultsin 5xFAD males and females will be compared to age-matched WT littermates. All imaging experiments will beconducted in the somatosensory cortex (S1) at rest and during ambulation in head-fixed mice. We willcorroborate some of our results with hippocampal investigations using electrophysiology in the slice and alsomeasure spatial and memory processes using the radial arm water maze (RAWM). Our work will investigatenetworks of neurons astrocytes and blood vessels as targets of amyloidogenesis and vascular impairmentacross sex and will also test the hypothesis that astrocytes represent a target of INI in the brain and can helpregulate the onset of Ca2+ dysregulation. Together a conceptually novel and experimentally rich set of data willbe extracted in order to address new potential therapeutic targets in AD and ADRD and to elucidate howparticular elements of the NVU integrate to maintain function in health and disease. Under the leadership of CoreA our proposed collaborations with the other projects and cores sharing resources and expertise will provide aunique opportunity to share experimental protocols data results and interpretation across groups and will leadto a thorough and unprecedented characterization of astrocytic reactivity through the lens of experienced leadersin the field. This project within the context of the P01 could lead to a paradigm shift such that astrocyte healthand reactivity are considered along with other biological manifestations of AD in the clinic 1 perhaps switchingfrom the ATN classification (amyloid/tau/neuron degeneration) to the ATRAN (amyloid/tau/reactiveastrocytes/neuron degeneration) classification.

project_terms:
Address;Age;Aging;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease related dementia;Amyloid;Astrocytes;Attention;Autopsy;Behavior;Bioenergetics;Biological;Blood - brain barrier anatomy;Blood Vessels;Blood flow;Brain;Cells;Classification;Clinic;Clinical;Cognition;Collaborations;Coupled;Coupling;Data;Data Set;Disease;Electroencephalography;Electrophysiology (science);Elements;Environment;Erythrocytes;Female;Frequencies;Future;Gene Expression Regulation;Glial Fibrillary Acidic Protein;Glucose;Glucose Transporter;Goals;Head;Health;Hippocampus;Human;Image;Impairment;In Situ;Injections;Insulin;Insulin Receptor;Insulin deficiency;Intention;Investigation;Knockout Mice;Knowledge;Leadership;Learning;Magnetic Resonance Spectroscopy;Measures;Metabolic;Metabolism;Microscopy;Modeling;Mus;Nerve Degeneration;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway interactions;Physiology;Play;Protocols documentation;Radial;Receptor Signaling;Reporting;Resolution;Resource Sharing;Rest;Rodent;Role;Sampling;Series;Signal Transduction;Site;Slice;Somatosensory Cortex;Specimen;Surface;Testing;Time;Translating;Work;adeno-associated viral vector;aged;amyloid pathology;amyloidogenesis;arm;brain dysfunction;brain metabolism;cell type;cellular targeting;cerebrovascular;cognitive function;data management;density;experience;experimental study;glucose sensor;glucose uptake;in vivo;insulin signaling;knock-down;large datasets;lens;male;memory process;mouse model;multi-electrode arrays;neurovascular unit;novel;overexpression;promoter;rhodamine dextran;sex;targeted treatment;tau Proteins;therapeutic target;two-photon;vector;water maze


application_id: 10897077
project_number: 5P01AG078116-03
project_title: Project 1 - Astrocytic end-feet and VCID
administering_ic: NIA
award_notice_date: 2024-06-26
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7469
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT 1 ABSTRACT/SUMMARYVascular contributions to cognitive impairment and dementia (VCID) are a major cause of dementia both aloneand co-morbid with Alzheimers disease (AD) and AD Related Dementias (ADRD). Astrocytic end-feet arephysically anchored to the vascular basement membranes via dystroglycan complexes. At the end-feet arepotassium and water channels Kir4.1 and aquaporin 4 (AQP4) as well as monocarboxylic acid transporters(MCTs). AQP4 and Kir4.1 channels are polarized at the end-foot and are co-anchored via a -syntrophin-dystrophin 1 complex. We have found that cerebral small vessel disease (cSVD) induced byhyperhomocysteinemia (HHcy) resulted in degeneration and dissociation of the astrocytic end-feet and anassociated loss of AQP4 and Kir4.1 from the end-feet. This suggests that the end-feet are particularlysusceptible to vascular injury and as such may mediate neuronal dysfunction and neurodegenerationassociated with dementia. We have observed increased activity of matrix metalloproteinases (MMPs) inparticular MMP9 coincident with astrocytic end-foot degeneration. We therefore hypothesize that MMP9 isnecessary and sufficient for astrocytic end-foot degeneration and associated neurovascular couplingand metabolic and ionic dyshomeostasis.We will test our hypothesis in mice by manipulating MMP9 in our well-characterized HHcy mouse model of VCIDand our multi-modal multi-faceted outcome measures leverage the specific expertise of our Cores includingintravital MRI/MRS and electrophysiological measures provided by Core B and human tissue images andbiospecimens from Core C. We collaborate extensively with Projects 2-4 to determine relationships betweenend-foot disruption and glutamate transporters K+ATP channels and insulin transporters. All data will flowthrough Core D to quantitatively assess relationships between MMP9 and astrocytic and neuronal function withinthis Project and across all Projects in our P01Strategies for Targeting Astrocyte Reactivity in ADRD P01.To test our hypothesis we propose three distinct aims. Specific Aim 1: MMP9 mediated astrocytic end-foot degeneration will result in cerebrovascular dysfunction impaired neurovascular coupling. Specific Aim 2: MMP9 mediated astrocytic end-foot degeneration will result in metabolic and ionicdyshomeostasis. Specific Aim 3: Astrocytic end-foot degeneration results in profound changes in gene and protein expression and end-foot proteins can be used as biomarkers of end-foot degeneration.

project_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Astrocytes;Autopsy;Basement membrane;Biochemical;Biological Markers;Blood Vessels;Brain;Brain region;Cerebral small vessel disease;Cerebrovascular Disorders;Collaborations;Complex;Data;Dementia;Dissociation;Dystroglycan;Dystrophin;Electrophysiology (science);Euthanasia;Gene Expression;Gene Expression Profile;Glutamate Transporter;Harvest;Hemorrhage;Histologic;Human;Hyperhomocysteinemia;Image;Impaired cognition;Impairment;Inflammatory;Insulin;Lasers;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinases;Measurement;Measures;Mediating;Metabolic;Microelectrodes;Microscopy;Monocarboxylic Acid Transporters;Mus;Nerve Degeneration;Neuronal Dysfunction;Neurons;Outcome Measure;Pathology;Perfusion;Plasma;Potassium Channel;Predisposition;Proteins;Radial;Regulation;Slice;Testing;Time;Water;Wild Type Mouse;Work;aquaporin 4;arm;awake;candidate identification;candidate marker;cerebrovascular reactivity;comorbidity;cytokine;digital;human tissue;in vivo;mouse model;multimodality;neurovascular coupling;novel;object recognition;overexpression;protein expression;syntrophin;two-photon;vascular cognitive impairment and dementia;vascular injury;water channel;water maze


application_id: 10897076
project_number: 5P01AG078116-03
project_title: Core D - Data Management and Statistics Core
administering_ic: NIA
award_notice_date: 2024-06-26
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7467
contact_pi_person_id: 12221415
contact_pi: KATSUMATA, YURIKO
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:
CORE D- ABSTRACT/SUMMARY The Data Management and Biostatistics (DMB) Core is an integral component of our team projectStrategies for Targeting Astrocyte Reactivity in Alzheimers Disease (AD) and AD related dementia (STAR-ADRD). The goal of the DMB Core is to provide a comprehensive multi-disciplinary resource for four STAR-ADRD projects by constructing and maintaining a centralized data repository and drawing biostatistical expertisefor the completion of their research. A unique aspect of this Core is the design and utilization of a StructuredQuery Language (SQL) server to store analytical data and metadata related to the four projects in a singlelocation for cross-project integration. The DMB Core will closely and regularly interact with other investigators toensure that all data are collected and deposited in alignment with the goal of generating rigorous andreproducible data repository. Given that interdisciplinary research requires researchers to use methods and datafrom a range of disciplines the role of the DMB Core is vital to the success of the STAR-ADRD team. The DMBCore will support these responsibilities through the following specific aims.Aim 1: Maintain and expand an integrated data warehouse and suite of Browser-based data collectionapplications and reporting platforms for the STAR-ADRD Cores and projects. Data management efforts will focuson collecting storing and sharing high quality data according to the standard operating procedures.Aim 2: Provide expertise on tailored and integrated statistical analyses. The DMB Core will provide statisticalanalyses individually tailored to the STAR-ADRD projects and Cores needs. The DMB Core will actively interactwith STAR-ADRD investigators examine their research hypotheses plan and suggest appropriate statisticalanalysis methods and models build tailored analysis pipelines interpret and discuss results create graphs andtables for presentations and manuscripts and write the statistical analysis section in manuscripts. Further theDMB Core will develop and apply statistical methodology on data harmonized and integrated across the fourSTAR-ADRD projects.Aim 3: Host training in data management practices for the research team. The DMB Core will offer in-person (orZoom) data quality and management workshops with the entire STAR-ADRD team. The materials developedand used for workshops will be documented and shared with STAR-ADRD team members. All four projects proposed in this P01 require data management and biostatistical expertise to ensure thatall data are reliable and statistically analytical. The DMB Core will play a key role in facilitating synergies acrossthe STAR-ADRD projects and Cores.

project_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Animals;Astrocytes;Binding;Bioinformatics;Biometry;Biostatistical Methods;Biostatistics Core;Communication;Complex;Computers;Data;Data Analyses;Data Collection;Data Security;Data Set;Data Storage and Retrieval;Database Management Systems;Deposition;Directories;Discipline;Educational workshop;Electrophysiology (science);Ensure;FAIR principles;Foundations;Goals;Graph;Human;Individual;Interdisciplinary Study;Language;Linux;Location;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Manuscripts;Metadata;Methodology;Methods;Microelectrodes;Mission;Modeling;Perception;Persons;Phase;Play;Practice Management;Procedures;Proteomics;Pythons;Quality Control;Reporting;Reproducibility;Research;Research Activity;Research Personnel;Research Support;Resource Sharing;Resources;Role;Secure;Series;Services;Standardization;Statistical Data Interpretation;Structure;System;Technology;Time;Training;Writing;analysis pipeline;biomedical imaging;data format;data harmonization;data integration;data integrity;data management;data quality;data repository;data reuse;data standards;data visualization;data warehouse;design;experimental study;large scale data;member;metabolomics;multi-photon;multidisciplinary;predictive modeling;statistics;success;synergism;transcriptomics


application_id: 10897074
project_number: 5P01AG078116-03
project_title: Core C - Human Consultation-Biosamples-Biomarkers Core
administering_ic: NIA
award_notice_date: 2024-06-26
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7464
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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:
CORE C: HUMAN CONSULTATION BIOSAMPLES BIOMARKERS (CBB)ABSTRACTThe Human Consultation Biosamples Biomarkers (CBB) Core (Core C) will complement and integrate theProjects of the P01 Strategies for Targeting Reactive Astrocytes in AD and ADRD. It is critical to validatethe translational relevance of mechanistic mouse models and to extend those results toward further clinicalstudies. Yet there are challenges when it comes to addressing the complex pathobiology of the dementia clinicalsyndrome. Core C will bridge those critical gaps through the following Specific Aims: Aim 1: Optimizeclinically-relevant study design and manage ongoing data streams incorporating human biomarker andautopsy data. This Aim will foster integration organization coherence and documentation for Core C. Themultimodal data include molecular metabolic and network-wide domains in human endophenotypes andhuman preclinical and clinical endpoints. Aim 2: From existing autopsy material and data generate a setof human cases from the UK-ADRC that encompasses the AD/ADRD phenotypes studied in all 4Projects (AD VCID LATE+HS and controls) and provides a common basis for downstream biochemicaland neuropathological endpoint assessments relevant to the Projects. We will analyze a panel of 100cases for this Aim. Aim 2a: Biochemistry. We will perform multi-level protein extracts and run immunoblotswith quantitative measurements on each sample with astrocytic proteins (e.g. AQP4 Kir4.1 GFAP SLC1A2ABCC9/SUR2 Insulin receptor) being studied in the Projects. We will separately assess snap-frozenhippocampal samples as well as frontal cortex (Brodmann Area 9) white matter and gray matter seperately.Aim 2b: Neuropathology. Neuropathologic endpoints will be characterized in a quantitative manner in thesame panel of 100 cases: Astrocytosis (GFAP+) A plaques TDP-43 proteinopathy and Tau tangles. Wealso will perform highly quantitative assessments of blood vessel morphology using CD34 (capillaries) and ?-SMA (arteriole) markers. Double-label IFC will characterize IR and SUR2 proteins cellular distributions.Samples will also be genotyped for ABCC9 risk alleles. Aim 3: From existing clinical outcome measuresgenerate a set of biomarker (in vivo) data from human participants that represents a common basis fordownstream biofluids and neuroimaging endpoint assessments relevant to the projects. Aim 3A:Neuroimaging. A 3D anatomical magnetization-prepared rapid acquisition with gradient echo (MPRAGE)cerebrovascular reactivity (CVR) from existing human imaging on a 3T MRI scanner will be generated andprovided to Projects and Core D. Drs. Powell and Bahrani in Core C are also performing parallel neuroimagingexperiments in mice (Core B). Aim 3B: Fluid Biomarkers. Cerebrospinal fluid (CSF) and plasma that arebanked from UK-ADRC and UK-MarkVCID participants will be assayed for MMP9 and GFAP using QuanterixSimoa assays and AQP4 Kir4.1 and Dp71 will be assayed using a standard colorimetric ELISA method.

project_terms:
3-Dimensional;ABCC9 gene;Address;Alzheimer's disease related dementia;Amyloid beta-Protein;Anatomy;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Biochemical;Biochemistry;Biological Assay;Biological Markers;Blood Vessels;Blood capillaries;Brain;Brodmann's area;CD34 gene;CRSP3 gene;Cerebrospinal Fluid;Clinical;Clinical Research;Complement;Complex;Consultations;Data;Data Management Resources;Dementia;Diagnosis;Documentation;Enzyme-Linked Immunosorbent Assay;Experimental Models;Fostering;Freezing;Funding;Genotype;Glial Fibrillary Acidic Protein;Hippocampus;Human;Image;Immunofluorescence Immunologic;Infrastructure;Insulin Receptor;Label;Liquid substance;Longitudinal cohort;MMP9 gene;Magnetic Resonance Imaging;Measurement;Measures;Metabolic;Methods;Molecular;Morphology;Mus;Neocortex;Neurofibrillary Tangles;Neuropsychology;Participant;Phenotype;Plasma;Proteins;Research;Research Design;Resources;Running;Sampling;Senile Plaques;Structure;Syndrome;Testing;Therapeutic Intervention;Tissues;Translating;Translational Research;Translations;Triton X100;United States National Institutes of Health;Urea;Western Blotting;Work;alpha synuclein;arteriole;biobank;biomarker identification;blood oxygen level dependent;cerebrovascular reactivity;clinical diagnosis;clinical material;clinical outcome measures;clinically relevant;data modeling;data streams;endophenotype;experimental study;frontal lobe;gray matter;human data;human imaging;human subject;in vivo;meetings;mouse model;multimodal data;neuroimaging;neuropathology;pre-clinical;protein TDP-43;risk variant;sarkosyl;specific biomarkers;synergism;tau Proteins;white matter


application_id: 10896337
project_number: 5R01AI150767-05
project_title: Structure and function of Burkholderia contact-dependent growth inhibition (CDI) systems
administering_ic: NIAID
award_notice_date: 2024-08-13
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 150767
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2020-09-17
project_end_date: 2026-08-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 10751521
contact_pi: GARCIA, ERIN C
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:
ABSTRACTSocial interactions between bacteria impact infectious disease transmission and progression. The molecularmechanisms underlying bacteria-bacteria competition and communication also represent a largely unexploredset of therapeutic targets that could be manipulated to treat or prevent infections. Contact-dependent growthinhibition (CDI) is a phenomenon in which Gram-negative bacteria deliver the toxic C-terminus of a largepolymorphic surface protein (BcpA) to the cytoplasm of neighboring bacteria upon direct cell-cell contactinhibiting the growth of the targeted recipient cell unless it produces an appropriate immunity protein (BcpI).While CDI systems have been investigated almost exclusively for their ability to mediate inter-bacterialcompetition our previous work indicated that CDI systems also facilitate inter-bacterial communication byinducing specific gene expression and phenotypic changes in immune recipient bacteria (those producing theappropriate immunity protein BcpI). Thus CDI systems enable bacterial self/nonself discrimination throughseveral overlapping mechanisms all of which could be exploited therapeutically. However fundamental gapsin knowledge of CDI system molecular function prevent a clear understanding of how these proteins impactbacterial sociality and limit the development of CDI system-based antimicrobials decontaminants or vaccines.Thus our long term goal is to identify the molecular mechanisms underlying CDI system function towardmanipulating these proteins for the treatment or prevention of infectious disease. Our preliminary data showthat Burkholderia species provide a tractable model system for interrogating CDI system biology. This proposalseeks to understand how BcpA is delivered from one bacterium to another and how this process shapesbacterial behavior. Toward these goals the proposal tests the hypothesis that Burkholderia BcpA exchange iscontrolled by BcpA-specific domains recipient cell receptors and the physiological state of the recipient cellwhich together impact microbial community development. The proposed model will be tested by (1) identifyingthe recipient factors that impact BcpA import and (2) defining BcpA domains responsible for maintainingappropriate delivery to recipients and testing the role of BcpA delivery in Burkholderia communities. Togetherthis research will provide critical insight into a specific mechanism of bacterial cell-cell communication leadingto advancement in the prevention or treatment of bacterial infections.

project_terms:
Address;Adhesions;Anti-Bacterial Agents;Bacteria;Bacterial Antibiotic Resistance;Bacterial Infections;Bacterial Proteins;Behavior;Binding;Biogenesis;Biological;Biological Models;Burkholderia;Burkholderia pseudomallei;Cell Communication;Cell surface;Cell-Cell Adhesion;Cells;Communicable Diseases;Communication;Communities;Community Developments;Complex;Cytoplasm;Data;Decontaminant;Development;Discrimination;Disease Progression;Ecology;Escherichia coli;Family;Foundations;Future;Gene Expression;Goals;Gram-Negative Bacteria;Growth;Immune;Immunity;Infection;Infection prevention;Investigation;Knowledge;Lipopolysaccharides;Mediating;Membrane;Membrane Proteins;Microbial Biofilms;Modeling;Modification;Molecular;Pathogenicity;Periodicity;Phenotype;Physiological;Play;Predisposition;Prevention;Process;Proteins;Receptor Cell;Research;Role;Shapes;Signal Transduction;Social Interaction;Structure;Surface;System;Systems Biology;Testing;Therapeutic;Toxic effect;Toxin;Vaccines;Work;antimicrobial;disease transmission;genetic approach;insight;microbial community;mouse model;new therapeutic target;novel therapeutic intervention;nuclease;prevent;protein function;receptor;social;therapeutic target

public_health_relevance:
PROJECT NARRATIVEMany bacteria including pathogenic Burkholderia species utilize specific surface proteins todeliver an anti-bacterial protein toxin to neighboring bacteria upon direct cell-cell contact. Ourproposed studies aim to determine the molecular requirements on both the `killer' and `target'cells for this inter-bacterial communication. By studying anti-bacterial proteins produced bythese bacteria this research will lay the foundation for the development of new antimicrobialtherapies against Burkholderia and other antibiotic resistant bacteria.


application_id: 10896208
project_number: 5R01HL166280-02
project_title: Mechanisms of L-type Calcium Channel Regulation in Heart Health and Disease
administering_ic: NHLBI
award_notice_date: 2024-05-28
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;Adrenergic Receptor;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;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: 10896154
project_number: 5R01AI167297-04
project_title: HDAC6 regulation of myeloid cell responses in sepsis
administering_ic: NIAID
award_notice_date: 2024-08-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 167297
program_official: MINNICOZZI, MICHAEL
project_start_date: 2021-09-17
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-IDIA-E(02)M]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummarySepsis is a life-threatening disease caused by dysregulated host responses to infection. Sepsisremains a major health problem worldwide with high mortality. Myeloid cell responses such asendotoxin tolerance epigenetic modification metabolic failure and apoptosis are profoundlyaffected in sepsis which leads to systemic dysfunction of immune cells and progenitor cells. Theregulation of myeloid cell responses in sepsis remains largely unknown. The histone deacetylaseHDAC6 regulates a variety of cellular responses. However HDAC6 regulation of myeloid cellresponses in sepsis has not been investigated. Our preliminary studies indicate that HDAC6 is akey mediator of cell signaling in myeloid cells. Myeloid-specific HDAC6 deletion reduces themortality in septic mice. Furthermore selective HDAC6 inhibition can modulate myeloid cellresponses in the mouse models of sepsis. In the proposed studies we will test the hypothesisthat HDAC6 activation mediates myeloid cell dysfunction in sepsis and HDAC6 inhibition couldimprove myeloid cell function and survival rate in sepsis.

project_terms:
Acetylation;Affect;Apoptosis;Bacteria;Cell Differentiation process;Cell Physiology;Cell Survival;Cells;Clinical Trials;Cytoskeleton;Deacetylation;Development;Disease;Endotoxins;Epigenetic Process;Failure;Functional disorder;Future;Generations;Genetic Transcription;HDAC6 gene;Health;Histone Deacetylase;IRF1 gene;Immune;Immune System Diseases;Immune response;Infection;Inflammation;Inflammatory;Interferons;Life;Macrophage;Mediating;Mediator;Metabolic;Microtubule Stabilization;Microtubules;Modification;Mus;Myelogenous;Myeloid Cells;Myeloid Progenitor Cells;Myeloid-derived suppressor cells;Pathway interactions;Phenotype;Play;Regulation;Reporting;Role;STAT1 gene;Sepsis;Signal Transduction;Suppressor-Effector T-Lymphocytes;Survival Rate;Testing;Therapeutic;Therapeutic Effect;alpha Tubulin;hematopoietic stem cell expansion;immunoregulation;improved;mortality;mouse model;novel;response;septic;stem cells;transcriptomics

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


application_id: 10895677
project_number: 1R01CA284532-01A1
project_title: Fatty Acid Synthase as a Novel Molecular Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2024-02-19
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 284532
suffix: A1
program_official: CHEN, WEIWEI
project_start_date: 2024-03-01
project_end_date: 2029-02-28
study_section: Mechanisms of Cancer Therapeutics C Study Section [MCTC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Altered metabolism is recognized as a common hallmark of cancer. Dysregulation of glucose metabolismhas been extensively studied; however the role of fatty acid (FA) metabolism in tumorigenesis and diseaseprogression as well as treatment resistance remains poorly understood. Following our initial discovery of FASNa key enzyme of de novo lipid biosynthesis as an important regulator or tumor progression in colorectal cancer(CRC) studies from our group and others have firmly established an oncogenic role of FASN in multiple tumortypes. Increased fatty acid biosynthesis is needed not only to accommodate high rates of proliferation byproviding building blocks for membrane synthesis but also to enhance cancer cells ability to defend againstoxidative stress- or chemotherapy-induced cell death by changing membrane lipid composition. Given the strongrationale for targeting FASN in cancer therapy a new class of potent and selective small molecule inhibitors ofFASN (TVBs) have been developed and characterized in pre-clinical and clinical investigations. Our group hasconducted a double-blind randomized placebo-controlled window trial with TVB-2640 in patients with resectablecolon and other cancers. Results from the interim analysis of this ongoing clinical investigation revealed thatshort-term oral TVB-2640 therapy demonstrates excellent on-target inhibition of de novo lipogenesis andmanageable safety profile. However our preclinical studies using CRC patient-derived xenografts (PDXs)showed that FASN inhibitors only modest reduce tumor growth despite a significant decrease in lipogenesis invivo. Thus targeting FASN alone is unlikely to be sufficient to eradicate cancer cells. In exciting new findingswe showed that FASN inhibition potentiates chemotherapy drug-induced DNA damage in colon cancer cells asa result of altered histone acetylation. In addition we discovered that FASN inhibition promotes the activation ofthe cGAS/STING pathway and downstream type I interferon (IFN) response. The overall objective of this studyis to identify novel mechanisms that can enhance the antitumor efficacy of FASN inhibitors in CRC. The centralhypothesis driving this proposal is that a combination treatment strategy which includes FASN inhibition willprevent chemoresistance by blocking DNA damage response and potentiating the activation of innate immunesignaling via epigenetic mechanisms. The following Specific Aims are proposed: 1) to define the molecularmechanisms by which FASN inhibition blocks DNA repair pathways; 2) to delineate the functional significanceof FASN inhibition on modulating tumor immune microenvironment; and 3) to determine the impact of FASNinhibition on enhancing the efficacy of CRC therapies in vivo. Our highly collaborative group has the requisiteexpertise innovative model systems state-of-the-art technology and novel inhibitors to make rapid progressthat will potentially provide novel treatment options to improve patient outcome.

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

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


application_id: 10894810
project_number: 5T32CA165990-11
project_title: Interdisciplinary Research Training in Cancer Biology
project_terms: Cancer Biology;Interdisciplinary Study;Research Training
administering_ic: NCI
award_notice_date: 2024-06-24
opportunity_number: PA-20-142
application_type: 5
activity_code: T32
ic: CA
serial_number: 165990
program_official: DAMICO, MARK W
project_start_date: 2013-04-01
project_end_date: 2027-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: EVERS, BERNARD MARK
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
project_abstract:
ABSTRACTOur interdisciplinary program will focus on training pre-doctoral students and post-doctoral fellows in cancerbiology so they can effectively decipher important research questions associated with human cancer. This willbe accomplished by integrating established successful programs in diverse cancer biology themes together withclinical exposure into one cohesive program. Trainees will receive didactic and non-didactic instruction;laboratory-based basic science research training in cancer research and cutting-edge clinical applications; andcareer development as independent cancer biologists. To further growth as important members of the scientificcommunity students and fellows will receive ample training to articulate their ideas and communicate themeffectively evaluate biomedical research and mentor others in scientific excellence. This program assembles acohesive group of faculty from various departments at the University of Kentucky (UK) College of MedicineCollege of Arts and Sciences and College of Pharmacy. In the past 10 years our program faculty trained 104doctoral students and 109 post-doctoral students; our faculty have the experience and interdisciplinary focus toguide this group of trainees to function in research teams pursuing multidisciplinary investigations. We mentortrainees to be proficient at utilizing hypothesis-driven approaches as well as discovery-oriented research designto address key problems. All trainees are required to complete foundation courses in graduate-level GeneticsBiochemistry Immunology Pharmacology Physiology Cell Biology Molecular Biology Ethics Biostatistics andBioinformatics as well as Biology and Therapy of Cancer which emphasizes clinical aspects of human cancer.Unique features of this program include interdisciplinary training emphasizing bench to bedside (and vice versa)research topics as well as a mandatory Clinical Perspectives in Oncology workshop that encompasses tumorboards and clinician shadowing to provide a bridge between the fundamental biology of cancer and clinicalcancer. Training also involves mandatory participation in the weekly Markey Cancer Center (MCC) SeminarsCancer Biology journal club training workshops in specialized topics and the Fellowship Boot Camp to increasethe number of individual fellowships and grants from our trainees. The ultimate objective of this program is todevelop a cadre of future scientists who will lead integrative team approaches and understand the complex issueof cancer as it relates to potential prevention and treatment strategies. To ensure our commitment to the clinicaltranslation of basic science discoveries MCC Associate Director Kathleen OConnor PhD and Director B. MarkEvers MD will serve as PIs for this team-based training program. UK places a significant emphasis on trainingminority students post-doctoral researchers and physicians; this program will continue to ensure the inclusionof individuals from underrepresented racial ethnic and underserved background to better serve our diversesociety. Accordingly with the enthusiastic support of the MCC and the UK Vice President for Research thistraining program will mentor the next generation of cancer researchers to better understand and treat cancers.

public_health_relevance:
PROJECT NARRATIVEThis multidisciplinary training program represents a team approach involving multiple principal investigators whowill continue to mentor predoctoral students and post-doctoral fellows. The program will emphasize fundamentalaspects of cancer biology translational science of cancer and therapeutics and clinical cancer as well asprepare trainees as independent scientists and investigators who can become fully integrated in multidisciplinarycancer care teams.


application_id: 10894684
project_number: 5R35GM138636-06
administering_ic: NIGMS
award_notice_date: 2024-07-30
opportunity_number: PAR-17-190
application_type: 5
activity_code: R35
ic: GM
serial_number: 138636
program_official: MASKERI, BAISHALI
project_start_date: 2020-08-01
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-CB-K(55)R]
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: 2024-08-01
project_title:
Understanding how structural mutations and individual RNA isoforms are involved in human health and disease

project_abstract:
PROJECT SUMMARY/ABSTRACTIn todays efforts to personalize medicine it does not seem reasonable to personalize medicinewithout constructing and utilizing an individuals genome structure for both haplotypes. Currentstandards force the reference genomes structure on each individual. The same principle appliesto understanding the function for individual RNA isoforms. Structural variants are involved in ordirectly cause a broad range of diseases including cancer autism schizophrenianeurodegenerative diseases and Crohns disease among others. We seek to better understandhow structural variants affect disease by helping characterize structural variants and theirdownstream effects combining this information with RNA isoform sequencing (IsoSeq). Thehistocompatibility complex which contains the human leukocyte antigen (HLA) genes is aparticular region of interest for my lab because this region has been implicated in dozens ofdiseases. Similarly we seek understand the role for individual RNA isoforms for all genes.Protein-coding human genes average seven RNA isoforms resulting in unique protein products.For practical reasons standard short-read RNA sequencing studies treat all isoforms as a singlegenean oversimplification of the underlying biology; this is also true when considering sexdifferences in human health and disease. While females and males have many similarities bothsexes have unique biology with clear differences in disease prevalence therapeutic needs andresponses. Females in particular have not received adequate attention in human health anddisease research. A next critical step in all of biology research especially in disease researchwill be to determine individual isoform function and how that changes between sexes. We wantto contribute to this effort and propose to employ long-read sequencing technologies toaccomplish these goals.

project_terms:
Affect;Attention;Biology;Code;Crohn's disease;Disease;Female;Genes;Genome;Goals;HLA Antigens;Haplotypes;Health;Human;Individual;Major Histocompatibility Complex;Malignant Neoplasms;Mutation;Neurodegenerative Disorders;Prevalence;Protein Isoforms;Proteins;RNA;Research;Role;Schizophrenia;Sex Differences;Structure;Technology;Therapeutic;Variant;autism spectrum disorder;interest;male;personalized medicine;reference genome;response;sex;transcriptome sequencing

public_health_relevance:
PROJECT NARRATIVEWhile females and males have many similarities both sexes have unique biology with cleardifferences in disease prevalence therapeutic needs and responses. Females in particularhave not received adequate attention in human health and disease research. We seek to betterunderstand how structural variants and individual RNA isoforms affect disease by helping tocharacterize them and their roles in human health and disease.


application_id: 10894486
project_number: 4R00AI166116-03
project_title: Bacterial anti-inflammatory lipid mediators
administering_ic: NIAID
award_notice_date: 2023-08-24
opportunity_number: PAR-19-343
application_type: 4
activity_code: R00
ic: AI
serial_number: 166116
program_official: GONDRE-LEWIS, TIMOTHY A
project_start_date: 2022-02-17
project_end_date: 2026-08-31
study_section: NSS
contact_pi_person_id: 14354764
contact_pi: RADKA, CHRISTOPHER DAVID
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe rapid response of the innate immune system to infections relies on the detection of pathogen-associatedmolecular patterns (PAMPs) such as lipopolysaccharides that activate a robust inflammatory response toinvading organisms. My research program focuses on an unappreciated countermeasure deployed bycommensal bacteria and pathogens that attenuates the immune response to PAMPs. Oleate hydratase (OhyA)is an enzyme that is expressed in commensal bacteria and the important human pathogen Staphylococcusaureus. OhyA stereospecifically hydrates the 9-cis double bond of unsaturated fatty acids to produce 10-hydroxy-fatty acids (hFAs); however bacteria expressing OhyA do not synthesize unsaturated fatty acids.OhyA substrates are only encountered at the interface of host tissues where unsaturated fatty acids areabundant. I hypothesize that hFAs produced by commensal or pathogenic organisms serve as signalingmolecules that blunt the innate immune response to PAMPs. Indeed S. aureus ohyA knockouts fail toestablish infections in mice illustrating the importance of OhyA and hFAs to S. aureus virulence. Thus hFAswhich were first discovered in the gut microbiome may provide an important mechanism for commensalbacteria to attenuate gastrointestinal inflammation and create tolerant symbiotic environments. My pilotexperiments and some previous reports provide preliminary evidence for the anti-inflammatory action of hFAsbut the mechanism(s) of immune suppression by hFAs are unknown. To address this shortcoming I willreceive formal immunology instruction through coursework and hands-on training in the laboratory of Dr. PaulThomas an expert immunologist during the K99 phase. We will determine whether hFAs directly antagonizeextracellular PAMP binding to immune cell receptors bind to CD1 lipid-presenting molecules for T-cell receptorrecognition to antagonize T cell activation or intercept signaling downstream of PAMP-receptor activation bystimulating G-protein coupled receptors and/or PAPR. The results of these experiments will uncover themechanistic basis for hFA modification of immune cell responses. OhyA has no mammalian homolog andvalidating the importance of OhyA for virulence coupled with the X-ray structures of OhyA will provide the keyinformation required to determine whether OhyA is a candidate target for antimicrobial drug discovery. Duringthe R00 phase I will test the hypothesis that OhyA is packaged into extracellular vesicles released by S.aureus to interact with surrounding host tissues to form a halo of hFA mediators around the infection site. Myfindings will provide an atomistic mechanistic understanding of how OhyA binds to and influences membranestructure to promote vesicle formation. The K99/R00 research plan is designed to leverage my expertise inbiochemistry and structural biology while receiving new training in immunology to advance the understandingof immune regulation by bacteria and launch a productive and successful career in which I will lead a researchprogram to elucidate the role bacteria lipid products play in controlling host responses.

project_terms:
Address;Anti-Inflammatory Agents;Area;Arrestins;Attenuated;Bacteria;Bacterial Infections;Bifidobacterium;Binding;Biochemical;Biochemistry;Biological Assay;CD1 Antigens;Cell Culture Techniques;Cells;Complement;Coupled;Cryoelectron Microscopy;Encapsulated;Environment;Enzymes;Fatty Acids;Flow Cytometry;Foundations;G Protein-Coupled Receptor Signaling;G-Protein-Coupled Receptors;Genetic Transcription;Goals;Homologous Gene;Hydration status;Hydroxylation;Immune;Immune Evasion;Immune response;Immune signaling;Immunologics;Immunologist;Immunology;Immunosuppression;Infection;Inflammation;Inflammatory Response;Innate Immune Response;Innate Immune System;Instruction;Intercept;Intestines;Invaded;Investigation;Knock-out;Laboratories;Lead;Life;Ligand Binding;Lipids;Lipopolysaccharides;Lipoproteins;Luciferases;Mammalian Cell;Measures;Mediating;Mediator;Membrane;Mentors;Modeling;Modification;Molecular;Molecular Conformation;Mus;Oleates;Organism;Pathogen detection;Pathogenesis;Pathogenicity;Pathway interactions;Pattern;Pertussis Toxin;Phase;Phospholipids;Play;Productivity;Receptor Activation;Receptor Cell;Receptor Signaling;Reporter;Reporting;Research;Roentgen Rays;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Site;Skin Tissue;Soft Tissue Infections;Staphylococcus aureus;Structure;Symbiosis;System;T cell response;T-Cell Activation;T-Cell Receptor;TLR2 gene;Techniques;Testing;Tissues;Toll-like receptors;Training;Unsaturated Fatty Acids;Vesicle;Virulence;antimicrobial drug;biophysical techniques;career;commensal bacteria;cytokine;design;drug discovery;experimental study;extracellular;extracellular vesicles;gastrointestinal;gut inflammation;gut microbiome;human pathogen;hydroxy fatty acid;immunoregulation;inhibitor;interest;lipid mediator;lipid metabolism;multidisciplinary;novel;pathogen;pathogenic bacteria;pi bond;programs;receptor;recruit;response;structural biology;vesicular release

public_health_relevance:
Project NarrativeLipid mediators are major signaling molecule constituents in all kingdoms of life and bacteria producebioactive lipid mediators that are not made by mammalian cells. Inflammation in the intestine or sites ofbacterial infections exemplifies the immune response to agonistic bacterial lipid mediators but some bacteriaalso produce lipid countermeasures such as hydroxy fatty acids that can suppress the inflammatoryresponse. This project will elucidate the immune signaling pathways that respond to hydroxy fatty acids tosuppress immune responses and the biosynthetic pathways by which commensal and pathogenic bacteriarelease hydroxy fatty acids.


application_id: 10893999
project_number: 5R01DC020303-03
project_title: Perception of speech in context by listeners with healthy and impaired hearing
administering_ic: NIDCD
award_notice_date: 2024-07-25
opportunity_number: PAR-21-063
application_type: 5
activity_code: R01
ic: DC
serial_number: 020303
program_official: KING, KELLY ANNE
project_start_date: 2022-09-22
project_end_date: 2024-08-02
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 11529504
contact_pi: STILP, CHRISTIAN EDMUND
other_pis: WINN, MATTHEW BRANDON
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary / AbstractPerceptual systems operate in context: perception of a given object/event is influenced by the objects/eventsthat surround it. Speech perception operates in the same way where perception of speech sounds is heavilyinfluenced by the acoustic properties of contextual sounds that surround them. These acoustic context effectsare critically important to perception because they help maintain perceptual constancy in the face ofconsiderable variability in speech acoustics and listening environments. Despite this importance there is apoor understanding of how acoustic context shapes speech perception. The well-established ways ofmeasuring speech perception routinely present stimuli without any context or when they do it is to study asingle context effect in quiet for listeners with normal hearing (NH). These approaches severely impedeunderstanding of speech perception in everyday listening conditions (in context amidst background noise) andfor listeners with hearing difficulties. The long-term goal of this project is to improve our understanding of themechanisms underlying these acoustic context effects in speech perception in normal and impaired auditorysystems. This goal is addressed through three specific aims. The first aim is to define the unifying relationshipsbetween different context effects in speech perception by NH and hearing-impaired (HI) populations.Experiments in the first aim utilize an individual differences approach to explore auditory context effects as aunified system rather than individual isolated effects. The second aim is to study the impact of backgroundnoise on these context effects for NH and HI populations. Experiments in the second aim will test competingpredictions regarding whether noise diminishes the influence of context via masking or enhances the influenceof context via streaming. The third aim is to investigate context effects in speech perception by cochlearimplant (CI) users. Experiments in the third aim with real- and simulated-CI listening will elucidate mechanismsunderlying context effects and the impacts of different aspects of CI processing. These aims are supplementedby computational modeling of neural responses to the speech stimuli in order to clarify peripheral versuscentral mechanisms underlying these context effects. Overall the results will provide new insights into howNH HI and CI populations perceive sounds in the context of other sounds and in background noise. Theseefforts will produce better understanding of auditory perception with the realistic and prominent constraint ofcontextual influence and will help to provide a neural and behavioral framework for translational applications.

project_terms:
Acoustics;Address;Affect;Auditory;Auditory Perception;Auditory system;Behavioral;Bypass;Cochlear Implants;Code;Communication;Communication difficulty;Computer Models;Cues;Environment;Event;Experimental Models;Foundations;Frequencies;Goals;Grain;Hearing Aids;Hearing problem;Impairment;Individual;Individual Differences;Intervention;Investigation;Knowledge;Link;Measures;Methods;Modeling;Nerve;Noise;Pattern;Perception;Peripheral;Play;Population;Process;Property;Psychoacoustics;Reporting;Role;Sensorineural Hearing Loss;Shapes;Speech;Speech Acoustics;Speech Perception;Speech Sound;Stimulus;Stream;System;Testing;Time;Work;auditory pathway;auditory processing;contrast enhanced;experimental study;hearing impairment;improved;insight;model design;neural;neural model;neuroadaptation;neuromechanism;normal hearing;response;sensory system;sound;spectral energy;translational applications;translational framework

public_health_relevance:
This project investigates the perception of speech in the context of surrounding sounds for the normal auditorysystem and the effects of background noise hearing loss and cochlear implant processing on speechperception. These context effects play a critically important in perception allowing us to maintain stableperception despite considerable variability in sounds and in listening environments. An improvedunderstanding of context effects should lead to improvements in hearing aids and cochlear implants which willhelp individuals with hearing difficulties communicate more effectively.


application_id: 10893927
project_number: 5P20GM135004-05
project_title: Leveraging Zika virus driven myeloid cell responses to treat GBM
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
program_official: BERNAL, FEDERICO
project_start_date: 2020-02-01
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4
subproject_number: 9777
contact_pi_person_id: 12629057
contact_pi: NAIR, SHARMILA
other_pis: CHESNEY, JASON A.
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:
Oncolytic viral therapy shows promise for high-grade solid tumors but none have been shown to provide curative potential. This study explores the potential of harnessing the natural tropism of Zika virus (ZIKV) to target glioblastoma stem cells (GSCs) and reprogram the typically immune suppressive GBM tumor environment to an inflammatory antigen-presenting environment that induces GBM-specific CD8+ T cell responses. The first goal of this proposal is to identify the cellular mechanisms that drive anti-tumor T cell responses following ZIKV treatment. Our research will examine the functional roles of two distinct myeloid cell subsets induced following ZIKV treatment - CCR2+ monocytes in the tumor microenvironment (TME) and dendritic cell subset-2 (DC-2s) in draining lymph nodes (dLN) - in driving anti-tumor T cell responses against GBM. Additionally our study will examine the synergistic therapeutic potential of a highly novel Flt3 ligand therapy and ZIKV combination therapy as a strategy to activate both dendritic cell subset-1 (DC-1s) and DC-2 to maximize anti-tumor CD8+ T cell responses and subsequent GBM rejection. This research is significant because 1) it addresses the potential of ZIKV as an effective oncolytic virus for GBM treatment 2) identifies key cellular mechanisms that contribute to its anti-tumor effects and 3) addresses the current failure of immunotherapy and maps a therapeutic path forward.

project_terms:
Address;Antigen Presentation;Automobile Driving;CD8-Positive T-Lymphocytes;Cancer Center;Combined Modality Therapy;Dendritic Cells;Environment;FLT3 ligand;Failure;Glioblastoma;Goals;Immune;Immunotherapy;Inflammatory;Maps;Myeloid Cells;Oncolytic viruses;Research;Role;Solid Neoplasm;T cell response;Therapeutic;Tropism;Zika Virus;antitumor effect;cancer immunotherapy;draining lymph node;monocyte;novel;oncolytic virotherapy;programs;response;stem cells;tumor;tumor immunology;tumor microenvironment


application_id: 10893303
project_number: 5P20GM130456-05
project_title: Elucidating the chemical biology of the druggable targets in enteric pathogens C. jejuni & E. coli
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: FRINCU, CRINA
project_start_date: 2020-03-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9
subproject_number: 9790
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
project_abstract:
This proposals objective is to elucidate the chemical biology of microbial metabolites and small molecules to specifically target intestinal pathogens which cause intestinal infection & inflammation. The findings will facilitate the development of intervention strategies to specifically control the emergence and spread of antibiotic resistance in this significant human pathogen without altering the entire gut microbiota.

project_terms:
Antibiotic Resistance;Biology;Campylobacter jejuni;Centers of Research Excellence;Chemicals;Escherichia coli;Intervention;Pharmacologic Substance;Research;druggable target;enteric infection;enteric pathogen;gut inflammation;gut microbiota;human pathogen;innovation;microbial;small molecule;therapy development


application_id: 10892855
project_number: 5R01DK133076-02
project_title: Origins of Skeletal Fragility in Type 1 Diabetes
administering_ic: NIDDK
award_notice_date: 2024-05-20
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;Intervention;Knockout Mice;Laboratories;Ligands;Maps;Molecular;Mus;Observational Study;Osteoblasts;Osteogenesis;Osteoporosis;PI3 gene;Pathway interactions;Personal Satisfaction;Persons;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;osteoprogenitor cell;pharmacologic;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: 10892129
project_number: 5R01EY033190-04
project_title: Visual mechanisms of intermediate distance space perception during self-motion
administering_ic: NEI
award_notice_date: 2024-06-21
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: EY
serial_number: 033190
program_official: WIGGS, CHERI
project_start_date: 2021-09-30
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-J(02)M]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: OOI, TENG LENG
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryEvery day we rely on our vision to judge the absolute distances of objects around us to plan and guide ouractions such as walking and driving. This wayfinding process of ascertaining ones position and planning forpossible routes of actions cannot be accomplished without reliable perception of visual space in the intermediatedistance range (~2-25m from the observer). Thus the broad long-term objective of this project is to uncover themechanisms underlying intermediate distance space perception that supports distance judgment.Yet less is known about the underlying mechanisms of intermediate distance space perception compared tothose of near space perception (<2m). Moreover extant knowledge is predominantly obtained from testing staticobservers making it difficult to generalize to the more common situation where observers plan and execute self-motion. The latter situation is more complex because self-motion is accompanied by retinal image motion ofstatic objects in the surrounding environment potentially requiring the visual system to simultaneously track thelocations of all objects in the environment. The visual system also requires more processing capacity becauseit has to simultaneously compute the visual space representation explore the environment implement motorcontrols etc. Clearly both challenges  coding complexity and capacity limitation  could pose as potentialthreats to our ability to efficiently judge absolute distances and implement actions. We hypothesize the visualsystem overcomes both challenges by: (a) spatially updating the moving observers position using an allocentricworld-centered spatial coordinate system for representing visual space and (b) use spatial working memory(spatial-image) during spatial updating. We will investigate both hypotheses in three specific aims. Aim 1: Investigate the implementation of the allocentric world-centered spatial coordinate system Aim 2: Investigate the factors affecting the spatial updating of visual space Aim 3: Investigate the role of spatial-image memory in visual space perceptionOur psychophysical experiments will measure human behavioral responses in the real 3D environment. Thisapproach allows us to understand how our natural ecological niche namely the ground surface both constrainsand supports space perception and action in the real world. We will test human observers ability to judge targetlocations in impoverished visual environments under various conditions such as while manipulating theobservers cognitive load (attention and memory) or available visual and idiothetic (vestibular andproprioception) information while they plan and/or execute self-motion (walking). The outcomes of this researchwill advance the space perception literature bridge theoretical knowledge of visual space perception andmemory-directed navigation (cognitive maps) as well as reveal the influence of vestibular and somatosensorysignals. In turn the theoretical advancements provide insights for better understanding of intermediate distancespace perception related to eye and visual impairments and their impacts on mobility in the real 3D environment.

project_terms:
3-Dimensional;Activities of Daily Living;Address;Adopted;Affect;Attention;Automobile Driving;Behavioral;Characteristics;Code;Cognitive;Complex;Cues;Darkness;Defect;Environment;Eye;Human;Image;Judgment;Knowledge;Literature;Location;Maps;Measures;Memory;Motion;Movement;Neurologic;Outcomes Research;Performance;Positioning Attribute;Poverty;Process;Proprioception;Psychophysics;Research;Resources;Role;Route;Short-Term Memory;Signal Transduction;Space Perception;Surface;System;Testing;Texture;Update;Vision;Visual;Visual Perception;Visual System;Visual impairment;Visuospatial;Walking;behavioral response;cognitive load;experimental study;insight;motor control;neural;neuromechanism;operation;phenomenological models;retinal imaging;somatosensory;vestibular system;visual coding;visual information;way finding

public_health_relevance:
Project NarrativeThe ability to judge the locations of various objects from oneself during self-motion in the intermediate distancerange (~2-25m) is crucial for successful performance of activities of daily living such as walking and driving.However little is known about the mechanisms of visual space perception involved in judging distance the focusof this project in the planning and/or execution of self-motion in the natural 3D environment. The theoreticalknowledge to be gained from this project will contribute to the scientific literature and provide insights into howeye and neurological defects could impair visual space perception wayfinding and mobility.


application_id: 10892017
project_number: 5K23DE031807-02
administering_ic: NIDCR
award_notice_date: 2024-08-01
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: DE
serial_number: 031807
program_official: FUQUA, CHANTEL FAYSAN
project_start_date: 2023-09-01
project_end_date: 2025-08-31
study_section: ZDE1-AC(04)
contact_pi_person_id: 11936065
contact_pi: BOGGERO, IAN ANDRES
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-01
project_title:
Initial Evidence for a Brief Psychological Telehealth Intervention for Patients with Chronic Masticatory Muscle Pain

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

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

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


application_id: 10891301
project_number: 4UG1HD107649-02
project_title: Neonatal Opioid Withdrawal Syndrome (NOWS) in Kentucky: Improving Outcomes for Infants
administering_ic: NICHD
award_notice_date: 2023-08-30
opportunity_number: RFA-HD-21-031
application_type: 4
activity_code: UG1
ic: HD
serial_number: 107649
program_official: CHAKHTOURA, NAHIDA ABDO
project_start_date: 2021-09-17
project_end_date: 2026-08-31
study_section: ZHD1-DSR-T(50)
contact_pi_person_id: 8880455
contact_pi: DEVLIN-PHINNEY, LORI ANN
other_pis: TELANG, SUCHETA
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The medical and non-medical use of opioids and other psychoactive drugs in women of childbearing age isa significant public health concern in the United States. Prolonged in utero exposure of the developing fetus tomaternal opioids often results in Neonatal Opioid Withdrawal Syndrome (NOWS) after delivery. Infants withNOWS may have mild signs of withdrawal that minimally impact their ability to function or they may havesignificant withdrawal that requires a prolonged course of pharmacologic therapy and a lengthy newborn hospitalstay which stresses families communities and the healthcare system. Prolonged hospitalization may result indecreased maternal and infant bonding and attachment and have a negative impact on neurodevelopmental andbehavioral outcomes of affected children. The prevalence of opioid use during pregnancy and the subsequentoccurrence of NOWS after delivery is disproportionately higher in rural and underserved areas. Kentucky is ahighly rural and underserved state and has an estimated rate of NOWS that is approximately three times thenational average. Despite the significance of this problem the clinical care for neonates with NOWS is complicated by a lackof nationally accepted standardized approaches which leads to significant site-to-site variation. Such variation isdue in part to a lack of generalizable evidence to inform clinical practice. Previous research has been limited byboth small sample sizes due to difficulty with recruitment and retention and inherent limitations in study designs.In order to identify the most effective treatment and thereby optimize the care of infants with NOWS a directcomparison of pharmacologic treatment regimens in a generalizable population is urgently needed. Collaboration with local community partners and with other clinical sites will be undertaken within theproposed research consortium to design implement and conduct a multicenter randomized controlled clinicaltrial. The goal of the trial is to provide a direct comparison of pharmacologic treatment for infants with NOWSaccount for confounding variables such as non-pharmacologic care and adjuvant medications and evaluateneurodevelopmental and behavioral outcomes in the first years of life. The anticipated results of this RCT will behighly generalizable to improve care for infants with NOWS in KY and throughout the nation.

project_terms:
Accounting;Address;Adjuvant Analgesic;Affect;Caring;Child;Childhood;Clinic;Clinical;Clinical Nursing Research;Clinical Pharmacology;Clinical Practice Guideline;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Confounding Factors (Epidemiology);Country;Data Analyses;Dedications;Development;Dose;Enrollment;Ensure;Evaluation;Family;Female of child bearing age;Fetal Development;Frequencies;Geography;Goals;Health;Health Personnel;Healthcare Systems;Hospitalization;Hospitals;Infant;Infant Care;Infrastructure;Kentucky;Leadership;Length of Stay;Life;Medical;Medical Care Team;Mothers;Multi-Institutional Clinical Trial;Multi-site clinical study;Neonatal;Neonatal Abstinence Syndrome;Neonatal Intensive Care Units;Newborn Infant;Opioid;Outcome;Patient Recruitments;Patients;Pharmacological Treatment;Play;Population;Population Heterogeneity;Pregnancy;Prevalence;Psychotropic Drugs;Public Health;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Recording of previous events;Research;Research Design;Research Personnel;Role;Rural;Sample Size;Scientist;Site;Solid;Standardization;Stress;Treatment Protocols;United States;United States National Institutes of Health;Universities;Variant;Visit;Withdrawal;Work;behavioral outcome;care outcomes;clinical care;clinical practice;clinical research site;clinically relevant;comparative effectiveness trial;compare effectiveness;data sharing;design;effective therapy;evidence base;experience;follow-up;high risk;improved;improved outcome;infant outcome;member;neonate;opioid epidemic;opioid misuse;opioid use;opioid use in pregnancy;optimal treatments;outreach;pediatric department;pediatrician;pharmacologic;prenatal exposure;programs;prospective;recruit;rural area;rural underserved;standard of care;suburb;underserved area;urban underserved

public_health_relevance:
PROJECT NARRATIVEThe increased use and misuse of opioids during pregnancy and resulting Neonatal Opioid Withdrawal Syndrome(NOWS) are critical public health concerns in the United States. We will collaborate as a member of the proposedresearch group to design and conduct a multicenter clinical trial to directly compare the effectiveness ofpharmacologic treatments for infants with NOWS. We anticipate that our studies will identify the optimal treatmentfor NOWS to improve the care and overall health and neurodevelopmental outcomes of infants with NOWSthroughout the US.


application_id: 10890800
project_number: 5R44DA053848-04
project_title: Digital Therapeutic Development of Virtual Cognitive-Affective Training for Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2024-07-15
opportunity_number: RFA-DA-19-019
application_type: 5
activity_code: R44
ic: DA
serial_number: 053848
program_official: ANGELONE, LEONARDO MARIA
project_start_date: 2021-05-15
project_end_date: 2025-03-01
study_section: ZDA1-GXM-A(03)R
contact_pi_person_id: 7594377
contact_pi: WEISBERG, RISA B
other_pis: Not Applicable
congressional_district: 02
department: Unavailable
primary_duns: 080772307
primary_uei: PYRCCX2DHMJ7
duns_number: 080772307
uei: PYRCCX2DHMJ7
fips: US
organization_id: 10047086
organization_name: BEHAVR, LLC
organization_city: ELIZABETHTOWN
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 427014430
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary: The US is experiencing an opioid crisis with an estimated 2.5 million Americans meetingfull criteria for opioid use disorder (OUD). Medications for opioid use disorder (MOUD) like buprenorphine arecurrently the most effective form of intervention for OUD. In spite of the proven efficacy of MOUD nearly half ofpeople who begin a MOUD relapse within six months. As such novel and efficacious behavioral adjuncts toMOUD are needed to improve treatment outcomes. Mindfulness-Oriented Recovery Enhancement (MORE) acognitive-affective training intervention generated through a NIDA-funded treatment development process hasshown significant promise demonstrating therapeutic effects in four randomized controlled trials (RCTs) byreducing opioid use and misuse and modulating neurophysiological responses during drug cue-reactivity andnatural reward processing. However the MORE intervention requires significant human interaction and istherefore resource intensive. Further in light of the COVID-19 pandemic people with OUD may be reticent toengage in face-to-face interventions due to the risk of viral spread. To overcome these implementation barriersand increase access to treatment the proposed project will develop and test a virtual reality version of theMORE intervention (MORE-VR) built on BehaVR LLC's VR existing commercially available platform theDynamic eXperience Engine (DXE). The DXE uses machine learning to integrate biometrics into the VRexperience to personalize addictions treatment boosting patient engagement and optimizing the efficacy ofclinical intervention. In Phase I we will develop and test the MORE-VR prototype in a single arm clinical studyof OUD patients receiving buprenorphine in an opioid treatment program (OTP) focusing on patient safety andengagement. If the prototype is perceived to have adequate usability and Net Promoter Scores as well as toproduce improvements in proximal measures of craving and affective state the project will progress to PhaseII. In Phase II we will first develop the MORE-VR Minimal Viable Program using feedback from our Phase Istudy to optimize the intervention and then conduct a RCT of MORE-VR vs. MOUD treatment as usual. Ourrobust and unbiased research design will triangulate clinical outcome measurement with biochemicalverification of abstinence ecological momentary assessments (EMA) and neurophysiological assessment ofcue-reactivity. Further we will integrate the MORE-VR Program into the OTP operational environment buildingFast Healthcare Interoperability Resources interfaces to ingest patient data from electronic medical records(EMRs) and to export patient utilization assessment and biometric data back to EMRs to create patientrecords and inform clinicians of patient progress. Activities in Phase I and Phase II will help define theregulatory pathway and establish regulatory feasibility to precede Food and Drug Administration (FDA)approval of the MORE-VR system as a Class II medical device. In sum this project will translate an evidence-based biobehavioral treatment approach into an innovative digital therapeutic for OUD.

project_terms:
Abstinence;Adherence;Affect;Affective;American;Area Under Curve;Back;Behavior Therapy;Behavioral;Biochemical;Biometry;Brain;Buprenorphine;COVID-19 pandemic;Clinic;Clinical;Clinical Research;Cloud Computing;Cognitive;Computerized Medical Record;Data;Development;Dropout;Drug Modulation;Ecological momentary assessment;Educational Intervention;Electronic Health Record;Environment;Epidemic;Fast Healthcare Interoperability Resources;Feedback;Funding;Goals;Health Services Accessibility;Human;Human Resources;Individual;Ingestion;Intervention;Light;Link;Machine Learning;Measures;Medical Device;National Institute of Drug Abuse;Opioid;Outcome;Outcome Measure;Participant;Patients;Persons;Pharmaceutical Preparations;Phase;Process;Protocols documentation;Psychophysiology;Randomized Controlled Trials;Records;Recovery;Regulatory Pathway;Relapse;Research Design;Resources;Rewards;Risk;Safety;Self Efficacy;Services;Signal Transduction;Small Business Innovation Research Grant;Specific qualifier value;Sum;System;Techniques;Teleconferences;Testing;Therapeutic Effect;Training;Translating;Treatment outcome;United States;United States Food and Drug Administration;Viral;addiction;affective neuroscience;arm;barrier to care;biobehavior;chronic pain;clinical efficacy;commercialization;craving;cue reactivity;design;digital treatment;effective intervention;efficacy study;electronic data;evidence base;experience;implementation barriers;improved;innovation;medication for opioid use disorder;meetings;mindfulness;neurophysiology;novel;opioid epidemic;opioid misuse;opioid treatment program;opioid use;opioid use disorder;patient engagement;patient safety;phase 1 study;pilot test;programs;promoter;prototype;relapse prevention;remediation;response;reward processing;satisfaction;skills;success;therapeutic development;therapy development;treatment as usual;treatment program;treatment risk;treatment strategy;usability;virtual;virtual machine;virtual reality;virtual reality system

public_health_relevance:
Project NarrativeMedications for opioid use disorder (MOUD) like buprenorphine are currently the mosteffective form of intervention for opioid use disorder (OUD); however novel behavioraladjuncts are needed to remediate dysregulation in brain reward systems enhance MOUDadherence and prevent relapse. BehaVR LLC will meet this need by translating anevidence-based biobehavioral treatment approach into an innovative digital therapeuticfor OUD that will increase accessibility to services to improve the patient's chances oflong-term treatment success.


application_id: 10890772
project_number: 5R01CA264652-04
project_title: Plk1 as a prognostic biomarker for prostate cancer
administering_ic: NCI
award_notice_date: 2024-06-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 264652
program_official: WEINREICH, MICHAEL DALE
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Plk1 as a prognostic biomarker for prostate cancerAbstractBecause androgen receptor (AR) signaling is essential for development of prostate cancer (PCa)including castration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) arebecoming the first line treatment for CRPC. However the limited clinical success of ASIs makes iturgent to develop new approaches to treat ASI-resistant CRPC. Ionizing radiation is another majorapproach to treat CRPC with limited efficacy. Olaparib a PARP1 inhibitor is recently developed andused to target cancers with a defect in DNA repair such as BRCA mutations. Unfortunately the usageof olaparib in CRPC is profoundly limited by the fact that BRCA mutations only occur in lowpercentages of PCa. Thus identifying additional critical regulators that control DNA damage response(DDR) is of significance as it will identify specific patient populations who will be responsive to olaparib.The objective is to define the role of polo-like kinase 1 (Plk1) in regulating DDR and to exploit its uniqueimpact on the efficacy of olaparib for ASI-resistant CRPC patients. The central hypothesis is that Plk1phosphorylation of Mre11 a component of MRN (Mre11/Rad50/Nbs1) complex and MDC1 (mediatorof DNA damage checkpoint 1) leads to premature termination of DNA damage checkpoint reducedDNA repair thus increased olabparib efficacy based on the concept of synthetic lethality. Our datashow that Plk1 directly phosphorylates Mre11 whose activation is the first step in response to DNAdamage and that Plk1 phosphorylation of Mre11 leads to recovery from DNA damage checkpoint andreduced DNA repair. We also show that MDC1 a protein that further amplifies DDR signals is a Plk1substrate. Our hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1phosphorylation of Mre11 regulates the MRN complex; (2) to test whether Plk1 phosphorylation ofMDC1 contributes to premature termination of checkpoint; and (3) to determine whether Plk1 is aprognostic biomarker for PCa. These complementary aims will be accomplished using biochemicalanalyses of signaling intermediates and employing both cell culture systems and genetic strategieswith inducible mouse models. The rationale for the research is that it will probe the importance of Plk1to DDR and to examine whether Plk1 can be a predictable biomarker for the efficacy of olaparib inCRPC. This contribution is significant because if positive the results of the proposed study will supportan immediate clinical trial to compare the efficacy of olaparib in CRPC patients carrying different levelsof Plk1. The research is innovative as it approaches the disease from a novel Plk1 signaling pathwaychallenging the traditional view that Plk1 functions solely to regulate mitotic events. These studiesprovide a new paradigm for therapies by identifying the key regulator of DDR that is critical for theefficacy of olaparib in CRPC.

project_terms:
Affect;Androgen Receptor;Androgens;BRCA mutations;Biochemical;Biological Markers;Cancer Patient;Castration;Cell Culture System;Cells;Chromatin;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;Creativeness;DNA Damage;DNA Repair;DNA Repair Gene;DNA Repair Inhibition;DNA Repair Pathway;DNA amplification;DNA damage checkpoint;Data;Defect;Development;Disease;Event;Exhibits;Fostering;Frequencies;Genetically Engineered Mouse;Goals;Health;Investigation;Ionizing radiation;Malignant Neoplasms;Malignant neoplasm of prostate;Mediator;Meiotic Recombination;Mission;Mitotic;Mus;Mutation;Outcome;PLK1 gene;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Poly(ADP-ribose) Polymerase Inhibitor;Prognostic Marker;Proteins;Public Health;Receptor Signaling;Recovery;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tumor Subtype;Withdrawal;Work;abiraterone;androgen independent prostate cancer;ataxia telangiectasia mutated protein;brca gene;cancer cell;clinically relevant;comparative efficacy;cytotoxic;design;efficacy evaluation;enzalutamide;genetic approach;improved;inhibitor;innovation;mouse model;novel;novel strategies;overexpression;patient population;premature;prostate cancer cell;prostate cancer progression;response;success;tumor

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NCI's mission of fostering creative discoveries and innovative researchstrategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 10889353
project_number: 1R21AG083820-01A1
project_title: Deciphering genetics of PLCG2 alternative splicing to understand AD risk
administering_ic: NIA
award_notice_date: 2024-04-15
opportunity_number: PAR-22-094
application_type: 1
activity_code: R21
ic: AG
serial_number: 083820
suffix: A1
program_official: YAO, ALISON Q
project_start_date: 2024-04-15
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1 AN-Q (55)]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
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:
The majority of Alzheimers disease (AD) risk is genetic and genome wide association studies (GWAS)have identified 75 AD-associated SNPs. In other fields pharmacologic agents targeting proteins identifiedthrough genetics have produced striking success. However the AD field has lagged partly because we havestruggled to identify the molecular mechanisms whereby genetic variants impact AD. This proposal focuses onthe phospholipase PLCG2 which was initially associated with AD through a missense SNP rs72824905(P522R) that strikingly reduces AD risk. PLCG2 modulates microglial function by mediating signaling fromTREM2 and related receptors. P522R appears a hypermorphic mutation that increases PLCG2 functionthrough an unclear mechanism. However homozygosity for P522R is apparently deleterious suggesting thatPLCG2 activity must be tightly controlled for optimal brain aging. In considering PLCG2 genetics and AD werecognized that PLCG2 expression and splicing relative to AD genetics have not been scrutinized. Indeed aSNP upstream of PLCG2 rs12446759 was recently associated with AD risk in a GWAS; the actions of thisGWAS SNP are not clear although eQTL compendia suggest that this SNP is associated with expression ofthe lncRNA RP11-960L18 some isoforms of which include PLCG2 beginning at exon 2. To address the gapin our knowledge regarding PLCG2 expression and AD genetics we propose to elucidate the extent thatgenetics modulate PLCG2 expression and splicing to identify the underlying mechanisms and to identifyproof-of-concept approaches to improve PLCG2 expression to reduce AD risk. In preliminary work weidentified a novel PLCG2 splice variant D65-PLCG2 in human brain quantified this isoform in AD and non-ADbrain samples and identified a SNP rs1071644 within the variant exon that correlates with expression of thisnovel isoform. Remarkably rs1071644 is associated with increased AD risk (p=9x10-8). Rs1071644 appearsto be a novel AD risk factor because this SNP is not co-inherited with either the GWAS SNP rs12446759 orP522R according to LDpair. In summary our global hypothesis is that genetic variants impact PLCG2 splicingand/or expression to alter PLCG2 function and thereby modulate AD risk. To explore this hypothesis wepropose these Specific Aims: 1: Identify and quantify PLCG2 isoforms expressed in human brain as afunction of AD neuropathology and genetics. 2: Compare PLCG2 and D65-PLCG2 protein expressionand function. 3: Translate PLCG2 splicing genetics to identify modulators predicted to reduce AD risk.Successful completion of these studies will reveal rs1071644 as a novel AD risk factor that acts via PLCG2splicing show that the AD GWAS SNP rs12446759 alters expression of a novel RP11-960L18_PLCG2isoform test whether the D65-PLCG2 represents a gain or loss of function and begin to translate thesefindings to pharmacologic modulation. By defining the extent that genetics regulate PLCG2 expression to alterAD risk these results will inform drug development targeting this pathway.

project_terms:
Address;Affect;Alternative Splicing;Alzheimer's Disease;Alzheimer's disease risk;Binding;Biological Assay;Brain;Exons;Genetic;Genetic Diseases;Genetic Polymorphism;Human;Inherited;Knowledge;Length;Mediating;Molecular;Mutation;PLCG2 gene;Pathway interactions;Phospholipase;Population;Protein Isoforms;Proteins;RNA;RNA Decay;RNA Splicing;Receptor Signaling;Risk Factors;Role;Sampling;Signal Transduction;TREM2 gene;Testing;Translating;Variant;Work;aging brain;drug development;genetic variant;genome wide association study;improved;in silico;insight;knock-down;loss of function;neuropathology;novel;pharmacologic;protein expression;protein function;prototype;receptor;success;targeted agent

public_health_relevance:
We have identified a novel PLCG2 splice variant that is increased in human brain by a polymorphism that isassociated with the risk of Alzheimers disease. In this proposal we will confirm these preliminary findings testwhether the PLCG2 isoform generates a stable and functional PLCG2 protein and identify splicing modulatorsthat improve PLCG2 splicing to reduce AD risk. Overall this proposal will provide quantitative insights intoPLCG2 expression relative to AD risk test the role of splicing in PLCG2 and begin to translate our findingsinto a potential pharmacologic approach.


application_id: 10888380
project_number: 5R21HL169804-02
project_title: The Role of Lipids in Obesity-mediated Protection in Sepsis
administering_ic: NHLBI
award_notice_date: 2024-06-13
opportunity_number: RFA-HL-23-018
application_type: 5
activity_code: R21
ic: HL
serial_number: 169804
program_official: ZHOU, GUOFEI
project_start_date: 2023-07-15
project_end_date: 2025-06-30
study_section: ZHL1-CSR-K(M1)
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: SHRIDAS, PREETHA
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
TITLE: The role of lipids in obesity-mediated protection in sepsisABSTRACTSepsis is an important clinical problem for which no specific therapies are currently available. Clinical studiesindicate that obesity is paradoxically associated with improved survival in sepsis; however as obesity is a riskfactor for a wide variety of pathologies it cannot be recommended as an option to protect against sepsis. It istherefore important to understand the underlying mechanisms that lead to obesity-mediated protection in sepsisas a step towards the development of novel therapeutic approaches. In this study we will utilize existing clinicaldata and biospecimens derived from sepsis patients to explore a connection between metabolic adaptation andobesity-mediated protection in sepsis. In Specific Aim 1 we will evaluate the association between obesity statusand plasma lipid levels during sepsis using existing clinical data and plasma samples from the ARDSNet-SAILSclinical trial. In Specific Aim 2 we will determine whether plasma lipid levels influence sepsis outcomes by firstcorrelating plasma lipid levels with major sepsis outcomes such as mortality length of hospital stay organdysfunction and related biological/physiological variables. Additionally we will investigate whether the protectiveeffect of obesity in improving sepsis survival is abolished with the lipid-lowering drug rosuvastatin. The long-termgoal of this work is to identify parameters related to obesity-mediated protection in sepsis which can be furthermechanistically investigated and lead to the development of potential therapeutic interventions for sepsis.

project_terms:
Abbreviations;Acceleration;Acute;Acute Lung Injury;Acute-Phase Proteins;Adipose tissue;Biological;Biological Specimen Banks;Body mass index;Carbohydrates;Cardiovascular Diseases;Categories;Characteristics;Cholesterol;Citric Acid Cycle;Clinical;Clinical Data;Clinical Research;Clinical Trials;Critical Illness;Data;Development;Energy Supply;Energy-Generating Resources;Fatty Acids;Fever;Functional disorder;Funding Opportunities;Future;Glucose;Goals;Human;Human Biology;Impairment;Inflammation;Ketone Bodies;Length of Stay;Life;Lipids;Lipolysis;Malignant Neoplasms;Measures;Mediating;Medical;Metabolic;Mission;Modeling;National Heart Lung and Blood Institute;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;Obese Mice;Obesity;Organ;Outcome;Pathology;Pathway interactions;Patients;Phagocytosis;Pharmaceutical Preparations;Physiological;Placebos;Plasma;Play;Process;Production;Proteins;Recommendation;Reporting;Research;Risk Factors;Role;Sampling;Science;Sepsis;Tachycardia;Therapeutic Intervention;Translational Research;Triglycerides;Up-Regulation;Work;anorexic;data repository;diet-induced obesity;healthy weight;human disease;immune activation;improved;improved outcome;lipid metabolism;mortality;mouse model;novel therapeutic intervention;pre-clinical;protective effect;response;rosuvastatin;septic;septic patients;therapeutic development;translational potential;treatment group

public_health_relevance:
PROJECT NARRATIVEObesity is paradoxically associated with improved survival during sepsis and other critical illnesses; howeverthe mechanistic basis for this protection is not understood. This project will investigate whether circulatinglipids which are elevated in the obese are associated with improved outcomes in sepsis patients. Theobtained data will allow for future mechanistic studies to further understand the processes at play.


application_id: 10888223
project_number: 5R01HD080205-10
administering_ic: NICHD
award_notice_date: 2024-07-17
opportunity_number: PA-18-480
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(90)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-08-01
project_title:
Effects of activity dependent plasticity on recovery of bladder and sexual function after human spinal cord injury

project_abstract:
AbstractBladder and bowel complications have consistently been rated as of the upmost importance bythe spinal cord injury (SCI) population. Importantly both bladder and bowel distention havebeen identified as primary triggers of autonomic dysreflexia (AD) in individuals with cervical andupper thoracic level lesions (majority of SCI population) a systolic blood pressure rising oftenmore than 20 mmHg and remaining at these values with intolerable symptoms (poundingheadache and/or chills for example). We have recently documented as part of our current R01this massive unmodulated sympathetic reflex which causes widespread vasoconstriction(presenting as severe hypertension) as a limitation for bladder capacity in numerous researchparticipants. Anecdotally many who use clean intermittent catheterization for bladdermanagement report using AD symptoms daily as a signal of bladder fullness and time foremptying an unsafe practice that needs addressing. Additionally we and others havedocumented in questionnaires regular occurrences of AD symptoms during bowel programs andin ongoing lab-based studies there have been numerous instances of AD upon insertion of arectal probe either for bladder cystometry (for recording abdominal pressure) or during anorectalmanometry. The goals of the current multi-disciplinary study incorporating critical cross viscero-visceral intersystem interactions are 1) to investigate in a controlled laboratory setting and thenwith mobile at-home monitoring the extent severity and frequency of occurrence of AD withrespect to daily bladder and bowel function in conjunction with identifying potential underlyingmechanisms by examining urinary biomarkers for several specific vasoactive hormones and 2)to regulate cardiovascular (CV) function therapeutically as part of bladder and bowelmanagement using spinal cord epidural stimulation which our CV team have shown cannormalize blood pressure.

project_terms:
Address;Anodes;Atrial Natriuretic Factor;Attenuated;Autonomic Dysfunction;Autonomic Dysreflexia;Biological Markers;Bladder;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Caring;Catheterization;Cathodes;Cervical;Chest;Chills;Data;Electrodes;Event;Feedback;Frequencies;Goals;Guidelines;Headache;Heart Rate;Home;Home environment;Homeostasis;Hormones;Human;Hypertension;Hypotension;Individual;International;Intestines;Laboratories;Lesion;Location;Maintenance;Manometry;Measures;Monitor;Norepinephrine;Outcome;Participant;Persons;Physiological;Piloerection;Population;Quality of life;Questionnaires;Recommendation;Recovery;Rectum;Reflex action;Renin;Reporting;Research;Severities;Sex Functioning;Signal Transduction;Societies;Spinal Cord;Spinal cord injury;Symptoms;System;Tension Headache;Therapeutic;Time;Training;Urodynamics;Vasopressins;Visceral;abdominal pressure;blood pressure elevation;blood pressure regulation;improved;indexing;mobile application;multidisciplinary;pressure;prevent;programs;psychologic;response;time interval;urinary;vasoconstriction;voltage;wearable device

public_health_relevance:
NarrativeBoth bladder and bowel distention have been identified as primary triggers of autonomicdysreflexia in individuals with spinal cord injury a sudden sharp rise in blood pressure withintolerable symptoms such as pounding headache and/or chills. We have recently documentedas part of our current R01 this massive unmodulated sympathetic reflex which causeswidespread vasoconstriction (presenting as severe hypertension) as a limitation for bladdercapacity in numerous research participants. The goals of the current multi-disciplinary studyincorporating intersystem interactions are 1) to investigate in a controlled laboratory setting andthen with mobile at-home monitoring the extent severity and frequency of occurrence ofautonomic dysreflexia with respect to daily bladder and bowel function in conjunction withidentifying potential underlying mechanisms by examining urinary biomarkers for severalspecific vasoactive hormones and 2) to regulate cardiovascular function therapeutically as partof bladder and bowel management using spinal cord epidural stimulation.


application_id: 10887478
project_number: 5K23AR079583-03
project_title: Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness
administering_ic: NIAMS
award_notice_date: 2024-07-10
opportunity_number: PA-20-205
application_type: 5
activity_code: K23
ic: AR
serial_number: 079583
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2022-08-08
project_end_date: 2027-07-31
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 14923231
contact_pi: MAYER, KIRBY P
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Survival of critical illness such as sepsis and acute respiratory failure is accompanied by seriousphysical complications with many patients acquiring long-term impairments. Mechanisms and factors thatimpede the recovery of muscle size and function after hospitalization are not understood. It is unclear ifrecovery after critical illness leads to a subsequent deficiency in the ability to make new proteins (proteinsynthesis) or if a catabolic/inflammatory environment persists preventing muscle regrowth which involvesmuscle stem cell (satellite cell) fusion to myofibers. We will address gaps in knowledge by studying skeletalmuscle proteostasis cellular environment and RNA and mitochondrial biogenesis after critical illness withclosely aligned physical function outcomes. Understanding the cellular environment in the period after hospitalrelease and how it impacts muscle protein turnover will direct efforts to effective therapies to acceleratemuscle regrowth. The overall goal of this application is to identify cellular properties of muscle that maycontribute to long-term physical disability in survivors of critical illness. Overall I hypothesize that aberrantcellular processes in muscle are underlying prolonged functional impairments in patients after critical illness. InAim 1 we will determine the longitudinal trajectory of muscle and physical function recovery and establishmuscle morphological and cellular characteristics in patients after critical illness. We hypothesize that patientswith higher severity of illness in the ICU and with longer duration of mechanical ventilation will have the mostpersistent muscle weakness and deficits in muscle power in recovery. In Aim 2 we will identify cellularmechanisms that contribute to muscle dysfunction after critical illness. We hypothesize that patients withpersistent muscle weakness and fatigue have impaired mitochondrial function compared to controls. Moreoverwe hypothesize that survivors of critical illness have elevated myofibrillar protein synthesis and ribosomebiogenesis in early recovery but muscle regrowth does not occur due to elevated proteolysis. The overarchinggoal of this proposal focuses on elucidating the factors that lead to muscle mass dysregulation in recovery andinform why some patients develop persistent disability and others gradually improve. The proposed mentoringteam provides the knowledge and training to develop into an independent clinical investigator integrating basicand applied science. The proposed training plan in Aim 1 emphasizes clinical trial methodologies and complexlongitudinal analyses. For aim 2 the training focuses on skeletal muscle experiments; specifically knowledgeto assess muscle proteostasis mitochondrial content and function and muscle morphology. I will learn thetechnical skills to examine skeletal muscle including stable isotope labeling immunohistochemistry westernblot analysis and microscopy will be gained. Moreover the proposed research and training plan provides thenecessary training and mentorship to translate findings in this proposal into the development of targetedrehabilitation and pharmacological interventions in future R01 studies.

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

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


application_id: 10886074
project_number: 5K23HD109471-02
project_title: Systemic Mediators and Biomarkers of Injury in Preterm Infants with Intermittent Hypoxemia
administering_ic: NICHD
award_notice_date: 2024-06-13
opportunity_number: PA-20-205
application_type: 5
activity_code: K23
ic: HD
serial_number: 109471
program_official: CHAKHTOURA, NAHIDA ABDO
project_start_date: 2023-07-12
project_end_date: 2024-08-18
study_section: Pediatrics Study Section[CHHD-A]
contact_pi_person_id: 14544147
contact_pi: ABU JAWDEH, ELIE G
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT This proposal describes a mentored training and research plan that will facilitate the development of ElieAbu Jawdeh M.D. Ph.D. to an independent clinical and translational investigator in neonatal respiratory controland intermittent hypoxemia (IH). Dr. Abu Jawdeh will complement his current background as a neonatologistand a clinical scientist to attain new knowledge in basic science methods and biomarker science. The goal oflearning basic science techniques and methods is imperative for Dr. Abu Jawdeh to make the leap intounderstanding mechanisms of injury from IH and develop treatments in the future. He will achieve these goalsthrough structured mentorship rigorous hands-on laboratory experiences formal classwork and skills training.A team of mentors with an established track record in clinical translational and basic sciences will oversee Dr.Abu Jawdehs development and progress to research independence. Despite significant progress in neonatal intensive care preterm infants continue to suffer from significantmorbidities and neurodevelopmental impairment. The societal cost of prematurity is approximately 26 billiondollars with the cost of care for an extremely preterm infant being 20 times that of a late preterm infant. Majorconsequences of prematurity are apnea and lung disease that lead to repeated occurrences of IH; episodic dropsin blood oxygen saturation. These IH episodes occurring up to hundreds of events/day have a cumulative effecton neonatal outcomes. While the evidence linking IH to impairments is mounting the degree of IH associatedwith injury and pathophysiological mechanisms for IHs contribution to injury remain unclear. This knowledgegap in the mechanistic understanding of IH creates a critical barrier to improving clinical outcomes. Our goal forthis proposal is to better understand mechanisms and biomarkers of injury from IH in order to discover and titratetreatments in the future. Through both a prospective clinical cohort of preterm infants and in vitro cell cultureexperiments we will first test the hypothesis that IH increases systemic circulating ligands (bio-mediators) thatinjure brain cells using in vitro cell culture system of oligodendrocyte progenitor cells (OPC). Identifying bio-mediators and pathways of cell death and injury from IH will help develop treatments that we will also explore invitro. Then we will investigate a promising biomarker Neurofilament-L (NfL) for IH-related brain injury andpredictor of early neurological outcome. Identifying biomarkers of injury will allow prognostication of neonataloutcomes and monitoring of IH treatment effectiveness and titration in the future. We have pilot data to supportboth our Aims and hypotheses. This will be the first time such studies and mechanisms are investigated inpreterm infants with IH.

project_terms:
Adult;Animal Model;Apnea;Axon;Basic Science;Biological Markers;Blood;Blood - brain barrier anatomy;Brain Injuries;Caffeine;Caring;Cell Culture System;Cell Culture Techniques;Cell Death;Cells;Central Nervous System;Cessation of life;Clinical;Clinical Investigator;Clinical Sciences;Complement;Data;Development;Development Plans;Disease;Doctor of Medicine;Doctor of Philosophy;Drops;Early identification;Enzyme-Linked Immunosorbent Assay;Event;Exclusion;Frequencies;Future;Generations;Goals;Health Care Costs;Hypoxemia;Impairment;In Vitro;Incubated;Infant;Inflammation;Inflammatory;Injury;Intervention;Knowledge;Lead;Learning;Ligands;Link;Lung Diseases;Measures;Mediator;Mentors;Mentorship;Methods;Monitor;Morbidity - disease rate;Neonatal Intensive Care;Neonatal Intensive Care Units;Nervous System Trauma;Neurodevelopmental Impairment;Neurofilament-L;Neurological outcome;Neurological status;Newborn Infant;Nurses;Oligodendroglia;Outcome;Oxygen;Pathway interactions;Patients;Pattern;Plasma;Premature Birth;Premature Infant;Process;Protein Fragment;Proteomics;Published Comment;Quality of life;Research;Risk;Role;Science;Scientist;Severities;Statistical Models;Structure;Supplementation;TLR2 gene;Techniques;Testing;Time;Titrations;Training;Translational Research;Treatment Effectiveness;Urine;Ventilator;Work;biomarker identification;blood-brain barrier crossing;blood-brain barrier function;brain cell;care costs;cell injury;clinical biomarkers;cohort;comparison control;early detection biomarkers;efficacious treatment;experimental study;extreme prematurity;improved;indexing;inhibitor;laboratory experience;neonatal morbidity;neonatal outcome;neonatal respiration;neurobehavior;oligodendrocyte progenitor;outcome prediction;premature;prognostication;prospective;pulmonary function;receptor;respiratory;skills training;societal costs;stem cells;synergism;systemic inflammatory response;therapy development;tool;translational scientist;treatment strategy;white matter injury

public_health_relevance:
PROJECT NARRATIVEPreterm infants (~0.4 million born in the US yearly) are at risk for frequent blood oxygen drops (IntermittentHypoxemia (IH)) that are linked to multiple short- and long-term neonatal morbidities leading to both lifelongimpairments and increased burden on health care cost. Our study investigates both markers and mechanismsof brain injury from increased intermittent hypoxemia in preterm infants. These data will contribute to ourunderstanding of brain injury from intermittent hypoxemia and identify potential targets for developing treatmentsin the future to improve IH and associated impairments.


application_id: 10885972
project_number: 5R01DE030939-04
project_title: A T.fosythia-derived protease inhibitor in periodontal health and disease
administering_ic: NIDCR
award_notice_date: 2025-05-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 030939
program_official: MCNEALY, TAMARA L
project_start_date: 2021-07-12
project_end_date: 2027-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: BAGAITKAR, JUHI
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:
Chronic inflammation in periodontitis is driven in part by the excessive uncontrolled proteolytic activity in theinfected periodontium. Well recognized periodontal pathogens including Porphyromonas gingivalis (Pg)Treponema denticola Tannerella forsythia (Tf) and Prevotella intermedia secrete proteases that contribute toinitiation and propagation of inflammatory reaction. The inflammation is inadvertently associated with release ofhost proteases from immune which not only add to tissue destruction by degradation of proteinaceouscomponents of extracellular matrix and enhancement of inflammation but are also the major executioners ofirreversible periodontal tissue damage. On the other side neutrophil serine proteases (NSPs) are essential forneutrophil antibacterial functions and control of inflammatory processes. In this respect it is fascinating that Tfproduces a lipoprotein a bacterial serpin (serine protease inhibitor) referred to as miropin. Miropin located onthe Tf cell surface efficiently inhibits a broad range of serine and cysteine proteases of diverse specificities andorigin including human NSPs (elastase and cathepsin G) cysteine cathepsin L and bacterial enzymes includingLys-specific gingipain (Kgp) produced by Pg. Kgp together with Arg-specific gingipains (RgpA and RgpB) isabsolutely essential virulence factor responsible for P. gingivalis pathogenicity in several animal models ofinfection. Nevertheless it was surprising that wild-type Tf totally abolished Pg-induced morbidity and mortality inmiropin-dependent manner during co-infection in a murine subcutaneous chamber model (our preliminary data).Based on these results we hypothesized that Tf-derived miropin plays a dual yinyang role in the pathobiologyof periodontitis. Furthermore we theorized that taking advantage of miropin unique structural features allowingit to inhibit proteases of different specificities using at least 3 different active sites within the reactive site loop wewill produce supermiropins of selective specificities targeting either host- or bacteria-derived proteases.Cumulatively the main objective of this proposal is to unravel the role of miropin-expressing Tf in thepathobiology of periodontitis as outlined in Specific Aims: (i) determine effect of miropin in Tf-Pg co-infection ongingival inflammation and alveolar bone loss (ABL) in a mouse oral gavage periodontitis model; (ii) geneticallyengineer Tf mutant strains expressing a supermiropin that inhibits a wide range of host and gingipains; (iii)investigate effects of purified recombinant inhibitors and Tf strains expressing them on neutrophil functions; and(iv) elucidate the mechanisms underlying the roles of host proteases and gingipains in pathogenic interactionsbetween Pg and Tf in oral lung and chamber models of infection using Tf strains expressing supermiropinstargeting selective sets of proteases. This knowledge will create novel perspectives in the treatment ofperiodontitis.

project_terms:
Active Sites;Affect;Alveolar Bone Loss;Animal Model;Anti-Bacterial Agents;Automobile Driving;Bacteria;Binding Sites;Biological Response Modifiers;Blood coagulation;Caspase;Cathepsin G;Cathepsin L;Cell surface;Cells;Chronic;Clinical;Communities;Complex;Cysteine;Data;Dental Plaque;Disease;Elastases;Enzymes;Event;Extracellular Matrix;Extracellular Matrix Proteins;Forsythia;Genetic Engineering;Gingiva;Goals;Gram-Negative Anaerobic Bacteria;Growth Factor;Health;Human;Immune;Infection;Inflammation;Inflammatory;Knowledge;Light;Lipoprotein (a);Lung;Lys-gingipain;Modeling;Morbidity - disease rate;Mus;Names;Nature;Nutrient;Oral;Organism;Osteitis;Outcome;Pathogenesis;Pathogenicity;Peptide Hydrolases;Periodontal Diseases;Periodontal Pocket;Periodontitis;Periodontium;Play;Porphyromonas gingivalis;Prevention;Prevotella intermedia;Process;Prokaryotic Cells;Protease Inhibitor;Reaction;Recombinants;Research;Resolution;Role;Serine Protease;Serine Proteinase Inhibitors;Serpins;Side;Signal Transduction;Site;Specificity;Testing;Thrombus;Tissues;Treponema denticola;Virulence;Virulence Factors;Yin-Yang;chronic inflammatory disease;co-infection;controlled release;design;dysbiosis;fascinate;gingipain;in vivo Model;inhibitor;member;mortality;mutant;neutrophil;novel;pathobiont;pathogen;periodontopathogen;receptor;scaffold;subcutaneous;subgingival biofilm;subgingival microbiome;theories

public_health_relevance:
Tannerella forsythia is a Gram-negative anaerobic bacterium a member of dysbiotic subgingival bacterial floraconsidered the causative agent of a chronic inflammatory disease of the periodontium (chronic periodontitis).This bacterium is a unicorn among prokaryotes since it produces a unique protease inhibitor referred to miropinefficiently targeting host and bacterial serine and cysteine proteases of divergent specificities. As such miropinmay play a dual yinyang role in the pathobiology of periodontitis and this study is designed to cast light on thecontribution of miropin-expressing T. forsythia to health or disease of the periodontium.


application_id: 10885944
project_number: 5R01DE026963-07
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2024-07-01
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 026963
program_official: MCNEALY, TAMARA L
project_start_date: 2017-09-01
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Periodontitis is a highly prevalent disease associated with several debilitating systemic conditionsincluding vascular and lung diseases diabetes mellitus and pre-term birth. The most recent epidemiologicalevidence suggests that tobacco smoking accounts for the majority of destructive periodontal disease cases indeveloped nations. Smoking enhances infection rates and enriches numbers of a key periodontal pathogenPorphyromonas gingivalis. However the mechanisms underlying this phenomenon are in need of elucidation. Inthe first iteration of award facilitated by a two year NIGMS-funding mechanism we generated an 80000 colonytransposon sequencing library for P. gingivalis strains ATCC 33277 and exploited this resource to: (i) Successfully identify 256 genes that are putatively essential for surviving tobacco-induced stress; (ii) Delineate a core stress genome commonly required for tobacco-survival epithelial colonization and subcutaneous abscess formation; and (iii) Validated several genes as conditionally essential for P. gingivalis to survival of cigarette smoke- induced stress in vitro by generating single gene deletion mutants that exhibit either reduced absolute fitness in competition assays with the parental P. gingivalis strain in smoked medium; (iv) We have also generated a novel murine model of tobacco-exacerbated periodontitis. We now plan to build on these successes via three specific aims as follow:Aim 1: Further elucidate P. gingival CSE-related survival strategies by generating mutants in single genesthat are both CSE-essential (TnSeq data) ;and tobacco-regulated (RNAseq and qPCR); yet not compromised intheir ability to colonize oral epithelial cells (TIGK model) or immune resistance (murine abscess model).Aim 2: Determine in vivo relevance of putatively CSE-essential genes using a murine smoke-exposurechamber model in a chronic Baker model of P. gingivalis-induced periodontitis.Aim 3: Establish the broad applicability of data gathered in Aims 1 and 2 by confirming biological functionand distribution of CSE essential genes in multiple P. gingivalis strains. Long term advances are likely to include (a) A better understanding of how P. gingivalis thrives in atobacco-toxin rich environment; (b) Future therapeutic targeting of essential genes to control P. gingivalisinfection in smokers (CSE-essentiality data) and in general (multiple disease-relevant conditions core stressgenome data); (c) Alternate treatment regimens for smokers based on mechanistic insight into smoke-inducedand/or exacerbated periodontal diseases;and (d) The establishment of an essential gene database for tobacco-enhanced pathogens that will facilitate the identification of common bacterial strategies for surviving tobaccosmoke exposure thus broadening the significance of the research beyond the oral cavity.

project_terms:
Abscess;Adult;Alveolar Bone Loss;Anaerobic Bacteria;Award;Bacteria;Basic Science;Biological Assay;Biological Process;Blood Vessels;Cells;Chronic;Cigarette;Clinical;Communicable Diseases;Complex;Consumption;Data;Databases;Developed Countries;Diabetes Mellitus;Disease;Dose;Economic Burden;Environment;Epidemiology;Epithelial Cells;Epithelium;Essential Genes;Exhibits;Exposure to;Financial cost;Funding Mechanisms;Future;Gene Deletion;Genes;Genome;Gingiva;Growth;Health;Homologous Gene;Immune;Immune response;In Vitro;Infection;Inflammation;Invaded;Libraries;Lung Diseases;Modeling;Mouth Diseases;Mus;National Institute of General Medical Sciences;New Zealand;Nicotine;Oral;Oral cavity;Osteitis;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Persons;Physiology;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Prevention;Refractory;Research;Resistance;Resources;Scandinavia;Smoke;Smoker;Smoking;Standardization;Stress;Subcutaneous abscess;System;Testing;Tissues;Tobacco;Tobacco smoke;Tobacco smoking behavior;Tooth structure;Toxin;Treatment Protocols;Variant;Vascular Diseases;Virulence;Work;biological adaptation to stress;cigarette smoke;cigarette smoke-induced;fitness;immune resistance;in vivo;infection rate;insight;mouse model;mutant;non-smoker;novel;novel vaccines;oral cavity epithelium;pathogen;periodontopathogen;success;therapeutic target;tobacco regulation;tobacco smoke exposure;trait;transcriptome;transcriptome sequencing;translational potential;transposon sequencing

public_health_relevance:
PROJECT NARRATIVETobacco smoking is the leading environmental cause of periodontitis (a destructive gum disease).Many periodontal pathogens are highly resistant to the plethora of toxic insults contained in cigarette smokeincluding the representative bacterium Porphyromonas gingivalis.We will identify and characterize those P. gingivalis genes that facilitate this Gram-negative anaerobe not onlyto survive but to thrive in tobacco-rich environments.


application_id: 10885423
project_number: 1R21AG087332-01
project_title: Changes in protein glycosylation due to translation of mannosidases encoded by circular RNAs
administering_ic: NIA
award_notice_date: 2024-04-23
opportunity_number: PAR-22-094
application_type: 1
activity_code: R21
ic: AG
serial_number: 087332
program_official: GRAY, ERIN EMILY
project_start_date: 2024-05-01
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1 AN-Q (55)]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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:
SummaryChanges in protein N-glycosylation are a hallmark of Alzheimers disease (AD) but the molecular mechanismsfor alterations in protein N-glycosylation are unknown. Mannosidases are key enzymes in protein N-glycosylationthat participate in glycan processing in the Golgi. Only two pre-mRNAs involved in protein N-glycosylation formabundant circular RNAs (circRNAs): MAN2A1 and MAN1A2. CircMAN2A1 expression correlates withAlzheimers disease whereas circMAN1A2 remains constant. We found that circMAN2A1 is translated after itundergoes adenosine to inosine RNA editing catalyzed by ADAR1-p150 (adenosine deaminase acting on RNA).During AD progression the overall RNA editing of circRNA increases suggesting that circRNA-encoded proteinswill be more and more translated. Due to their generation through backsplicing circMAN2A1 encoded proteinslack the endoplasmic signal sequence and are cytosolic. Two of the three circMAN2A1 encoded proteins containthe catalytic active site and could be active. Transfection studies followed by lectin blots showed thatcircMAN2A1-encoded proteins change protein N-glycosylation. We hypothesize that the expression ofcircMAN2A1-encoded proteins correlates with AD progression and alters protein N-glycosylation. Similarly theincrease in circRNA editing will increase circMAN1A2-encoded protein expression. The hypothesis will be testedin two specific Aims where in Aim#1 we characterize the expression of circMAN2A1 and circMAN1A2 in brainduring AD development using immunohistochemistry Western blot and RNAseq on tissue from AD subjectstest their suitability as biomarkers and determine their intracellular localization. In Aim#2 we will determine theinfluence of circMAN2A1 and circMAN1A2-encoded proteins on glycan formation using in vitro assays and celltransfections followed by glycan analysis.The work is highly innovative using the first antisera against circRNA-encoded proteins and investigates for thefirst time the role of an endogenous circRNA-encoded protein. It is significant as it addresses protein N-glycosylation as a key pathological feature for AD for which no molecular mechanisms are known so far.

project_terms:
ADAR1;Active Sites;Address;Adenosine;Affect;Alpha-mannosidase;Alternative Splicing;Alzheimer's Disease;Alzheimer's disease brain;Antibodies;Biochemical;Biological Markers;Brain;Brain region;Cells;Cerebrospinal Fluid;Complex;Cytosol;Development;Disease;Disease Progression;Dolichol;Endoplasmic Reticulum;Enzymes;Fractionation;Generations;Genetic Transcription;Golgi Apparatus;Hippocampus;Human;Immune Sera;Immunohistochemistry;Inflammation;Inosine;Interferon alpha;Lectin;Link;Mannose;Mannosidase;Measures;Modification;Molecular;Neurofibrillary Tangles;Neurons;Parietal Lobe;Pathologic;Peptide Signal Sequences;Polysaccharides;Protein Glycosylation;Protein Isoforms;Proteins;RNA;RNA Editing;RNA-specific adenosine deaminase 3;Research;Role;Serum;Severity of illness;Site;Testing;Time;Tissues;Transfection;Translating;Translations;Transmembrane Domain;Western Blotting;Work;beta-site APP cleaving enzyme 1;circular RNA;dsRNA adenosine deaminase;early detection biomarkers;endoplasm;entorhinal cortex;experimental study;glycosylation;in vitro Assay;in vitro testing;induced pluripotent stem cell;innovation;knock-down;mRNA Precursor;new therapeutic target;novel;overexpression;protein expression;response;tau Proteins;tau aggregation;therapeutic target;transcriptome sequencing

public_health_relevance:
Changes in protein N-glycosylation are a hallmark of Alzheimers disease. The expression of circular RNAsencoding mannosidase MAN2A1 correlate with AD progression and we showed that they are translated. Wewill test the correlation of circMAN2A1 encoded proteins with AD and the contribution of the encoded proteinsto changes in protein N-glycosylation.


application_id: 10884906
project_number: 5R01MD016864-03
project_title: K-VAC: Kentucky Vaccinating Appalachian Communities
administering_ic: NIMHD
award_notice_date: 2024-03-04
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: MD
serial_number: 016864
program_official: JONES, NANCY LYNNE
project_start_date: 2022-07-15
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-HDM-V(90)]
contact_pi_person_id: 6914381
contact_pi: KIVINIEMI, MARC T
other_pis: CARDARELLI, KATHRYN MARIE
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTVaccination of adults is central to control of SARS-CoV-2/COVID-19 and multiple other infectious diseases.Failure to engage in vaccine uptake is a complex multilevel systems problem--individual factors such asfatalism lack of factual information medical and government mistrust and political affiliation are all knowninhibitors to vaccine uptake as are community factors such as lack of access limited delivery mechanismsand messages from untrusted communicators. Thus addressing vaccine hesitancy requires a multilevelintervention that aligns and addresses individual relational and structural elements to incorporate all of thenecessary and sufficient components to increase uptake. COVID-19 vaccine uptake among Appalachianresidents has been unacceptably low with rates plateauing months ago. Appalachian Kentucky encompassesa number of population characteristics that add up to a "perfect storm" for a vaccine hesitant population.Structurally the region is rural with many communities geographically isolated and lacking access to healthcare. This in addition to poverty low education and high levels of chronic disease place this population atsignificant risk of complications and mortality due to COVID-19 infection. In a population that historically hasdistrusted institutions vaccination interventions must leverage culturally appropriate community partnershipsand strategies. The purpose of this community-engaged study is to optimize SARS-CoV-2 vaccine uptake bythis highly vulnerable Appalachian Kentucky population. We will achieve three specific aims: Aim 1: Using acommunity-engaged approach elucidate: a) key themes for message content and framing that addressindividual-level factors b) trusted communicators to deliver culturally-sensitive messages and c) structuralbarriers to effective vaccine delivery as well determining to what degree such factors are community-specificversus more generalizable. Aim 2: Using a cluster randomized trial design assess the efficacy of a multilevelintervention that delivers individual-level target messaging tailored for theme and presentation by trusted localcommunicators AND that provides structural components to facilitate easy and acceptable access tovaccination delivery. Aim 3: Determine the process factors that affect reach acceptance and implementationfidelity for the intervention components as well as necessary adaptation components for broadertransferability dissemination and delivery of the intervention. Our long-term goal as a research team is todevelop effective multilevel intervention strategies that can be used to address vaccine hesitancy inAppalachian and similar rural populations for existing vaccination concerns.

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

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


application_id: 10884522
project_number: 5R01HL160910-03
project_title: Platelet Metabolism in Diabetes Mellitus
administering_ic: NHLBI
award_notice_date: 2024-09-05
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 160910
program_official: GOLDBERG, ILANA GRACE
project_start_date: 2022-09-20
project_end_date: 2026-06-30
study_section: Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT]
contact_pi_person_id: 8688832
contact_pi: WANG, QINGJUN
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Heart disease and stroke are the No. 1 and 5 causes of deaths in the US. Type 1 diabetes mellitus (T1DM)significantly increases the risk for heart attacks and strokes. Intense glycemic control has been reported toreduce major cardiovascular events by >30% suggesting that hyperglycemia is one of the major contributors toT1DM-associated heart attack and stroke risk escalation. However how T1DM and hyperglycemia exacerbatesuch risk is unclear. Platelets are vascular first-responders that activate for hemostasis upon blood vesseldamage; whereas pathogenic platelet activation leads to spurious thrombosis and acute vascular obstruction.T1DM and hyperglycemia lead to platelet hyperactivity and increased propensity to form thrombi. This proposalsaims to understand how hyperglycemia causes platelet hyperactivity and thrombosis in T1DM and to developnew therapeutic strategies to mitigate T1DM-associated heart attacks and strokes. Utilizing an integratedmetabolism toolkit including state-of-the-art Stable Isotope Resolved Metabolomics (SIRM) we demonstratedcritical role of altered platelet metabolism in thrombin-induced platelet activation. Specifically thrombinstimulation alters platelet metabolism that is centered on glycogen metabolism pentose phosphate pathway(PPP) and fructose 16-bisphosphate (F16BP) namely the glycogen-PPP-F16BP axis modulating energyredox and calcium homeostasis in platelets and leading to their activation. Literature and our compellingpreliminary data further reveal that hyperglycemia increases glycogen storage and its mobilization that generatesATP PPP inhibition reactive oxygen species and intracellular calcium all of which are in line with increasedpropensity for platelets to activate. Therefore our overarching hypothesis is that hyperglycemia changes theglycogen-PPP-F16BP axis in platelets to drive platelet hyperactivity and thus thrombotic risk in T1DM. In Aim 1we will delineate these hyperglycemia-induced changes in the glycogen-PPP-F16BP axis in platelets isolatedfrom T1DM patients and normal healthy platelets subject to acute hyperglycemia in vitro. In Aim 2 we willdetermine how modulation of the glycogen-PPP-F16BP axis by pharmacological and genetic means suppresseshyperglycemia-induced platelet hyperactivity in vitro. In Aim 3 we will determine how modulation of the glycogen-PPP-F16BP axis by pharmacological and genetic means reduces hyperglycemia-exacerbated thrombosis andstroke in animal models. Our team is in a unique position to address our hypothesis as we possess recognizedexpertise in metabolism and metabolomics (Qingjun Wang PhD and Matthew Gentry PhD) platelet biology(Sidney Whiteheart PhD) T1DM (Lisa Tannock MD) and stroke (Justin Fraser MD and Jill Roberts PhD) andwe have strong partnership with the University of Kentucky Metabolomics Redox Metabolism and RodentSurgery Cores. Upon completion of the proposed project we will have presented a novel mechanism formetabolic dysregulation in platelets to mediate hyperglycemia-induced platelet hyperactivity and thrombosis inT1DM and will have identified new therapeutic targets for mitigating T1DM-associated heart attacks and strokes.

project_terms:
Acute;Address;Affect;Animal Model;Arterial Injury;Binding;Biological Assay;Biology;Blood Glucose;Blood Platelets;Blood Vessels;Blood coagulation;Buffers;Calcium;Carbon;Cardiovascular system;Cause of Death;Chelating Agents;Citric Acid Cycle;Clot retraction;Coagulation Process;Consumption;Data;Development;Diabetes Mellitus;Doctor of Philosophy;Enzymes;Event;Fibrin;Fructose;Genetic;Gluconeogenesis;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glycogen;Glycogen Phosphorylase;Glycolysis;Heart Diseases;Hemostatic function;Homeostasis;Human;Hyperactivity;Hyperglycemia;Impairment;In Vitro;Incidence;Insulin-Dependent Diabetes Mellitus;Kentucky;Kinetics;Knowledge;Lead;Learning;Literature;Mediating;Metabolic;Metabolic Pathway;Metabolism;Middle Cerebral Artery Occlusion;Modeling;Morbidity - disease rate;Mus;Myocardial Infarction;NADP;Obstruction;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Pathogenicity;Pathway interactions;Patients;Pentosephosphate Pathway;Phosphoric Monoester Hydrolases;Phosphorylases;Platelet Activation;Positioning Attribute;Production;Protein Dephosphorylation;Pulmonary Embolism;Reactive Oxygen Species;Reduced Glutathione;Regulation;Reporting;Rest;Risk;Risk Reduction;Rodent;Role;Source;Streptozocin;Stroke;Testing;Thrombin;Thrombosis;Thrombus;Universities;chelation;diabetic patient;first responder;glucose metabolism;glucose uptake;glycemic control;glycogen metabolism;in vivo;inhibitor;inorganic phosphate;metabolomics;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;pharmacologic;platelet function;stable isotope;stroke risk;thrombotic;tool

public_health_relevance:
Project Narrative Type 1 diabetes mellitus (T1DM) a condition of high blood glucose greatly increases the risk of heartattacks and strokes; yet how T1DM exacerbates heart attacks and strokes is unclear. This proposal looks intohow high blood glucose alters glucose-related metabolic pathways in platelets making them more prone toactivation and blood clot formation. The knowledge gained from our studies will facilitate development of newtherapeutic strategies to reduce the risk of heart attacks and strokes in diabetic patients.


application_id: 10883923
project_number: 4R01AG070952-02
project_title: Dynamic GABA and Glutamate Neurotransmission in Alzheimers Disease and Aging
administering_ic: NIA
award_notice_date: 2024-01-29
opportunity_number: PAR-19-070
application_type: 4
activity_code: R01
ic: AG
serial_number: 070952
program_official: DIBATTISTA, AMANDA
project_start_date: 2021-02-15
project_end_date: 2026-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTAlzheimers disease (AD) progression and normal aging are complex and often heterogeneous processesinvolving functional changes to neuronal and glial elements that are not just related to neuronal cell loss [1-4143]. Prior in vitro and in vivo data support that aberrant regulation of glutamate neuronal systems can be acontributor to neuronal degeneration in aging and likely a contributor to the age-dependent development of AD[1 4 6-8]. We think that because there is a dearth of treatment and monitoring options our study will help in thefuture development of therapeutics and non-invasive spectroscopic monitoring techniques for AD. Recently wehave successfully adapted our enzyme-based microelectrode arrays (MEAs) which are designed to preciselymeasure tonic and phasic neurotransmitter release in discrete brain structures in awake animals for use in agedrodents and AD mouse models [54-56 79 112]. A major knowledge gap in AD and aging involves changes inthe excitatory/inhibitory balance between glutamate (Glu) and GABA release and regulation [9-15]. We believethat the use of our new recording technology will improve our understanding of the glutamate/GABA interplay inan AD model and in normal aging. Our recent studies using this superior technology now allows themeasurements of tonic and phasic glutamate levels found that rats >18 months of age have normal or elevatedbasal Glu levels compared to younger rats. Thus some animals have elevated glutamate while others do not.As outlined in NIH Notice NOT-AG-18-051 & related announcement PAR-19-070 issues surrounding age andits role in dementia are critical in furthering our understanding of the metabolic and pathological changes thataffect signaling in neuronal circuits and networks. We will use young and aged normal and the APPNLh/NLh xPS1P264L/P264L knock-in mouse (APP/PS1 KI) that does not overexpress APP or PS1 or use artificial promotersmaking it an ideal system for the study of how aging affects the development of AD-related neuropathology [86-90]. We will use our novel methods to simultaneously record GABA and glutamate signaling in either the CA1region of the hippocampus or Frontal Cortex. We will first behaviorally characterize all animals so that we candetermine potential correlations between the behavioral performance of mice and glutamate and GABA releaseand/or regulation in the hippocampus (Morris water maze test) and frontal cortex (spatial memory variant ofMorris water maze test) [115] and performed as per [116]. Finally mice that are studied will undergo apathological examination to evaluate neurodegeneration by evaluating reactive gliosis may be present by lookingat Iba1 and GFAP. Collectively these studies will allow us to compare the effects of normal aging in male andfemale to the effects seen from a mouse model of AD on the balance of glutamate and GABA signaling and itsrelationship(s) to cognitive function in both male and female animals towards the development of noveltherapeutics to possibly treat the development and progression of AD.

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

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


application_id: 10883861
project_number: 3R35ES032876-03S2
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2023-07-07
opportunity_number: PA-21-071
application_type: 3
activity_code: R35
ic: ES
serial_number: 032876
suffix: S2
program_official: CARLIN, DANIELLE J
project_start_date: 2022-02-09
project_end_date: 2029-06-30
study_section: ZES1-LWJ-D(R3)
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTLung cancer is the leading cause of cancer death with little improvement in survivability over many decades.Understanding and support for lung cancer have suffered from the stigma that the disease is merely aconsequence of tobacco use when in fact other agents are a major factor in the disease. Many people with lungcancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However whilelung cancer kills more people than colon breast and prostate cancer combined it receives less federal fundingthan each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All establishedlung carcinogens cause CIN yet the mechanisms for how they do have received little attention. Metal exposureis a worldwide health concern. Metals cause lung cancer and carcinogenic metals are a component in tobacco.Metals are poor mutagens but potently induce CIN yet how metals cause lung cancer and CIN is poorlyunderstood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induceCIN in lung cancer. We use hexavalent chromium [Cr(VI)] a human lung carcinogen of major public healthconcern as our primary metal of interest although we will compare Cr(VI) outcomes with other metal lungcarcinogens. We will study how Cr(VI) induces structural and numerical CIN considering human lung fibroblastepithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types tomore complex three-dimensional mixed cell culture studies. We enhance and deepen our understanding ofthese mechanisms with a One Environmental Health approach which leverages the ability of wildlife to resistCr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover we maximize theimpact of these findings by translating our outcomes into animals and into a powerful and unique collection ofhuman subjects and populations ranging from workers with primarily Cr(VI) exposure to workers with a mixedmetal exposure including Cr. This combined approach of humans animals and cell lines with One EnvironmentalHealth tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particularwe will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable atthe cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus ourproposed R35 program will revolutionize our understanding of Cr(VI) CIN metal carcinogenesis and lungcancer while also providing important insights for other cancers that involve CIN. Outcomes will include majorscientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic;2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells thathave transformed and 4) how to prevent neoplastic change from occurring leading to improved risk assessmenttreatments and health outcomes for people exposed to metals.

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

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


application_id: 10883701
project_number: 5R01DA049333-05
administering_ic: NIDA
award_notice_date: 2024-07-26
opportunity_number: PAR-18-747
application_type: 5
activity_code: R01
ic: DA
serial_number: 049333
program_official: DUNSTON, SHEBA KING
project_start_date: 2020-09-30
project_end_date: 2026-07-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-08-01
project_title:
Research Examining Factors Associated with the Opioid Crisis among Underserved African Americans (REFOCUS)

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

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

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


application_id: 10883625
project_number: 5R01AA030487-03
administering_ic: NIAAA
award_notice_date: 2024-06-07
opportunity_number: RFA-AA-21-016
application_type: 5
activity_code: R01
ic: AA
serial_number: 030487
program_official: FREEMAN, ROBERT
project_start_date: 2022-08-15
project_end_date: 2027-05-31
study_section: ZAA1-DD(17)V
contact_pi_person_id: 12488104
contact_pi: LAUCKNER, CAROLYN
other_pis: KERSHAW, TRACE S
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-06-01
project_title:
Evaluation of a Combined Motivational Interviewing and Ecological Momentary Intervention to Reduce Risky Alcohol Use among Sexual Minority Males and Transgender Individuals

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

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

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


application_id: 10883565
project_number: 5F32HD112067-02
administering_ic: NICHD
award_notice_date: 2024-03-19
opportunity_number: PA-21-048
application_type: 5
activity_code: F32
ic: HD
serial_number: 112067
program_official: NURMINSKAYA, MARIA
project_start_date: 2023-04-24
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1-F10B-C(20)L]
contact_pi_person_id: 78669791
contact_pi: OWEN, MEREDITH
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-24
project_title:
Establishing the Relationship Between Muscle Quality and Joint Loading for Individuals with Transtibial Amputation

project_abstract:
ABSTRACTThe loss of function following an amputation is profound and life altering. To date interventions to improve longterm functional abilities and limit detrimental secondary injuries (e.g. osteoarthritis) have not been effective.While multifactorial the effect of altered muscle quality specifically of the quadriceps on functional outcomesfor individuals with transtibial amputation is poorly understood. Work by our group in other conditions showsthat muscle quality changes after injury and is directly related to loss of function including protracted strengthdeficits. My long-term career goal is to combine my background in bioengineering with the skills developedthrough this F32 training grant to develop novel therapeutic strategies and devices to improve function andquality of life for individuals with lower limb loss. This training award will allow me to 1) assess the musclequality of the thigh of the intact and residual limbs with novel magnetic resonance imaging sequences 2)predict the relationship between thigh muscle quality and muscle strength and finally 3) characterize therelationship between muscle quality muscle strength and knee joint loading for individuals with transtibialamputation. Muscle quality will be assessed using novel magnetic resonance imaging techniques includingT1rho mapping and diffusion tensor imaging. These techniques will provide new insights on the muscle tissuemorphology including any increases in fibrotic tissue or decreases in pennation angle and fiber tract lengththat affect the muscle's overall ability to function properly and efficiently. To evaluate muscle strength andmobility participants will complete maximum voluntary isometric knee flexion and validated surveys targetingself-reported mobility. Finally joint contact forces of the intact limb will be assessed through a computationalmusculoskeletal model. Through the work proposed for this NRSA F32 I will refine and gain skills critical for asuccessful career as an independent translational researcher seeking to collaborate with clinician scientists.Training will include skills development in medical imaging acquisition and analysis clinically relevant strengthassessment instrumented motion analysis musculoskeletal modeling clinical research management andstatistical analysis. Including in the training plan are accessory career development activities including relatedcourse work (e.g. biomechanics statistics medical imaging) grant writing workshops opportunities forresearch dissemination and mentorship that will all be key components to developing a well-rounded skill setfor a future academic career. My selected sponsor institution and mentors will provide the perfectenvironment for encouraging success.

project_terms:
Activities of Daily Living;Affect;Amputation;Anisotropy;Award;Biomechanics;Biomedical Engineering;Clinical Research;Collaborations;Computer Models;Data;Degenerative polyarthritis;Development;Devices;Diffusion Magnetic Resonance Imaging;Educational workshop;Environment;Evaluation;Event;Fellowship;Fiber;Fibrosis;Foundations;Functional disorder;Future;Gait;Goals;Grant;Health;Image;Imaging Techniques;Individual;Infiltration;Injury;Institution;Intervention;Isometric Exercise;Joints;Kinetics;Knee;Knee joint;Length;Life;Limb structure;Lower Extremity;Magnetic Resonance Imaging;Maps;Measures;Mechanics;Medical Imaging;Mentors;Mentorship;Modeling;Morphology;Motion;Movement;Muscle;Muscle Fibers;Muscle function;Musculoskeletal;National Research Service Awards;Orthopedics;Outcome;Participant;Patient Self-Report;Postdoctoral Fellow;Property;Quality of life;Relaxation;Research Personnel;Risk;Scientist;Side;Statistical Data Interpretation;Surveys;Technical Expertise;Techniques;Testing;Thigh structure;Time;Tissues;Training;United States;Walking;Work;Writing;career;career development;clinically relevant;design;functional improvement;functional outcomes;image processing;improved;insight;instrument;joint loading;kinematics;limb amputation;limb loss;long-term sequelae;loss of function;muscle strength;novel;novel imaging technique;novel therapeutic intervention;prosthesis wearer;prosthetic socket;quadriceps muscle;research data dissemination;residual limb;skill acquisition;skills;statistics;success;translational scientist

public_health_relevance:
Project NarrativeStrength deficits following transtibial amputation contribute to gait asymmetries resulting in increased risk ofosteoarthritis development in the intact knee for the over 1 million individuals with limb loss in the UnitedStates. The underlying causes of muscle dysfunction leading to these negative secondary complications arepoorly understood. We propose to characterize the relationships between muscle quality and strength of thequadriceps of the amputated side to resulting knee joint loading of the intact limb.


application_id: 10883173
project_number: 1R01AG081356-01A1
project_title: Phase I Cell Therapy for Maintaining Cholinergic Circuits in the Spectrum of Alzheimers Disease
administering_ic: NIA
award_notice_date: 2024-06-13
opportunity_number: PAR-23-081
application_type: 1
activity_code: R01
ic: AG
serial_number: 081356
suffix: A1
program_official: CLARKE, AKANNI YAO
project_start_date: 2024-06-15
project_end_date: 2029-05-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: QUINTERO, JORGE E;SLEVIN, JOHN T.;VAN HORNE, CRAIG
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTCognitive decline in the spectrum of Alzheimers disease (AD) including Dementia with Lewy Bodies (DLB) andParkinsons disease with dementia (PDD) takes a severe toll on patients family and society in suffering andcost. The memory and cognitive deficits observed in AD DLB and PDD are attributable in large part to a loss ofcholinergic function and neurons in the brain especially but not limited to cells in the nucleus basalis of Meynert(NBM). The greatest unmet need for AD DLB and PDD are therapies that can go beyond symptom treatment topossibly stabilize or maintain cholinergic circuits. As part of clinical trials we have been delivering mixed-cellpro-regenerative peripheral nerve tissue (PNT) to areas of the brain affected in neurodegenerative disease. Herewe propose a Phase I single surgical-center double-blinded clinical trial involving bilateral autologous PNT intothe NBM to address repair cell support of cholinergic neurons. The major goal of this trial is to identify thefeasibility and safety of bilateral implantation of reparative PNT to the NBM with the eventual goal to improvefunction of cholinergic neurons in dementias. Twenty-four participants diagnosed with PD and who haveselected qualified and agreed to undergo DBS surgery of the globus pallidus internus (GPi) will be followed for24 months as part of a trial to receive at the time of DBS surgery PNT implanted bilaterally into the NBM (twelveparticipants) or an alternate target also affecting cognition in this population the substantia nigra (SN). DBS willbe implanted and programmed to provide the standard of care. Feasibility objectives will be based on the numberof participants receiving PNT delivery and the number of participants completing the 12- month and 24-monthstudy visits. For the safety objective the number of serious adverse events related to the procedure will becollected for 24 months following surgery. Cognitive safety endpoints at 12 and 24-months following surgery willbe defined as  1.5 standard deviation decrement relative to the participants estimated pre-morbid functioning.To aid in future trial designs secondary outcome analyses will use neuropsychological testing of subjects (at 12and 24-months after surgery compared to baseline) and Movement Disorder Society  Unified ParkinsonsDisease Rating Scale (MDS-UPDRS) evaluations and quality of life assessments at 6 12 and 24-months aftersurgery compared to baseline. We will continue to expand our brain bank activities in conjunction with theUniversity of Colorado Anschutz Medical Campus to assess the histological effects of the investigational celltherapy in participants who have donated their brain after death and to better characterize the disease processin our study subjects. This study is a critical step for identifying the feasibility of this NBM vs. SN design for trialingin subsequent multicenter Phase II studies and for continuing to move this approach forward as an eventualmonotherapy for the treatment of the Spectrum of AD.

project_terms:
Address;Affect;Agreement;Alzheimer's Disease;Amyloid beta-Protein;Area;Autologous;Autopsy;Basal Nucleus of Meynert;Bilateral;Brain;Cell Therapy;Cell Transplantation;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive deficits;Colorado;Contralateral;Data;Deep Brain Stimulation;Dementia;Dementia with Lewy Bodies;Deposition;Development;Diagnosis;Disease;Double-Blind Method;Etiology;Evaluation;Family;Future;Globus Pallidus;Goals;Health Care Costs;Histologic;Impaired cognition;Implant;Individual;Literature;Measures;Medical;Memory impairment;Morphology;Motor;Movement Disorder Society Unified Parkinson's Disease Rating Scale;Nerve Tissue;Neurodegenerative Disorders;Neurologic;Neurons;Neuropsychological Tests;Operative Surgical Procedures;Outcome;Parkinson's Dementia;Participant;Pathology;Patients;Performance;Peripheral Nerves;Pharmacological Treatment;Phase;Phase I Clinical Trials;Phenotype;Population;Procedures;Process;Qualifying;Quality of Life Assessment;Safety;Secondary to;Serious Adverse Event;Side;Societies;Study Subject;Substantia nigra structure;Supporting Cell;System;Time;Universities;Vascular Diseases;Visit;alpha synuclein;basal forebrain;cholinergic;cholinergic neuron;cognitive change;cognitive testing;cost;design;dopaminergic neuron;functional improvement;implantation;improved;in vivo;neurocognitive test;neuropathology;open label;pharmacologic;phase 2 study;regenerative;repaired;restoration;safety and feasibility;secondary outcome;standard of care;sural nerve;symptom treatment;tau Proteins;trial design

public_health_relevance:
PROJECTIVE NARRATIVEThe memory and cognitive deficits observed in Alzheimers disease (AD) dementia with Lewy bodies(DLB) and Parkinsons disease dementia (PDD) are largely attributable to a loss of cholinergic function andneurons in the nucleus basalis of Meynert (NBM). Here we propose a Phase I single surgical-centerdouble-blinded clinical trial involving bilateral autologous peripheral nerve tissue (PNT) into the NBM toaddress repair cell support of cholinergic neurons. The major goal of this trial is to identify the feasibility andsafety of bilateral implantation of reparative PNT to the NBM with the eventual goal to improve function ofcholinergic neurons in dementia.


application_id: 10882981
project_number: 1R01DK135603-01A1
project_title: AHR-NLRP6 interactions in gut barrier dysfunction and colitis
administering_ic: NIDDK
award_notice_date: 2024-04-23
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 135603
suffix: A1
program_official: SHEA-DONOHUE, TEREZ
project_start_date: 2024-05-01
project_end_date: 2028-04-30
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
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:Inflammatory Bowel Diseases (IBD) which consist of ulcerative colitis and Crohns disease affect as many as1.4 million people in the USA. Intestinal barrier dysfunction is one of the hallmarks associated with IBD. Currentlythere are no treatments available to target gut barrier dysfunction in IBD pathogenesis. The aryl hydrocarbonreceptor (AHR) is a transcription factor expressed in several cell types and is activated by a variety of exogenousand endogenous ligands including microbial metabolites. Activation of AHR regulates many pathophysiologicalfunctions including inflammation and gut barrier integrity. Recently we identified that the microbial metaboliteUrolithin A (UroA) is an AHR ligand that enhances gut barrier function. Treatment with UroA mitigated colitis inpre-clinical models. This proposal originated from the novel observation that selective activation of AhR by UroAin intestinal epithelial cells (IEC) is critical for the regulation of gut barrier function. This process requiresactivation of the NLRP6-IL-18 pathway in IEC to induce IL-22 from type 3 innate lymphoid cells (ILC3).Furthermore we identified that UroA-induced genes are responsible for goblet cell differentiation leading toincreased mucins and enhanced gut barrier function. In this proposal we will test the hypothesis that UroAselectively activates the AHR-NLRP6-dependent secretion of homeostatic levels of IL-18 in IEC leading to highlydifferentiated goblet cells that enhance gut barrier function reduce unwarranted inflammation and mitigate IBD.We propose three specific aims to test this hypothesis. Aim 1 will determine the role of each component of theAHR-NLRP6-IL-18/IL-22 axis in UroA-mediated protective activities against IBD pathogenesis using pre-clinicalmodels of colitis. We will establish the novel cross-talk mechanisms of IEC selective activation of AHR-NLRP6pathways that regulate IL-18 and IL-18 dependent IL-22 production from ILC3. In Aim 2 we will examine themechanisms of UroA-mediated goblet cell differentiation and production of different types of mucus that enhancegut barrier function. Aim 3 will establish the translational relevance of selective activation of IEC AHR-IL-18pathway by UroA in human IBD patient samples. Upon completion of this study the mechanisms and beneficialeffects of selective activation of the AHR-NLRP6-IL-18 axis to enhance gut barrier function and the therapeuticimplications in IBD will be established.

project_terms:
Affect;Affinity;Aryl Hydrocarbon Receptor;Attenuated;Biopsy;Cell Differentiation process;Cell Lineage;Cells;Colitis;Crohn's disease;Data;Epithelial Cells;Exhibits;Family member;Flare;Functional disorder;GKLF protein;Generations;Genes;Goblet Cells;Homologous Gene;Human;IL18 gene;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Intestines;Knock-out;Knowledge;Ligands;Lymphoid Cell;Mathematics;Mediating;Mediator;Mucin-2 Staining Method;Mucins;Mucous body substance;Mus;Natural regeneration;Nucleotides;Pathogenesis;Pathologic;Pathway interactions;Patients;Persons;Physiological;Play;Population;Pre-Clinical Model;Process;Production;Protein Family;Regulation;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tissues;Toxic effect;Tracer;Transgenic Mice;Ulcerative Colitis;Up-Regulation;aryl hydrocarbon receptor ligand;cell type;gut homeostasis;gut inflammation;improved;interleukin-18 receptor;interleukin-22;intestinal barrier;intestinal epithelium;intestinal homeostasis;microbial;mouse model;murine colitis;novel;novel therapeutics;nucleotide receptor;pre-clinical;protective effect;protective pathway;receptor;restoration;stem cells;transcription factor

public_health_relevance:
Project NarrativeUrolithin A (UroA) is a microbial metabolite and treatment with UroA attenuated colitis in pre-clinical modelswithout exhibiting toxicity. Current proposal investigates the mechanisms of selective activation of intestinalepithelial cell AHR-NLRP6 axis by microbial metabolite UroA in regulating gut barrier function under inflammatorybowel diseases (IBD) conditions. Identifying such novel mechanisms and compounds that restore guthomeostasis and block unwarranted inflammation would offer new therapeutic options to control IBD.

study_section:
Digestive System Host Defense, Microbial Interactions and Immune and Inflammatory Disease Study Section[DHMI]


application_id: 10882648
project_number: 1R01AA031043-01A1
project_title: An ethanol-sensitive Bmp-PCP dependent pathway regulating endoderm cell behaviors
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AA
serial_number: 031043
suffix: A1
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
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;Fetal Heart;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.


