# projects

application_id: 10844401
project_number: 5P20GM113226-09
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2024-03-20
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3(C2)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville (UofL) Hepatobiology and Toxicology (H&T) COBRE is a unique thematiccenter focused on liver research. The UofL H&T COBRE concentrates on the mechanisms and therapeuticstrategies for multiple forms of liver disease/injury including: Non-alcoholic fatty liver disease/non-alcoholicsteatohepatitisthe most common liver disease in the US/worldwide and is highly linked to the metabolicsyndrome; Alcoholic Liver Diseasea common problem among those who drink; Environmental ToxicantInduced Liver Injuryan increasingly recognized problem and Louisville has been a leader in this area;Hepatitis B and Cimportant causes of cirrhosis and hepatocellular carcinoma worldwide; PersonalizedMedicinean increasingly important factor in medication efficacy and most drugs are metabolized in the liver;and Drug-Induced Liver Injurythe most common reason drugs are removed from the market and animportant cause of liver failure. This COBRE brings together experienced senior mentors/investigators andpromising junior investigators to perform cross-cutting research on the unique topics of Hepatobiology andToxicology. We address critical barriers in our understanding of the development/ progression of liver diseaseand we define targets for prevention/treatment that could transform clinical practice. Specific Aims of the Hepatobiology and Toxicology COBRE are to:1. Expand and strengthen a thematically-focused program in Hepatobiology and Toxicology that helps buildand sustain the overall research infrastructure at UofL.2. Expand and strengthen the multidisciplinary program in research education mentoring and careerdevelopment in Hepatobiology and Toxicology and systematically track and evaluate the progress.3. Provide the necessary research resources and translational science/basic technologies to support state-of-the-art research in Hepatobiology and Toxicology and to ensure sustainability of the program.4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liverdiseases/toxicant exposures and communicate our findings to the public. In summary Phase I strengthened UofLs biomedical research infrastructure through the establishment ofa thematic multidisciplinary center in hepatobiology and toxicology to enhance the ability of investigators tocompete for independent funding. In Phase I we met or exceeded our metrics including 1) four of ourinvestigators transitioning to independent research funding; 2) 91 mentee and 162 total publications; 3) newrenovated laboratory space; 4) numerous presentations; 5) establishing new collaborations; and 6) >$75million in total new grant funding by H&T members. This Phase II proposal builds on our Phase I successextends and strengthens the scope of the program and provides a roadmap for sustainability.

project_terms:
Acute Liver Failure;Address;Adult;Affect;Alcoholic Liver Diseases;American;Area;Biomedical Research;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communication;Communities;Complex;Core Facility;Data Analyses;Development;Diabetes Mellitus;Discipline;Drug Interactions;Drug abuse;Ensure;Environment;Enzymes;FDA approved;Fostering;Funding;Goals;Grant;Health;Hepatitis A;Hepatitis B;Hepatitis C;Home;Homelessness;Industrialization;Industry;Injury;International;Kentucky;Laboratories;Link;Liver;Liver Failure;Liver diseases;Marketing;Mentors;Metabolic syndrome;Metabolism;Molecular Target;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Obesity;Organ;Overweight;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phase I Clinical Trials;Prevention;Primary carcinoma of the liver cells;Process;Program Sustainability;Publications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Scientist;Structure;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translational Research;United States National Institutes of Health;Universities;University resources;biobank;career development;clinical practice;drug induced liver injury;education research;experience;liver injury;liver transplantation;member;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;recruit;success;toxicant;viral liver disease

public_health_relevance:
The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic researchcenter. We have strengthened UofLs biomedical research infrastructure through the establishment of athematic multidisciplinary center in hepatobiology and toxicology to enhance the ability of investigators tocompete for independent funding. This Phase II proposal builds on our Phase I success and extends andstrengthens the scope of the program.


application_id: 10843789
project_number: 5R01AG079525-03
project_title: The impact of insulin sensitivity on the potential of metformin to delay age-related inflammation
administering_ic: NIA
award_notice_date: 2024-04-24
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 079525
program_official: SERRA, MONICA CHRISTINE
project_start_date: 2022-08-15
project_end_date: 2026-04-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
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
arra_indicator: N
project_abstract:
Inflammatory diseases limit healthspan defined as the length of one's life spent in good health. We propose anancillary study on deidentified samples from a recent NIA-funded trial Antecedent Metabolic Health andMetformin (ANTHEM) that will define traits of healthy people who would benefit from metformin interventionbefore onset of age-related health risks like chronic inflammation. ANTHEM queries an unexpected outcome ofdual interventions of metformin and exercise: metformin improved metabolic health over exercise alone inoverweight/obese insulin resistant subjects but metformin blunted exercise-mediated improvements inmetabolic health of otherwise similar insulin sensitive subjects. ANTHEM tests the impact of baseline metabolichealth on the effects of metformin monotherapy on insulin sensitivity and skeletal muscle mitochondria byrecruiting overall healthy subjects to address the general paradigm that lifespan enhancers must start prior toonset of age-related co-morbidities for maximal benefit. The proposed work will add an inflammation arm toANTHEM. The primary endpoint of our ancillary study will be cytokine profiles a bioinformatic combination ofcytokines that revealed a previously unappreciated Th17 profile that naturally develops systemically with age.This profile is similar to the systemic profile in type 2 diabetes and thus suggests a mechanistic link betweeninflammation and this major challenge to healthspan. Metformin-mediated repair of mitochondrialbioenergetics in combination with improved non-mitochondrial autophagy lowered the Th17 profile in samplesfrom older subjects. In contrast metformin lowered IL-10 production by cells from younger subjects arguablyincreasing inflammation. Our unique approach to defining inflammation thus clarified mechanisms ofmetformin action while echoing concepts from the exercise study summarized above: metformin may benefitsubjects with sub-clinical health challenges while having a negative effect on healthier people. We will applysimilar approaches to query metformin's effect on inflammation by analyzing deidentified ANTHEM samples totest the hypothesis that metformin intervention in healthy subjects with naturally low insulin sensitivity reducescytokines known to fuel chronic inflammation by improving mitochondrial bioenergetics and increasing non-mitochondrial autophagy in immune cells. The secondary hypothesis is that metformin will have either anegative or no impact on immune cells from highly insulin sensitive subjects. Mechanistic insights intometformin action on immune cells will be analyzed relative to changes in body composition aging biomarkersglycemic control and skeletal muscle outcomes collected for ANTHEM. Parallel ex vivo manipulation ofmitochondrial function and autophagy in immune cells will establish cause/effect relationships amongstmetformin cell physiology and cytokine profiles. Success with the proposed project coupled with ANTHEMoutcomes will define traits of people who would benefit from preventative metformin and perhaps moreimportantly to identify those who may be harmed by proactive metformin use.

project_terms:
Address;Age;Age of Onset;Age related comorbidities;Aging;Ancillary Study;Anti-Inflammatory Agents;Autophagocytosis;Bioenergetics;Bioinformatics;Blood specimen;Body Composition;Cell Physiology;Cells;Chronic;Clinical Trials;Complex;Confusion;Coupled;Data;Defect;Diabetes Mellitus;Disease;Double-Blind Method;Enhancers;Equilibrium;Exercise;FRAP1 gene;Funding;Goals;Health;Human;Immune;In Vitro;Inflammaging;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-10;Interleukin-6;Intervention;Length;Life;Link;Mediating;Metabolic;Metabolism;Metformin;Methods;Mitochondria;Muscle Fibers;Muscle Mitochondria;Muscle function;Myeloid Cells;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organelles;Outcome;Overweight;Oxidation-Reduction;Pathogenicity;Pathway interactions;Persons;Pharmaceutical Preparations;Placebos;Positioning Attribute;Production;Reporting;Risk;Sampling;Serum;Skeletal Muscle;Source;T-Lymphocyte;Testing;Tissues;Variant;Work;age related;age related decline;aged;aging biomarker;aging related;arm;clinical practice;cytokine;glycemic control;healthspan;improved;inflammatory marker;insight;insulin sensitivity;life span;predictive modeling;primary endpoint;recruit;repaired;response;success;systemic inflammatory response;trait

public_health_relevance:
Numerous studies support the premise that inflammation rises in aging. Drugs with anti-inflammatory actions such as metformin may promote healthspan the length of one's life spentin good health especially if given prior to onset of age-related declines. We will analyzedeidentified samples from an NIA-funded clinical trial to test the possibility that baseline insulinsensitivity impacts the ability of metformin to ameliorate pathogenic inflammation.


application_id: 10843375
project_number: 3R01MH119119-04S1
project_title: Estrogen Effects on ADHD and Cognition
administering_ic: NIMH
award_notice_date: 2023-09-06
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: MH
serial_number: 119119
suffix: S1
program_official: PACHECO, JENNIFER LYNN
project_start_date: 2023-08-06
project_end_date: 2024-08-31
contact_pi_person_id: 8204810
contact_pi: MARTEL, MICHELLE M
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:
This supplemental request is sought for a project for which the entire investment is at risk if the short-termlongitudinal follow up of our target N is not completed. Participant recruitment and retention for the first year ofthe project was negatively impacted by the Covid pandemic. Specifically laboratory protocols and procedureshad just been developed when Covid began and subsequently had to be retooled to allow for remoteadministration with resulting slowed initial recruitment rates. However as the pandemic has been ending wehave been able to begin making up ground with participant recruitment. We are currently running double thenumber of people originally projected each month. We currently have 85 participants who have completed orbegun data collection and at least 60 of those participants have completed data collection and have usabledata. Given we are averaging at least 6-8 additional participants per month we expect to reach an N of 100 bythe end of this final year of the project at least 80 of whom should have usable data. Therefore at this currentrate of data collection we project that we should need an additional 6-8 months to reach our projected N of120 a number chosen based on power analyses to allow us to detect the small to moderate effects typicallyseen in hormone work. Further allowing for anovulatory cycles or incomplete data or problems with hormoneassay of any samples (which is just beginning) a full one year cushion is desirable. Pilot data and initialhormone assay results look promising suggesting innovative effects consistent with aims but a full N is criticalto having sufficient power to conduct rigorous short term longitudinal mediation analyses. Most of theremaining budget or approximately 500000 of the remaining 700000 is allocated to hormone assay and if weachieve our target N as we are currently projected to with a one-year NCE we will need that money forhormone assay as well as participant pay. The critical currently unmet need is to continue to pay study staffnamely the project coordinator 2 graduate student RAs and PI to be able to recruit retain and followparticipants over one month run diagnostic and cognitive laboratory visits and administer the project byproviding oversight and overseeing meetings respectively. These expenses are minor compared to the largeremaining budget that will be used to cover paying participants and assaying saliva for hormones core to theproject aims. This investment is particularly important given the novelty and practical importance of pilot datafindings which suggest assessment of ADHD in young women needs to take into account cycle phase andthat ADHD treatments including medication need to account for cycle changes in ADHD symptoms in women(or assigned female at birth) and associated effects on its cognitive and affective mechanisms perhaps throughtitration of medication or timed intervention approaches.

project_terms:
Adolescence;Adult;Affect;Affective;Animal Experiments;Animals;Attention;Attention deficit hyperactivity disorder;Back;Basic Science;Biological;Biological Assay;Budgets;COVID-19 pandemic;Childhood;Clinical;Cognition;Cognitive;Communities;Data;Data Collection;Diagnostic;Estradiol;Estrogen decline;Estrogens;Exhibits;Feasibility Studies;Female;Goals;Gonadal Steroid Hormones;Hormonal;Hormones;Human;Impairment;Impulsivity;Intervention;Investments;Laboratories;Link;Longitudinal Studies;Mediation;Menstrual cycle;Minor;Neurocognitive;Ovarian hormone;Participant;Patient Recruitments;Persons;Pharmaceutical Preparations;Phase;Prevalence;Procedures;Progesterone;Protocols documentation;Puberty;Quasi-experiment;Rattus;Research Design;Risk;Risk Factors;Running;Sampling;Short-Term Memory;Symptoms;Testing;Thinking;Titrations;Translating;Visit;Withdrawal;Woman;Work;animal data;assigned female at birth;clinical practice;clinical predictors;clinically significant;cognitive function;cognitive performance;comorbidity;design;falls;follow-up;graduate student;hypothalamic pituitary gonadal axis;improved;innovation;male;meetings;pandemic disease;participant retention;perimenstrual;power analysis;recruit;remote administration;response;salivary assay;sex;treatment response;usability;young adult;young woman

public_health_relevance:
The current project will evaluate how changes in hormones across the menstrual cycle influence Attention-Deficit/Hyperactivity Disorder (ADHD) and thinking in young adult women. Results will change the way ADHDis understood by suggesting hormonal influences on ADHD symptom expression in women changing clinicalpractice by requiring consideration of sex pubertal status menstrual cycle phase or even hormone profiles inassessment and treatment of ADHD in women.


application_id: 10842251
project_number: 5R01GM138837-04
project_title: Ex vivo single molecule tools to analyze membrane receptor dynamics
administering_ic: NIGMS
award_notice_date: 2024-05-15
opportunity_number: PAR-19-253
application_type: 5
activity_code: R01
ic: GM
serial_number: 138837
program_official: YEH, ALVIN TIEN-WEI
project_start_date: 2021-06-03
project_end_date: 2026-05-31
study_section: Enabling Bioanalytical and Imaging Technologies Study Section[EBIT]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Membrane receptors play a crucial role in many physiological processes throughout the body bymediating communication between cells. Single molecule imaging has been used extensively tostudy membrane receptor assembly and stoichiometry in vitro using isolated protein and to alesser extent cell culture. While studies in isolated cellular systems provide insight into manyprocesses they lack the context of the complex environment present in an animal wherecommunication between cell types residing in tissue is critical for receptor activity. Single-molecule imaging of native proteins synthesized in vivo would provide a direct approach tomeasure processes such as receptor dimerization that regulate physiological activity. Howevercurrent methods are not capable of applying single molecule techniques to study the regulationof protein dynamics taking place within the complex environment of an animal. We have maderecent advances in the development of ex vivo single molecule techniques to monitor changes inprotein assembly that occur within specific organs. The goal of this proposal is to develop andvalidate ex vivo single molecule tools that provide new capabilities to monitor the properties ofoligomeric membrane receptor assembly resolve cell type and subcellular region specific singlemembrane receptors and automate single molecule data analysis using a machine learningplatform. This novel ex vivo technology will enable researchers to take a snap shot in time of themembrane receptor dynamics that took place in the mouse and monitor changes in membranereceptor assembly in response to changes in the animal's physiological environment such asdisease and exposure to therapeutics.

project_terms:
Address;Animal Communication;Animal Disease Models;Animal Model;Animals;Biological;Biological Models;Brain;Brain region;Cardiac;Cell Culture Techniques;Cells;Chemicals;Classification;Communication;Complex;Consumption;Data;Data Analyses;Data Set;Development;Dimerization;Disease;Encapsulated;Environment;Exposure to;Future;Genes;Goals;Heart;High Performance Computing;Image;In Vitro;Knock-in;Knock-in Mouse;Machine Learning;Manuals;Measurement;Mediating;Membrane;Membrane Proteins;Methodology;Methods;Monitor;Mus;Organ;Pharmaceutical Preparations;Pharmacotherapy;Physiological;Physiological Processes;Play;Population;Preparation;Process;Process Measure;Property;Protein Biosynthesis;Protein Dynamics;Proteins;Regulation;Research;Research Methodology;Research Personnel;Role;RyR2;Ryanodine Receptor Calcium Release Channel;Sampling;Signal Transduction;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Training;Vesicle;animal tissue;cell type;cluster computing;convolutional neural network;design;imaging capabilities;in vivo;insight;large datasets;molecular imaging;nanoscale;nanovesicle;novel;open source;postsynaptic neurons;presynaptic;protein purification;prototype;receptor;response;sex as a biological variable;single molecule;stoichiometry;technique development;therapeutic target;tissue preparation;tool;trafficking

public_health_relevance:
Membrane receptors are important therapeutic targets for many diseases and are expressed throughout thebody. Understanding the role of receptor assembly in the complex environment of a live animal is an importantstep in understanding their mechanism of activation and regulation. We will develop ex vivo single-moleculemethods that for the first time will enable quantitative studies of stoichiometry for receptors extracted frommice.


application_id: 10841481
project_number: 5P20GM148326-02
project_title: Sustained eIF5A hypusination at the core of brain metabolic dysfunction in TDP-43 proteinopathies
administering_ic: NIGMS
award_notice_date: 2024-04-22
opportunity_number: PAR-19-313
application_type: 5
activity_code: P20
ic: GM
serial_number: 148326
project_start_date: 2023-05-15
project_end_date: 2024-09-30
study_section: ZGM1-RCB-4
subproject_number: 8911
contact_pi_person_id: 12103073
contact_pi: SELENICA, MAJ-LINDA B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ ABSTRACT  TAR DNA-binding protein 43 (TDP-43) pathology is associated with clinical dementia and occurs in more than half of clinically diagnosed Alzheimers disease (AD) patients (1 2). The discovery of limbic-predominant TDP-43 encephalopathy (LATE) emphasized the importance of age-related TDP-43 proteinopathy with or without co-morbid AD pathological hallmarks. The lack of disease-modifying agents against TDP-43 pathology creates an urgent need to identify novel therapeutic pathways against TDP-43 proteinopathy. Interestingly regional disruption of glucose uptake and utilization is linked to the progression of AD neuropathology (3-5) and yet there is no consensus on the effect of TDP-43 on glucose and energy homeostasis in the diseased brain (6). This proposal will address this significant gap in knowledge by studying the impact of the eIF5A hypusination pathway on the brains metabolic state in TDP-43 pathology. eIF5A is an initiation/elongation factor and the only protein undergoing hypusination (eIF5AHyp). Deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) activity convert a single lysine to a hypusine moiety. Our feasibility data finds that TDP-43 pathology in AD brain and TDP-43 mouse models induces DHS expression and hypusine levels. Additionally we show that enhanced hypusination exacerbates TDP-43 pathology dysregulates brain glucose homeostasis and exerts mitochondrial bioenergetic defects. Our central hypothesis states that DHS-targeted strategies reducing hypusine levels will ameliorate TDP-43 neuropathogenesis by restoring brain glucose metabolism and mitochondrial bioenergetics upstream of cognitive decline and neurodegeneration. In Aim 1 we will establish how conditional deletion of the DHS (DHSko) in the adult forebrain of the TDP-43 transgenic mouse model will affect the brain metabolic transcriptomic profile via NanoString analysis and determine biological signatures that define the eIF5AHyp - TDP-43 phenotype. We will also utilize the CNS-Met Metabolomics Core to measure brain metabolite levels while biochemically determining metabolic proteins enzymes and TDP-43 pathology. We will further elucidate how DHSko can rescue LTP cognitive performance and neurodegeneration associated with TDP-43 phenotype of a novel TDP-43 animal model. In Aim 2 we will define the role of eIF5AHyp on the mitochondrial bioenergetics of neurons and astrocytic-responsive neurons. We will establish how DHS inhibition rescues mitochondrial bioenergetics and restores metabolite balance in primary cells. We will also determine the cellular and mitochondrial TDP-43 accumulation and mitochondrial structure integrity. Overall the proposed studies will provide evidence that the eIF5AHyp pathway in the TDP-43 phenotype is upstream of irreversible stages of dementia. It also offers the first detailed mechanisms of how reducing hypusine restores glucose dysregulation and mitochondrial dysfunction maintaining neuro-astrocytic support and healthy neuronal activity while rescuing the pathological phenotype in animal models of TDP-43 proteinopathy.

project_terms:
Adult;Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease patient;Amyloid;Animal Model;Astrocytes;Biochemical;Bioenergetics;Biological;Biological Assay;Biology;Brain;Brain Diseases;Brain region;Cells;Centers of Research Excellence;Clinical;Clinical Trials;Coculture Techniques;Consensus;Coupling;DNA-Binding Proteins;Data;Defect;Dementia;Disease;Elderly;Elongation Factor;Encephalopathies;Enzymes;Equilibrium;Failure;Functional disorder;Genes;Genetic;Genus Hippocampus;Glucose;Goals;Healthcare;Hemostatic function;Homeostasis;Imaging Techniques;Impaired cognition;Impairment;Knowledge;Link;Lysine;Mass Fragmentography;Measures;Metabolic;Metabolic dysfunction;Metabolism;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurologic;Neurons;Neuropathogenesis;Oxidative Stress;Pathologic;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Phenotype;Prosencephalon;Proteins;Rodent;Role;Severities;Structure;Synaptic plasticity;System;Technology;Therapeutic Effect;Transgenic Mice;Virulence Factors;Work;age related;behavioral phenotyping;blood glucose regulation;brain dysfunction;brain metabolism;clinical diagnosis;cognitive performance;comorbidity;deoxyhypusine monooxygenase;deoxyhypusine synthase;diabetic;diabetic patient;eIF-5A;glucose metabolism;glucose uptake;hypusine;limbic-predominant age-related TDP-43 encephalopathy;metabolomics;mitochondrial dysfunction;mouse model;nano-string;neuropathology;novel;novel therapeutics;pharmacologic;protein TDP-43;response;tau Proteins;therapeutic biomarker;therapeutic target;transcriptomics


application_id: 10841480
project_number: 5P20GM148326-02
administering_ic: NIGMS
award_notice_date: 2024-04-22
opportunity_number: PAR-19-313
application_type: 5
activity_code: P20
ic: GM
serial_number: 148326
project_start_date: 2023-05-15
project_end_date: 2028-02-29
study_section: ZGM1-RCB-4
subproject_number: 8910
contact_pi_person_id: 14823099
contact_pi: HUBBARD, WILLIAM BRAD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-03-01
project_title:
Investigating and treating metabolic deficits in the neurovascular unit following mild traumatic brain injury

project_abstract:
Traumatic brain injuries (TBIs) are a major societal and public health concern with over 1.7 million TBIs~80% of which mild are reported each year in the US. TBI is also a major risk factor for dementias andAlzheimers Disease. Mild TBI is characterized by dysfunction of the neurovascular unit (NVU) initiated bybreakdown of the blood-brain barrier and followed by synaptic dyshomeostasis. Mitochondrial dysfunction isapparent in the NVU after mild TBI accompanied by metabolic imbalance and oxidative damage. This projectwill examine the metabolic deficits of distinct components of the NVU including neuronal synapse and braincapillaries by using steady state metabolomics as well as intra-mitochondrial metabolic tracing following mildTBI. These results will be generated in conjunction with profiling of mitochondrial bioenergetics of the NVUcomponents. These studies will directly use the resources provided by the CNS-Met Metabolomics Core. P7C3-A20 which elevates NAD+ and demonstrates efficacy in TBI models will be administered alongside nicotinamidemononucleotide which is a NAD+ precursor to examine therapeutic effect at restoring alterations in metabolismand functional outcomes. The completion of these studies will generate an enhanced understanding ofmitochondrial dysfunction and metabolite flux in distinct components of the NVU following mild TBI and providesupportive data on a pathology-modifying drugs targeting NAD+ to treat this disease.

project_terms:
Acute;Alzheimer's Disease;Bioenergetics;Biological Assay;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;Carbon;Centers of Research Excellence;Cerebrovascular Circulation;Chronic;Citric Acid Cycle;Classification;Data;Disease;Dose;Drug Targeting;Endothelial Cells;Enhancers;Euthanasia;Female;Fostering;Foundations;Freezing;Functional disorder;Future;Genus Hippocampus;Glutamates;Glycolysis;Hippocampus;Impaired cognition;Impairment;Injury;Label;Long-Term Effects;Magnetic Resonance Imaging;Magnetism;Mass Fragmentography;Metabolic;Metabolic dysfunction;Metabolism;Mitochondria;Modeling;Neuroglia;Neurons;Nicotinamide Mononucleotide;Outcome;Oxidative Stress;Pathologic;Pathology;Patients;Pericytes;Procedures;Proteins;Public Health;Pyruvate;Rattus;Reporting;Resources;Sprague-Dawley Rats;Synapses;Techniques;Therapeutic;Therapeutic Effect;Tight Junctions;Traumatic Brain Injury;acute symptom;axonal degeneration;brain tissue;cell type;cellular targeting;cerebral capillary;cohort;dementia risk;design;functional outcomes;innovation;insight;male;metabolomics;mild traumatic brain injury;mitochondrial dysfunction;neural;neurobehavioral;neuron loss;neurovascular unit;novel;oxidative damage;primary outcome;protective efficacy;repaired;response;restoration;small molecule;therapeutic development;therapeutic target


application_id: 10841479
project_number: 5P20GM148326-02
project_title: Identifying Metabolomic Markers in Conversion to Cognitive Impairment in Parkinson's Disease
administering_ic: NIGMS
award_notice_date: 2024-04-22
opportunity_number: PAR-19-313
application_type: 5
activity_code: P20
ic: GM
serial_number: 148326
project_start_date: 2023-05-15
project_end_date: 2028-02-29
study_section: ZGM1-RCB-4
subproject_number: 8909
contact_pi_person_id: 11890992
contact_pi: YAMASAKI, TRITIA
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:
ABSTRACTParkinson's disease (PD) the most common neurodegenerative movement disorder affects anestimated six million people worldwide and costs over $23 billion annually in healthcare costs inthe US alone. A major portion of this cost is a direct result of the morbidity related to cognitiveimpairment that develops in 50-80% of PD patients. This morbidity appears to be driven bypathologic accumulation of the protein alpha-synuclein and Alzheimer disease (AD)-relatedpathologies. The ability to predict the development of cognitive impairment would have impact onprognosis treatment and clinical trial design for preventative therapies in PD. The goal of thisproject is to identify novel metabolomic markers associated with cognitive impairment in PD. Thisproject will utilize gas chromatography mass-spectroscopy (GC-MS) and liquid chromatography-mass spectroscopy (LC-MS) methods to assess the blood- and cerebrospinal fluid-derivedmetabolome from advanced PD patients without cognitive impairment. We will then assesssteady-state metabolomic profiles of plasma taken from patients before and after conversion tocognitive impairment which have been banked over time by the UK-Alzheimer's DiseaseResearch Center a portion of which have neuropathological correlation. The results of thesestudies will guide a more targeted approach to plasma biomarker evaluation before and after theconversion from normal to impaired cognition in patients drawn from the clinic population. Theresources of the CNS-Met Metabolomics Core will be essential to the completion of these aimsvia assessment of steady-state metabolomics utilizing GC-MS and LC-MS. These studies areexpected to provide new biomarker candidates for predicting conversion to cognitive impairmentin PD and data for future R01-level applications.

project_terms:
Affect;Age;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease related dementia;Amino Acids;Amyloid beta-Protein;Bile Acids;Biological Markers;Blood;Centers of Research Excellence;Cerebrospinal Fluid;Clinic;Clinical;Clinical Trials Design;Cognition;Cognitive;Communities;Consent;Data;Deep Brain Stimulation;Dementia;Deposition;Development;Diagnosis;Disease;Enrollment;Equipment;Essential Tremor;Fatty Acids;Future;Gas Chromatography;Genetic;Goals;Health Care Costs;Healthcare;Impaired cognition;Individual;Kentucky;Lipids;Mass Chromatography;Mass Spectrum Analysis;Measurement;Measures;Metabolic dysfunction;Metabolism;Methods;Mitochondria;Morbidity - disease rate;Movement Disorders;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Operative Surgical Procedures;Parkinson Disease;Parkinson's Dementia;Participant;Pathologic;Pathology;Pathway interactions;Patients;Persons;Plasma;Population;Preventive therapy;Process;Prognosis;Proteins;Protocols documentation;Publishing;Research;Resources;Sampling;Sphingolipids;Stress;Testing;Therapeutic Intervention;Time;Tissues;Tremor;Universities;Unsaturated Fatty Acids;Work;alpha synuclein;biomarker evaluation;brain tissue;candidate marker;clinical diagnosis;clinical subtypes;cognitive change;cognitive impairment in Parkinson's;cognitive testing;cost;demented;disorder control;falls;lipidomics;liquid chromatography mass spectroscopy;metabolome;metabolomics;mild cognitive impairment;mortality;motor impairment;multicatalytic endopeptidase complex;neuropathology;non-demented;novel;prognostication;sample collection;tau Proteins;therapeutic target;treatment trial


application_id: 10841476
project_number: 5P20GM148326-02
project_title: Center of Biomedical Research Excellence in CNS Metabolism
administering_ic: NIGMS
award_notice_date: 2024-04-22
opportunity_number: PAR-19-313
application_type: 5
activity_code: P20
ic: GM
serial_number: 148326
program_official: PEI, WUHONG
project_start_date: 2023-05-15
project_end_date: 2028-02-29
study_section: ZGM1-RCB-4(C1)
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
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:
Central nervous system (CNS) metabolism and neuronal excitability are interdependent and so CNSmetabolism is the biochemical basis of cognition memory and behavior. Dysregulation of CNS is implicated innumerous disorders including Alzheimers Disease epilepsy Parkinsons disease and brain injury but themechanistic connections between CNS metabolism and disease are poorly understood. The University ofKentucky (UK) College of Medicine has made significant investments over the last few years in investigatorswith metabolic and metabolomics expertise and instrumentation to support their research efforts which hasenhanced existing strengths in neuroscience cancer cardiovascular and diabetes and obesity research.Thus UK proposes to establish a unique multidisciplinary Center of Biomedical Research Excellence (COBRE)on CNS Metabolism (CNS-Met) as a strategically designed sustainable framework that promotes leading-edgeresearch focused on the role of metabolic mediators of brain function and disease. The proposedinterdisciplinary center leverages highly specialized expertise in glucose biology neuronal signalingmitochondrial metabolism systems neuroscience and data sciences as well as the presence of advancedmetabolomics and imaging capabilities to create an integrated research framework focused on CNSmetabolism. The overarching goals are to strengthen UKs neuroscience research enterprise by providing athematically focused and sustainable multidisciplinary infrastructure dedicated to defining the contribution ofmetabolism to CNS function and neurological diseases and to use this novel platform to develop promising andhighly-skilled early-stage investigators in an exciting and impactful area of CNS research. To accomplishthese goals we will meet four specific aims: (1) Develop a critical mass of funded investigators with researchprograms directly related to the COBREs unifying theme; (2) provide strong team-based mentoring combiningbasic and clinical expertise; (3) recruit new investigators to the COBRE in multidisciplinary areas of neurologicdysfunction through pilot project grant and recruitment of junior Research Project Leaders; and (4) createsynergy among research projects via critical links to strong research centers and core facilities at UK includingexisting COBREs. Emerging synergies will be developed through three research projects an AdministrativeCore a critical research core in Metabolomics all linked by strong biostatistics/bioinformatics support all ofwhich are critical to the proposed studies and will contribute to the development of institutional resources. Thescientific focus of the three research projects are brain metabolism interactions with neurological diseasespanning basic and translational perspectives. This concentration of multidisciplinary expertise focused onwidely recognized yet understudied metabolic mechanisms of neurological diseases promises significant newunderstandings of CNS metabolism overall. The CNS-Met will create a critical mass of skilled scientists whoare well equipped to lead a sustainable research center focused on CNS metabolism into the future.

project_terms:
Acceleration;Accounting;Alzheimer's Disease;Area;Behavior;Biochemical;Bioenergetics;Bioinformatics;Biology;Biometry;Brain;Brain Injuries;Cardiovascular system;Centers of Research Excellence;Central Nervous System;Chronic;Clinical;Cognition;Collaborations;Complex;Core Facility;Data Science;Dedications;Defect;Development;Diabetes Mellitus;Disease;Ensure;Epilepsy;Equipment;Extramural Activities;Faculty;Fostering;Funding;Future;Glucose;Goals;Grant;Homeostasis;Infrastructure;Institution;Investments;Kentucky;Life;Link;Malignant Neoplasms;Mediator;Medicine;Memory;Mentors;Metabolic;Metabolic dysfunction;Metabolism;Methodology;Nervous System Disorder;Nervous System Physiology;Neurologic Dysfunctions;Neurons;Neurosciences;Neurosciences Research;Obesity;Outcome;Oxidation-Reduction;Parkinson Disease;Phase;Pilot Projects;Positioning Attribute;Process;Research;Research Personnel;Research Project Grants;Resources;Rest;Role;Scientist;Severity of illness;Structure;Synapses;System;Techniques;Therapeutic;Training;Translations;Traumatic Brain Injury;United States National Institutes of Health;Universities;biomarker discovery;brain metabolism;cohort;collaborative environment;college;data science resource;defined contribution;design;glucose metabolism;imaging capabilities;insight;instrumentation;interest;investigator training;metabolome;metabolomics;mitochondrial metabolism;multidisciplinary;neuroinflammation;neuronal excitability;neuropathology;neurophysiology;neurotransmission;neurotransmitter biosynthesis;novel;programs;protein TDP-43;recruit;skills;success;sustainability framework;synergism;systems research;translational impact

public_health_relevance:
PROJECT NARRATIVE Brain metabolism central nervous system (CNS) metabolism and neuronal excitability are interdependentand dysregulation of CNS metabolism is implicated in numerous neurological disorders including AlzheimersDisease epilepsy Parkinsons disease and brain injury but the mechanistic connections between CNSmetabolism and disease are poorly understood. The unique multidisciplinary Center of Biomedical ResearchExcellence (COBRE) on CNS Metabolism (CNS-Met) proposed here is a strategically designed sustainableframework that promotes leading-edge research focused on the role of metabolic mediators of brain functionand disease with an emphasis on encouraging research excellence from Junior Research Project Leaders.


application_id: 10840784
project_number: 5R37CA227656-07
project_title: The Phosphatase PRL3 as a MYC Target and Pro-Survival Oncogene in Acute Lymphoblastic Leukemia
administering_ic: NCI
award_notice_date: 2024-03-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R37
ic: CA
serial_number: 227656
program_official: JHAPPAN, CHAMELLI
project_start_date: 2023-04-01
project_end_date: 2026-03-31
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_abstract:
ORIGINAL PROJECT SUMMARY There is a great need for the development of molecularly targeted therapies in Acute LymphoblasticLeukemia (ALL). The lack of targeted therapies for this disease is an important problem because ALL isprimarily a pediatric cancer and intensive rounds of general cytotoxic chemotherapy have severe and long-term adverse effects in children. Additionally adults and children whose ALL does not respond to cytotoxicchemotherapy or who develop relapse have a universally poor prognosis due to limited treatment options.The well-known drivers of ALL are mis-expressed transcription factors such as MYC which are not easilytherapeutically targeted without undesirable side-effects on normal cells. Preliminary data which built on anovel in vivo transplantation screen in a MYC-induced ALL model in zebrafish demonstrated that the tyrosinephosphatase PRL3 collaborated with MYC to enhance leukemia progression. In vitro and in vivo studies usinghuman cells showed that PRL3 is linked with MYC expression and plays a critical role in ALL survival.Phosphatases like PRL3 are most well-known as tumor suppressors and despite emerging evidence that somephosphatases have oncogenic abilities there are currently no phosphatase inhibitors used in the clinic forcancer patients and only one in clinical trial. The overall objective of this application is to clearly define theoncogenic role of the tyrosine phosphatase PRL3 in MYC-driven ALL and to establish that it is a novelmolecular target in this disease. The central hypothesis is that PRL3 is a direct transcriptional target of MYC andsynergizes with MYC to promote a pro-survival phenotype in ALL cells. The rationale for this research is thatPRL3 belongs to a unique family of phosphatases that can be selectively inhibited; defining the mechanismsthrough which PRL3 promotes ALL survival will provide a strong scientific rationale for the development ofPRL and other phosphatase inhibitors for use as targeted therapy for cancer patients. This hypothesis will betested by pursuing three specific aims: 1) Define a mechanism through which MYC regulates PRL3 expressionby using enChIP and biochemical approaches to assess MYC interaction with a novel enhancer region nearPRL3; 2) determine the pro-survival mechanisms that are controlled by PRL3 by utilizing an unbiased biotinligase approach to identify PRL3 substrates in ALL cells; and 3) establish that small molecule inhibition of thePRL family is a potent therapeutic strategy in ALL by completing comprehensive pre-clinical testing of threenew PRL inhibitors and a panel of FDA-approved tyrosine phosphatase inhibitors. This research is innovativebecause it departs from the status quo to use new methods to define an oncogenic role for a phosphatase incancer. The proposed research is also significant because it is expected to vertically advance and expandunderstanding of the role that phosphatases play in cancer progression. Ultimately this knowledge has thepotential to drive the development of a new class of targeted therapy for patients with acute lymphoblasticleukemia and other MYC-driven cancers.

project_terms:
Acute Lymphocytic Leukemia;Adult;Adverse effects;Apoptosis;Binding Sites;Biochemical;Biotin;Cancer Patient;Cells;Cessation of life;Child;Clinic;Clinical Trials;Collaborations;Cytotoxic Chemotherapy;DNA-Binding Proteins;Data;Defect;Development;Developmental Delay Disorders;Diagnosis;Disease;Disease Progression;Drug Targeting;Enhancers;FDA approved;Family;Gene Chips;General Population;Genes;Genetic Transcription;Growth;Human;Human Cell Line;In Vitro;Kinetics;Knowledge;Leukemic Cell;Life;Ligase;Link;MYC gene;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Methods;Mission;Modeling;Molecular Target;Normal Cell;Nucleic Acid Regulatory Sequences;Oncogenes;Oncogenic;Organ;Outcomes Research;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Play;Preclinical Testing;Prognosis;Protein Array;Protein Tyrosine Phosphatase;Public Health;Regimen;Relapse;Research;Role;Sampling;Second Primary Cancers;Signal Pathway;Single Nucleotide Polymorphism;TP53 gene;Testing;Therapeutic;Transcriptional Regulation;Transplantation;Tumor Suppressor Proteins;Zebrafish;acute lymphoblastic leukemia cell;antileukemic activity;cancer type;chemotherapy;in vivo;inhibitor;innovation;knock-down;leukemia;member;molecular targeted therapies;novel;patient derived xenograft model;pediatric patients;phosphatase inhibitor;preclinical trial;side effect;small molecule;synergism;targeted cancer therapy;targeted treatment;therapeutic target;transcription factor;translational impact;tumor progression

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because the discovery of the mechanisms through which thetyrosine phosphatase PRL3 drives leukemia progression is expected to re-define the roles that phosphatasescan have in cancer. The proposed research is therefore relevant to the NCI mission because it will provide astrong impetus for the development of phosphatase inhibitors which will be a new class of targeted therapyfor cancer patients.


application_id: 10840760
project_number: 6U01DP006632-03M001
administering_ic: NCCDPHP
award_notice_date: 2023-05-10
opportunity_number: RFA-DP-21-001
application_type: 6
activity_code: U01
ic: DP
serial_number: 006632
suffix: M001
project_start_date: 2021-05-01
project_end_date: 2026-04-30
study_section: ZDP1-KVA(02)
contact_pi_person_id: 10799084
contact_pi: JEWELL, TRACEY DANIELLE
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Kentucky Pregnancy Risk Assessment Monitoring SystemApplication for Core PRAMS funding RFA-DP-21-001

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

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


application_id: 10840376
project_number: 5K01AG070279-02
project_title: Cognitive Aging Trajectories in Survivors of Trauma
administering_ic: NIA
award_notice_date: 2024-01-17
opportunity_number: PA-20-190
application_type: 5
activity_code: K01
ic: AG
serial_number: 070279
program_official: TREVINO, MELISSA
project_start_date: 2023-05-15
project_end_date: 2028-01-31
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 8923142
contact_pi: LAWRENCE, KAREN ANN
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Dementia and the prodromal stages of cognitive decline together affect approximately 25-30% of older adultsacross the United States (U.S.). Posttraumatic Stress Disorder (PTSD) has been linked to a 111% increasedrisk of developing dementia of any type even after controlling for potential confounders such as traumatic braininjury (TBI). Therefore PTSD may be an important target for early prevention of cognitive decline and potentialprogression to dementia. Most studies on PTSD and cognition have used a cross-sectional study design andhave not examined important potential effect modifiers (e.g. sex and APOE4 carrier status) leaving a gap inour fundamental understanding of the effect of PTSD on longitudinal trajectories of cognitive functioning.Further although PTSD is more prevalent in women most research on PTSD and cognition has beenconducted in men. This proposal is of timely public health importance as the pre-pandemic lifetime prevalenceof PTSD in the U.S. was 6% but post-pandemic epidemiological findings have indicated a rise toapproximately 32% among young adults. COVID-19 events have also resulted in PTSD symptoms withoutmeeting Diagnostics and Statistical Manual of Mental Disorders 5th edition (DSM-5) Criterion A. Thereforecritical research gaps in our understanding of the effect of PTSD on cognitive aging include: 1) prospectiveinvestigation wherein temporal sequencing and rate of cognitive decline can be evaluated in the context ofPTSD 2) testing the potential modifying effects of sex and APOE4 carrier status on the relationship betweenPTSD status and cognitive decline and 3) understanding whether Criterion A is necessary when determiningthe relationship between PTSD and cognitive decline. Aims 1 and 2 will leverage existing data from theNational Alzheimer's Coordinating Center (NACC). In adults aged 55+ years multilevel modeling andinteraction analyses will determine the impact of PTSD status on trajectories rate and temporal sequence ofdomain-specific cognitive decline and will test sex and APOE4 carrier status as potential effect modifiers. ForAim 3 men and women participants aged 65+ with and without Criterion A trauma will be recruited andmultiple regression will be used to unambiguously clarify if PTSD severity (Criteria B through E) is associatedwith cognitive functioning without meeting Criterion A. This K01 award will provide training and mentorship inaging health cognitive aging sex-specific health effects of PTSD neuropsychology of PTSD longitudinalstudy design and advanced statistics and propel the PI to become an independent investigator with expertisein the effects of traumatic stress and biopsychosocial factors on cognitive aging with a sex-specific focus andin alignment with Goals B-3 B-4 and F-4 of NIAs Strategic Directions 2020-2025.

project_terms:
Accidents;Address;Adult;Affect;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Anxiety;COVID-19;COVID-19 pandemic;Clinical;Clinical Sciences;Cognition;Cognitive;Cognitive aging;Cross-Sectional Studies;DSM-V;Data;Data Collection;Dementia;Diagnosis;Diagnostic;Diagnostic and Statistical Manual of Mental Disorders;Disasters;Epidemiology;Episodic memory;Event;Funding;Goals;Health;Impaired cognition;Incidence;Intervention;Investigation;Kentucky;Link;Longitudinal Studies;Medical;Mental Depression;Mentored Research Scientist Development Award;Mentors;Mentorship;Modeling;Modification;National Center for Advancing Translational Sciences;Neuropsychology;Participant;Pharmaceutical Preparations;Post-Traumatic Stress Disorders;Prevalence;Prevention;Psychologist;Public Health;Recording of previous events;Research;Research Design;Research Personnel;Risk;Risk Factors;Severities;Sex Differences;Short-Term Memory;Survivors;Symptoms;Testing;Training;Translational Research;Trauma;Traumatic Brain Injury;United States;Universities;War;Woman;Women's prevalence;aged;apolipoprotein E-4;biopsychosocial factor;carrier status;clinical center;cognitive function;cohort;comorbidity;dementia risk;disability;executive function;first responder;functional decline;human old age (65+);meetings;men;mild cognitive impairment;military veteran;multilevel analysis;older adult;pandemic disease;post-pandemic;pre-clinical;pre-pandemic;processing speed;prospective;recruit;sex;sexual assault;statistics;traumatic stress;young adult

public_health_relevance:
PROJECT NARRATIVEPTSD prevalence is high and PTSD increases the risk of dementia. The proposed research will: a) investigatethe impact of PTSD on the rate of domain-specific cognitive decline b) test potential effect modifiers includingsex of the relationship between PTSD and rate of cognitive decline and c) determine the association betweencognitive functioning and PTSD severity with and without Criterion A trauma. Successful completion of thisproject has important public health implications including indicating whether PTSD should be considered atarget for the early prevention of cognitive decline that may lead to dementia and increasing understanding ofsex differences in the relationship between PTSD and cognitive decline.


application_id: 10839937
project_number: 5R01HL150581-04
project_title: Epidural spinal cord stimulation and respiratory motor function after injury
administering_ic: NHLBI
award_notice_date: 2024-02-29
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: HL
serial_number: 150581
program_official: NATARAJAN, ARUNA R
project_start_date: 2021-05-01
project_end_date: 2026-02-28
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractRespiratory motor control deficit is the leading cause of morbidity and mortality in patients with spinal cordinjury. The long-term goal of this research is to develop a rehabilitation strategy for respiration in patients withspinal cord injury as a standard of care. Our previous findings demonstrate that respiratory function in patientswith chronic spinal cord injury can be improved by using our original inspiratory-expiratory pressure thresholdrespiratory training protocol. However the effectiveness of this intervention is limited by the levels of functionalcapacity preserved below the neurological level of injury. Our preliminary data obtained for this proposaldemonstrate that electrical spinal cord stimulation applied epidurally at the lumbar level in combination withrespiratory can activate and re-organize spinal motor networks for respiration. We propose to investigaterespiratory motor control-related responses to epidural spinal cord stimulation alone and in combination withrespiratory training. By characterization of respiratory muscle activation patterns using surfaceelectromyography in association with pulmonary functional and related cardiovascular measures we expect todetermine specific stimulation parameters needed to increase spinal excitability below level of injury toenhance responses to the input from supraspinal centers that remain after injury and to promote the neuralplasticity driven by the respiratory training. This hypothesis will be tested by pursuing two specific aims: 1)Evaluate the acute effects of epidural spinal cord stimulation on respiratory functional and motor controlproperties; and 2) Evaluate the effectiveness of epidural spinal cord stimulation combined with respiratorytraining.

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

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


application_id: 10839867
project_number: 5R01AG037868-09
project_title: Chronic Stress Glucocorticoids and Progesterone in Brain Aging
administering_ic: NIA
award_notice_date: 2024-05-14
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: HAAKENSON, CHELSEA MARIE
project_start_date: 2011-03-01
project_end_date: 2026-05-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Evidence indicates that prolonged/ repeated behavioral stress promotes brain aging. This is thought to be dueat least in part to stress associated glucocorticoid (GC) secretion which in turn binds to glucocorticoid receptorsexerting transcriptional and other effects. A key downstream mediator in this signaling pathway serum-and-glucocorticoid kinase 1 (Sgk1) accelerates and the female sex steroid progesterone (P4) blunts the effects ofGCs. However despite the negative clinical consequences of chronic stress exposure with aging and/or infemale subjects little work has examined how aging may change the stress response the mechanisms throughwhich stress may accelerate brain aging the degree to which stress-accelerated aging is dependent on GC isdriven by Sgk1 or is inhibited by P4. Our preliminary data suggests that hippocampal Sgk1 is upregulated byaging stress and GCs in white matter oligodendrocytes and that the female sex hormone progesterone (P4)blunts the effects of stress/GCs and may serve as an endogenous protectant that is lost with age in females.To address these knowledge gaps we propose 3 aims to investigate: the age-course of the response to chronicstress or chronic GCs in males and females; whether viral overexpression of Sgk1 exacerbates or systemic P4administration ameliorates stress-accelerated aging; and whether the pharmacologic sensitivity of hippocampaltissue to GC and P4 is shifted with age or chronic stress/GC. Cognitive and anxiety-related behavior bloodhormone measures and a novel panel of 205 hippocampal genes that are robustly changed with aging acrossmultiple studies will be used to test for stress/GC-accelerated aging and intervention effects as will downstreamgray and white matter Sgk1 expression and microglial response to microinjury- two processes demonstrated tobe glucocorticoid sensitive and exaggerated in white vs. gray matter in preliminary data. Thus the proposedstudies will yield essentially the first comprehensive test of the hypothesis that chronic stress acceleratestranscriptional brain aging and will illuminate sex differences in stress responsiveness and the potential roles ofGC P4 and Sgk1 in gray and white matter. Even if all of our working hypotheses are rejected by the results theproposed studies should have translational value for geriatric medicine.

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

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


application_id: 10839419
project_number: 5R01CA207772-08
project_title: Roles of Hsp47 in Breast Cancer Progression
administering_ic: NCI
award_notice_date: 2024-05-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 207772
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2027-05-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and poor survivaloutcomes. One feature of obese adipose tissue is the excess extracellular matrix (ECM)deposition/remodeling in the form of fibrosis. However function and regulation of obesity-related ECMdeposition/remodeling in cancer progression largely remain to be determined. We recently identifiedHsp47 a chaperone protein facilitating collagen secretion as a hub of the ECM transcription network.Our new data showed that Hsp47 was highly expressed in adipose tissue. Importantly increased Hsp47expression in human and mouse adipose tissues was significantly associated with obesitydevelopment. We found that adipocyte-specific deletion of Hsp47 was sufficient to suppress high fatdiet (HFD)-induced obese and mammary tumor growth which is accompanied by reduced collagendeposition/alignment and macrophage infiltration in adipose tissue. The overall objective of thisproposal is to define the mechanism by which adipocyte Hsp47 promotes obese-related fibrosis andbreast cancer progression and to explore the value of Hsp47 as a potential target to suppress obesity-associated cancer progression. Using unbiased proteomics analysis we identified asporin as a newtarget of Hsp47 in adipocytes. Based on these data the central hypothesis of this proposal is thatHsp47 induces obesity-related fibrosis by facilitating asporin secretion in adipocytes and subsequentlyenhances adipocyte plasticity and breast cancer progression. Following aims are proposed to test ourhypothesis: Aim 1. Elucidate the molecular mechanism by which adipocyte Hsp47 induces obesity- andcancer-associated ECM remodeling; Aim 2. Determine how Hsp47 regulates obesity-associated andcancer-induced adipocyte plasticity; Aim 3. Define the potential of targeting Hsp47 to suppress obesity-associate fibrosis inflammation and breast cancer progression/metastasis.

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

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


application_id: 10837427
project_number: 3R01MD016236-03S1
administering_ic: NIMHD
award_notice_date: 2023-09-12
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: MD
serial_number: 016236
suffix: S1
program_official: GILLMAN, ARIELLE SAMANTHA
project_start_date: 2021-09-26
project_end_date: 2025-06-03
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 14786675
contact_pi: MOLONEY, MAIREAD
other_pis: BADOUR, CHRISTAL L.
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Sleeping well in a changing climate: The effects of rising temperatures and extreme weather events on sleep and other aspects of health in rural Appalachia

project_abstract:
Insufficient sleep (habitual sleep duration of 6 hours) is a costly public health problem that is more prevalentamong health disparity populations (e.g. racial minorities adults of low socioeconomic status). Climate changeand climate-sensitive disasters demonstrate a detrimental impact on sleep and associated downstream healthoutcomes. Increasing temperatures are linked to diminished sleep time and quality and negative impacts areheightened among populations with fewer economic resources. Extreme weather events due to climate changeoften result in displacement trauma and economic instability; these stressors directly impair sleep. The fast-growing burden of climate-related disaster recovery disproportionately disadvantages populations with existinghealth disparities. These data hold direct relevance to our parent R01: Researching Equitable Sleep Time inAppalachia (REST-KY; MD016236). REST-KY focuses on rural Appalachian adults whose serious healthinequities include multiple health morbidities premature mortality and high rates of insufficient sleep. Whileour project was designed to evaluate mechanisms contributing to pre-existing regional sleep and healthdeficiencies over a two-year period Appalachian Kentuckys July 2022 climate-change-related catastrophicflood event has led us to broaden the scope of our research. We will recruit a cohort of 400 adults from 6insufficient sleep hotspot counties (n=200) in Appalachian KY (where 25-58% of adults report insufficientsleep 15+ nights/month) and 6 similarly rural and economically distressed non-hotspot counties. Five of the12 counties suffered widespread flood damage. The use of a mixed method longitudinal burst design in theparent R01 will allow us to evaluate mechanisms contributing to both sleep deficiencies and health over twoyears in this rural community. The present supplement is responsive to the NOT-HD-23-006 NOSI andaddresses three of the four core pillars of the NIH Climate Change and Health Initiative (Health EffectsResearch Health Equity and Training and Capacity Building) by expanding our trans-disciplinary team to bringtogether climate and health scientists. The proposed activities are fully within the scope of the aims of theparent R01: a) collect objective measurements of outdoor and indoor temperature humidity and barometricpressure as additional predictors of objective sleep health; b) add quantitative measures of beliefs aboutclimate change and health to examine associations with sleep and other health outcomes; and c) addquantitative measures and conduct supplemental qualitative interviews with flood survivors in the parent R01cohort to evaluate perceptions of factors contributing to the flood disaster (including climate change) how theflood impacted their sleep and health and long-term recovery resources and needs. Our findings will offerunprecedented insight into the intersections of climate change sleep and health in an understudied rural healthdisparity population. Results will inform strategies to increase health equity in the face of a rapidly changingclimate and thus will have strong potential for public health impact.

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

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


application_id: 10837062
project_number: 5R01AG075583-03
project_title: Blood-Brain Barrier Repair in Alzheimers Disease with Epilepsy
administering_ic: NIA
award_notice_date: 2024-05-15
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 075583
program_official: NEWMAN, ELIZABETH
project_start_date: 2022-05-01
project_end_date: 2027-04-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
other_pis: BAUER, BJOERN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
More than 25% of patients with Alzheimers disease (AD) develop epilepsy as co-morbidity. In AD with epilepsy(ADxEpi) seizures accelerate cognitive decline and further reduce life expectancy compared to AD alone. Onehallmark of both AD and epilepsy is blood-brain barrier dysfunction. We discovered that barrier dysfunction ismore severe in ADxEpi patients compared to seizure-free AD patients. Collectively our data suggest that acombination of Ab and seizure-released glutamate (A/Glu) triggers a dual positive feedback loop which exac-erbates barrier dysfunction seizures and cognitive decline in ADxEpi. However the detailed mechanism(s) thatleads to barrier dysfunction in ADxEpi is/are unknown and treatment options for ADxEpi patients are limited toanti-seizure drugs that by themselves accelerate cognitive decline. This knowledge gap represents a critical andunmet need which will prevent us from achieving therapeutic advances for ADxEpi patients. Our overall objectivein this application is to define the mechanism that underlies barrier dysfunction in ADxEpi and to develop atherapeutic intervention. Based on preliminary data the central hypothesis is that blocking A/glutamate signal-ing repairs barrier dysfunction reduces seizure burden and slows cognitive decline in AD with epilepsy. Therationale for the proposed research is that its completion will provide the basis for a novel therapeutic interventionto successfully treat ADxEpi patients. The hypothesis will be tested by pursuing three specific aims: 1) Identifythe mechanism responsible for A/glutamate-mediated barrier dysfunction. 2) Define the relation between barrierdysfunction cognition and seizures in AD patients with epilepsy. 3) Develop a therapeutic intervention that re-pairs barrier dysfunction in AD with epilepsy. In Aim 1 we will determine signaling steps that lead to A/Glu-mediated neurovascular inflammation and barrier leakage in isolated mouse brain capillaries and verify thesefindings in vivo. In Aim 2 we will determine barrier dysfunction in brain tissue from ADxEpi patients and correlatethe degree of barrier dysfunction with seizure burden and patient cognition scores. In Aim 3 we will develop anintervention therapy designed to repair barrier dysfunction and we will evaluate the benefit of this interventionin two rodent ADxEpi models. The proposed research is innovative because it represents a substantive departurefrom the status quo by shifting the focus from traditional anti-seizure drugs to targeting molecular pathways torepair barrier dysfunction thereby improving seizure burden and slowing cognitive decline in ADxEpi. The pro-posed research is significant because it holds the promise of a new therapeutic approach that has translationalpotential for clinical use to advance the treatment of ADxEpi patients.

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

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


application_id: 10837005
project_number: 5R01DE029650-06
project_title: HPV16 E6 Antibody Detection as an Early Marker for Oropharyngeal Cancer Among Men Living with HIV
administering_ic: NIDCR
award_notice_date: 2025-05-21
opportunity_number: RFA-DE-20-001
application_type: 5
activity_code: R01
ic: DE
serial_number: 029650
program_official: BACCAGLINI, LORENA
project_start_date: 2021-02-05
project_end_date: 2026-04-30
study_section: ZDE1-GZ(13)
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
People living with HIV (PLWH) have an increased life expectancy due to effective therapies. This has resulted in anincreased incidence of non-AIDS defining cancers (NADCs) in particular cancers caused by human papillomavirus (HPV).The most rapidly increasing HPV-related malignancy in the general US population is HPV-driven oropharyngeal cancer(HPV-OPC) a type of head and neck that has increased in incidence by more than 200% over the past few decades.1 2PLWH are 1.5 to 4 times more likely to develop HPV-OPC than the general population.3 They are also more likely todevelop HPV-OPC at younger ages (51 versus 60)4 and have a less favorable cancer prognoses.5 Unlike cervical cancerwhere the introduction of highly effective screening has significantly reduced the incidence and mortality of cervicalcancer there are no methods for early detection of HPV-OPC. A major barrier for early detection has been the inabilityto identify PLWH at highest risk for HPV-OPC given that a precancerous precursor lesion for OPC has yet to be identified.Recently HPV16 E6 antibody positivity has been identified as a promising early biomarker. Previous work from ourgroup showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients6 and appear more than 10 yearsprior to diagnosis.7-9 Additionally we have shown that HPV16 E6 antibodies are highly specific for HPV-OPC10 and are notstrongly associated with the 5 other cancers caused by HPV.11 The objective of this study is to evaluate the ability of theHPV16 E6 marker to identify a sub-population of PLWH at highest risk for developing HPV-OPC and for which head andneck cancer screening would be most effective. To accomplish this we will conduct a natural history study of the HPV16E6 antibody marker. This study will focus on men aged 40+ living with HIV given that ~85% of HPV-OPC cases occur inmiddle aged men and HIV infection additionally elevates risk by up to 4-fold. Using the Tennessee Center for AIDSResearch (TN-CFAR) Biorepository banked blood samples from men aged 40+ living with HIV (N=3261) will be tested forHPV16 E6 antibodies. All HPV16 E6 seropositives and a subset of HPV16 E6 seronegatives (1:2 ratio) will be invited toparticipate in yearly (4 total) comprehensive head and neck cancer screening exams performed by a Vanderbilt IngramCancer Center (VICC) head and neck surgeon. Cancer screening visits will include: visual inspection of the mouth andpalpation of tonsils ultrasound imaging laryngoscope exam a detailed questionnaire and biospecimen collection. E6seropositive men will be compared to E6 seronegative men in terms of: a) markers of elevated HPV-OPC risk and b)development of HPV-OPC. The specific aims are: (1) Estimate the prevalence of HPV16 E6 antibodies among men aged40+ living with HIV; (2) Determine the association between HPV16 E6 seropositivity and markers of HPV-OPC risk; (3)Estimate the risk of developing: a) precancerous markers of HPV-OPC and/or; b) HPV-OPC by HPV16 E6 serostatus. Wehypothesize that men with HPV16 E6 antibodies will be more likely to have known risk factors associated with HPV-OPCdevelopment [sexual behavior persistent oral HPV infection] and will be more likely to develop HPV-OPC than menwithout HPV16 E6 antibodies. These efforts could help to generate evidence for oral health screening guidelines tailoredto PLWH. This work is particularly impactful given that HPV-OPC disproportionately affects PLWH.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;American men;Antibodies;Behavioral;Biological Markers;Blood;Blood Banks;Blood specimen;Cancer Center;Cancer Patient;Cancer Prognosis;Clinic;Collection;Comprehensive Health Care;Development;Diagnosis;Early Diagnosis;Eligibility Determination;General Population;HIV;HIV Infections;HIV Seronegativity;HPV oropharyngeal cancer;HPV-High Risk;Head and Neck Cancer;Head and Neck Surgeon;Head and neck structure;High Prevalence;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Incidence;Individual;Laryngoscopes;Lesion;Life Expectancy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Men with HIV;Methods;Natural History;Oncoproteins;Oral cavity;Oral health;Palpation;Patients;Persons;Population;Positioning Attribute;Prevalence;Quality of life;Questionnaires;Research;Resources;Risk;Risk Estimate;Risk Factors;Screening for cancer;Screening procedure;Seroprevalences;Sex Behavior;Surrogate Markers;Tennessee;Testing;Tonsil;Ultrasonography;Visit;Visual;Work;aged;antibody detection;biobank;cancer risk;chemoradiation;clinical examination;cohort;early detection biomarkers;effective therapy;high risk;improved;male specific;malignant oropharynx neoplasm;men;middle age;mortality;novel;oral HPV;oral HPV infection;premalignant;rapid detection;screening;screening guidelines;seropositive;younger age

public_health_relevance:
NARRATIVECases of human papillomavirusdriven oropharyngeal cancer (HPVOPC) now outnumber cervical cancer cases in the US men and people living with HIV (PLWH) are at highest risk. Unlike cervical cancer where the introduction of highlyeffective screening protocols significantly reduced the incidence and mortality due to cervical cancer there are nomethods for early detection of HPVOPC. We are proposing to use HPV16 E6 seropositivity an early biomarker of HPVOPC to develop a cohort of men living with HIV who are at highest risk for OPC to better understand HPV16 E6antibodies as an early marker of HPVOPC and b) to develop new methods of early detection for this rapidly increasingcancer.


application_id: 10836994
project_number: 5F30AG079506-02
administering_ic: NIA
award_notice_date: 2024-06-03
opportunity_number: PA-21-050
application_type: 5
activity_code: F30
ic: AG
serial_number: 079506
program_official: ROVESCALLI, ALESSANDRA C
project_start_date: 2023-05-10
project_end_date: 2025-11-09
study_section: Special Emphasis Panel[ZRG1-F01A-V(20)]
contact_pi_person_id: 78025226
contact_pi: LIBECAP, TJ
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-10
project_title:
Investigating Enlarged Perivascular Spaces as a Neuroimaging Biomarker of Cerebral Small Vessel Disease

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

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

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


application_id: 10836613
project_number: 4R00HG011657-03
project_title: Analysis of Somatic Mutations in Longitudinal Whole-genome Sequencing Data
administering_ic: NHGRI
award_notice_date: 2023-06-26
opportunity_number: PA-20-188
application_type: 4
activity_code: R00
ic: HG
serial_number: 011657
program_official: FELSENFELD, ADAM
project_start_date: 2023-07-01
project_end_date: 2026-06-30
study_section: NSS
contact_pi_person_id: 15791317
contact_pi: STEELY, CODY
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:
PROJECT SUMMARY While recent efforts have focused on better understanding the germline mutation rate of differenttypes of DNA variants the dynamics of somatic mutations in the human genome are poorly understood.Somatic mutations are a well-known cause of cancer and may play a causative role in other diseases andaging. Analyses of somatic mutations have generally been limited to single-cell or low-coverage studies.To accurately assess the rate of somatic mutations over time would require a longitudinal high coveragedataset. For ~450 individuals in the Utah CEPH (Centre d'Etude du Polymorphism Humain) pedigreesblood was drawn at two timepoints approximately 15 years apart. This proposal describes experiments todetermine the rate of somatic mutations throughout the human genome by utilizing high-coverage (720x)whole-genome sequencing data at both of these timepoints in a subset of CEPH individuals. The genomesincluded in this study will be used to determine the rate of somatic mutations and improve ourunderstanding of differences in this rate between individuals. Building on previous work performed at theUniversity of Utah we will determine the relationship between the germline and somatic mutation rate.Further using detailed phenotypic data collected for these individuals experiments will be performed todetermine how this rate is correlated with disease outcomes such as cancer and cardiovascular disease.From this work a series of filtering algorithms will be produced to allow for comprehensive analysis ofsomatic mutations occurring between two timepoints in the same individual. This dataset provides me witha unique opportunity to study somatic mutations over time using high-quality data.This proposal builds upon my experience in analyzing mobile element-mediated somatic mutationsin longitudinal whole-genome data of cancer patients and my recent work analyzing germline shorttandem repeat mutations in the CEPH pedigrees. The K99 portion of this project will focus on determiningthe rate of somatic mutations in longitudinal high-coverage whole-genome sequencing data while creatingfiltering algorithms to improve our detection capabilities. The additional training I will receive during thisperiod will lay the foundation of an independent research program that will determine the significance ofsomatic mutations in the human genome and how these relate to disease outcomes.

project_terms:
Age;Aging;Algorithmic Software;Algorithms;Blood;Body mass index;Cancer Etiology;Cancer Patient;Cardiovascular Diseases;Cells;Collection;Copy Number Polymorphism;DNA;DNA Repair;Data;Data Set;Detection;Disease;Disease Outcome;Elements;Event;Family;Foundations;Frequencies;Generations;Genetic Polymorphism;Genome;Germ Cells;Germ-Line Mutation;Goals;Hematopoiesis;Human;Human Genome;Individual;Malignant Neoplasms;Measures;Mediating;Modeling;Mutation;Organoids;Phenotype;Play;Postdoctoral Fellow;Process;Research;Role;Sampling;Series;Short Tandem Repeat;Single Nucleotide Polymorphism;Somatic Mutation;Testing;Time;Tissues;Training;Universities;Utah;Variant;Work;career;career development;computational pipelines;design;experience;experimental study;genetic pedigree;genome sequencing;human tissue;improved;member;phenotypic data;programs;time use;variant detection;whole genome

public_health_relevance:
PROJECT NARRATIVEMuch remains unknown about the rate and dynamics of human somatic mutations which are knowndrivers of cancer and are hypothesized to play a role in aging. This proposal aims to determine the rateand significance of somatic mutations in the human genome and their relationship to disease outcomes.


application_id: 10834744
project_number: 5K23AA029198-04
project_title: Lactobacillus rhamnosus: A Novel Probiotic Therapy for treating Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2024-05-02
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: AA
serial_number: 029198
program_official: WANG, JOE
project_start_date: 2021-05-10
project_end_date: 2026-04-30
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 11616840
contact_pi: VATSALYA, VATSALYA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This application is a proposal for a mentored clinical research award (K23) that will enable Dr. VatsalyaVatsalya to continue to develop his skills in clinical research; specifically identifying new therapeutic targets forthe treatment of patients with alcohol use disorder (AUD) and concomitant moderate alcohol associatedhepatitis (AH). AUD represents one of the leading causes of preventable deaths in the United States andefforts are in progress to identify new interventions. Emerging animal and human research suggest thatLactobacillus rhamnosus GG (LGG) a probiotic is involved in the restoration of a normal gut microbiomeattenuating gut dysfunction and lowering endotoxemia and inflammation. Dr. Vatsalyas overall goal is tocomplete mentored research and transition to independent research. He also plans to successfully obtain atenure-track faculty position that will allow him to fully establish his own independent research program. Dr.Vatsalyas training goals are to: (1) broaden his conceptual knowledge in researching theneuropharmacological mechanisms in AUD; (2) enhance his experience with human studies in the field of AUDand alcohol associated liver disease (ALD); (3) improve his methodological skills in order to conduct effectivelarge-scale trials; and (4) improve his grant- and publication-writing skills. These training goals will be achievedthrough: (a) the resources available at the University of Louisville; (b) the high quality of mentorship providedby his mentor and the mentor committee; (c) focused training and clinical experiences; and (d) the proposedresearch project. During the award period Dr. Vatsalyas goals are to: (1) complete the K23 research anddevelop preliminary data to conduct a larger bedside-to-bench study using the results and skills obtainedduring the K23 grant; and (2) apply for an NIAAA investigator-initiated (R01) grant based on the preliminaryoutcomes. Alcohol consumption is associated with altered microbiome and gut dysfunction increased gutpermeability systemic endotoxemia (gut-derived bacterial products in the circulation) and proinflammatoryactivity. The gut dysfunction observed with heavy drinking has also been associated with the development ofliver injury and inflammation observed in ALD. The research component of Dr. Vatsalyas application willinvestigate if LGG can restore normal gut function reduce gut permeability and proinflammatory activitythereby improving the symptomology of concomitant AUD and ALD. The proposed research project extendsDr. Vatsalyas previous work on the pharmacological treatment of AUD and on the role of LGG in mediating thegut-brain axis that could be expanded to identifying new interventional-mechanistic targets in AUD.

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

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


application_id: 10834041
project_number: 5R24ES030904-05
administering_ic: NIEHS
award_notice_date: 2024-04-17
opportunity_number: RFA-ES-18-009
application_type: 5
activity_code: R24
ic: ES
serial_number: 030904
program_official: GRAY, KIMBERLY A
project_start_date: 2020-05-06
project_end_date: 2025-04-30
study_section: ZES1-VSM-K(R)
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Retention Maintenance and Enhancement of the Communities Actively Researching Exposure Study (CARES)

project_abstract:
PROJECT SUMMARYManganese (Mn) plays an essential role in normal growth and development The Communities ActivelyResearching Exposure Study (CARES) was built upon community-engaged research practices. Participantsreside in three communities with the nation's highest levels of ambient Mn: Marietta and East Liverpool Ohioand Southeast Side Chicago Illinois. The CARES cohort consists of over 600 children and their primarycaregiver with two time-points (ages 7-9 years and ages 13-17 years) of extensive neurodevelopmentaloutcomes biomarkers of exposure and home environmental measures. The CARES has been supported bymultiple NIEHS-funded grants and has been instrumental in the training of next generation community-engaged environmental health scientists for over a decade. The cohort has been instrumental in thedevelopment of a lab-on-a-chip sensor for blood metals assessment and is currently exploring the impact ofMn on neuroanatomy function chemistry and physiology through magnetic resonance imaging. Through thisproject the CARES research team will be able to conduct the following: Aim 1) Maintain the integrity of theCARES cohort by implementing community-engaged research strategies to improve participant retention; Aim2) Expand CARES to enhance characterization of critical windows of exposure across the lifespan and assessthe role of caregiver child and community-level psychosocial factors on the etiology of toxicant-inducedneurodevelopmental deficits; and Aim 3) Maintain and enhance biorepository and data managementinfrastructure and develop methods to implement data sharing. The CARES is the only cohort poised toinvestigate ambient exposure to Mn and its relationship to brain function in both a pediatric and adolescentpopulation. The proposed cohort retention enhancement and maintenance plans will accelerate and sustainthe ability of the CARES cohort to investigate the impact of ambient Mn on neurodevelopmental outcomesinform federal polices related to ambient exposure to Mn and serve as a valuable resource for environmentalhealth science trainees and scientists across the globe.

project_terms:
Acceleration;Adolescent;Adult;Age;Air;Anatomy;Applications Grants;Biological;Biological Markers;Blood;Brain;Caregivers;Chemistry;Chicago;Child;Childhood;Cohort Studies;Collaborations;Communities;Community Developments;Data;Data Management Resources;Data Set;Development;Dust;Environmental Epidemiology;Environmental Exposure;Environmental Health;Environmental Impact;Equipment and supply inventories;Etiology;Evaluation;Exposure to;Funding;Grant;Growth and Development function;Hair;Home;Illinois;Infrastructure;Knowledge;Lab On A Chip;Laboratories;Magnetic Resonance Imaging;Maintenance;Manganese;Measurement;Measures;Metals;Methods;Motor;National Institute of Environmental Health Sciences;Neuroanatomy;Neurodevelopmental Deficit;Neuropsychology;Ohio;Outcome;Parents;Participant;Pediatric cohort;Pediatric epidemiology;Physiology;Play;Police;Population;Psychosocial Factor;Reporting;Resources;Role;Saliva;Sampling;Scientific Advances and Accomplishments;Scientist;Serum;Side;Soil;Structure of nail of toe;Time;Training;United States;Urine;Water;Whole Blood;biobank;cohort;community engaged research;data management;data sharing;deciduous tooth;early childhood;improved;innovation;life span;neurodevelopment;next generation;novel;participant retention;patient engagement;point of care;preservation;primary caregiver;research study;sensor;toxicant

public_health_relevance:
PROJECT NARRATIVEThe Communities Actively Researching Exposure Study (CARES) is a successful and well-establishedenvironmental pediatric epidemiology cohort study that has reported the impact of environmental manganeseexposure on pediatric brain function. This proposal will retain the over 600 child-parent pairs enhance therobust dataset with ambient and internal exposure characterization during early childhood development andbuild the infrastructure needed to share the unique data within the cohort.


application_id: 10833549
project_number: 5P50AA024337-09
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 5282
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The primary function of OMICS Core is to provide members of the University of Louisville Alcohol ResearchCenter (ULARC) with the expertise resources and facilities needed for metabolomic proteomic andbioinformatic analyses of biological samples collected to study nutrition gut flora/intestinal dysfunction andalcohol-induced organ injury and therapeutic interventions. OMICS Core personnel will assist with the designof sample collection protocols will drive the development and the execution of novel and robustchromatographic methods for sample separation and mass spectrometric methods for the analysis of proteinspeptides and metabolites with a goal of providing a greater understanding of the evolution of molecularmechanisms that correlate with or participate in liver dysfunction. OMICS Core will ensure uniformity andstandardization in sample preparation method development instrument performance data collection datareporting and data sharing. OMICS Core endeavors to contribute to the overall success and utility of theULARC and to enhance the infrastructure and the technical and academic capabilities of the institution as awhole. OMICS Core will also promote the education and training of the ULARC members with regards to thestate-of-the-art omics technologies. Furthermore OMICS Core will become an independent and self-supporting entity using a set comprehensive approaches that have been already been implemented and havedemonstrated their success in our current ULARC. The OMICS Core is projected to provide necessary andessential support to all ULARC projects.

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


application_id: 10833544
project_number: 5P50AA024337-09
project_title: Probiotic-derived nano-particles in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 5281
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Probiotics have been used to prevent/treat alcoholic liver disease (ALD). Live probiotics need to colonize the gutto exert their function. Unfortunately underlying disease states provide an unfavorable environment for probioticbacterial gut colonization which diminishes probiotics function. In the last few years we showed that LGGculture supernatant (LGGs without live bacteria) was effective in the prevention of ALD in experimental modelsof acute and chronic alcohol exposure in mice. However how LGG supernatant exerts its therapeutic effects isnot fully understood. Exosomes are nanoparticles (NPs) derived from cell endocytosis which act as transmittersbetween cells. Recent studies show that bacteria both Gram-negative and Gram-positive produce NPs. TheNPs derived from bad bacteria have been demonstrated to be pathogenic. However good bacteria-probiotics-derived NPs have not been studied. Our preliminary study showed that administration of LGG-derivedexosome-like NPs (LDNPs) effectively reversed ALD in the binge-on-chronic alcohol exposure mouse modelsuggesting that probiotic LGGs may exert its function through LDNPs in ALD. Administration of LDNPs markedlyincreased intestinal AhR activity IL-22 and regenerating islet-derived 3 (Reg3)  and  expression which playa key role in maintaining gut microbiota homeostasis and preventing bacterial intestinal transcytosis. In additionLDNPs administration significantly increased intestinal epithelial cell (IEC) tight junctions and decreasedcirculating LPS concentration associated with upregulation of intestinal Nrf2 signaling which is known forprotecting intestinal barrier junctions against oxidative stress-induced damage by alcohol. Metabolomic analysisrevealed that LDNPs contain high levels of microbial metabolites of tryptophan which are AhR ligands indicatingLDNPs may activate intestinal AhR signaling. Furthermore we demonstrated that ginger exosome-likenanoparticles (GDNPs) are preferentially taken up by LGG suggesting that GDNP may serve as a prebiotic toenhance the effects of LGG. These preliminary studies provide the groundwork for our central hypothesis thatby activating intestinal AhR-Nrf2 signaling LDNPs increase intestinal expression of Il-22 Reg3 and tightjunctions and modulate gut microbiota homeostasis and enhance intestinal barrier function leading to thesuppression of ALD. We will test our hypothesis in following four specific aims: (1) Determine the role of bacteria-derived NPs in ALD; (2) Define the mechanisms of the beneficial effects of LDNPs in ALD; (3) Determine whetherGDNPs treatment enhances LDNP production and AhR agonist enrichment that lead to improved effects ofLDNPs against ALD; and (4) Evaluate the intestinal AhR-Nrf2 signaling in alcoholic hepatitis patients treated withLGG. Completion of this study is expected to significantly impact the development of LGG-based probiotictherapeutics in the treatment of alcohol-associated liver diseases.

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


application_id: 10833540
project_number: 5P50AA024337-09
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 5280
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Enhancer-mediated transcriptional dysregulation in neural crest cells and ethanol-induced teratogenesis

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

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


application_id: 10833537
project_number: 5P50AA024337-09
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 5279
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Pathogenic Role of Loss of Butyrate Producing Bacteria in Immune Dysregulation and Development of Alcoholic Liver Disease (ALD)

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

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


application_id: 10833530
project_number: 5P50AA024337-09
project_title: Role of n3 PUFAs and inflammation-resolving lipid mediator RvD1 in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 5278
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alcoholic liver disease (ALD) is a major and increasing health problem in the US (especially in Kentucky) andworldwide. In spite of the magnitude of this problem there is no FDA-approved therapy for any stage of ALD. Inaddition the mechanisms and regulators of the disease progression and severity are not well understood. Dietaryfats play an important interactive role with alcohol consumption in ALD pathogenesis however the role of n3PUFAs in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD in part vian3-PUFA-derived pro-resolving mediators which facilitate inflammation resolution improvement in the gut-liveraxis and subsequent attenuation of liver injury. We propose that resolvin D1 (RvD1) is a potent therapeuticagent in severe ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and topromote repair of hepatocellular damage in part via enhancement of pro-restorative macrophages. Wepostulate that compromised inflammation resolution due to impaired RvD1 production/signaling is one of thecritical nutritional contributing factors to the progressive ALD and severity of alcoholic hepatitis (AH) in humans.The Specific Aims of the proposal are: Aim 1. To test whether n3 PUFAs exert beneficial effects on EtOH-associated liver injury/inflammation by enhancing the effectiveness of inflammation resolution and byrepair of hepatocellular damage through increase in n3-PUFA-derived specialized pro-resolving mediatorspromoting(SPMs) and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling andreprogramming pro-inflammatory macrophages into a pro-restorative phenotype. Wild Type (WT) Fpr2-/-Neat1-/- and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in thisAim. We will also examine the therapeutic effectiveness of RvD1 utilizing a novel nanoparticle technology oftargeted RvD1 delivery examine the role n3-PUFAsto the liver with plant-derived edible exosomes. Aim 2. Toand RvD1 in maintaining gut barrier integrity and in the resolution of intestinal inflammation in experimental ALD.We will: i) test in vivo in animal models and in vitro in intestinal organoid culture whether n3 PUFA or RvD1improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whetherdisruption of the RvD1-FPR2 axis exacerbates while blocking Neat1 signaling attenuates intestinal inflammationand alterations in the gut barrier integrity; iii) test a novel therapeutic strategy of administering an engineeredbacteria strain to convert n6 to n3 PUFAs in the intestine and thus to attenuate gut barrier dysfunction in mice.In Aim 3 we seek to translate and extend our findings in animal models to human ALD. Utilizing de-identifiedhuman samples we will: i) determine effects of n3-PUFA dietary supplementation on plasma SPM levels markersof liver injury systemic inflammation and intestinal permeability in heavy drinking individuals; ii) examine plasmaSPM levels and SPM synthesis in whole blood and peripheral blood monocytes (PBMCs) obtained from AHpatients; and iii) test whether RvD1 improves phagocytosis/efferocytosis of PBMCs obtained from AH patients.

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


application_id: 10833528
project_number: 5P50AA024337-09
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 5277
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) is a multidisciplinary group ofinvestigators focusing on nutrition gut flora/intestinal dysfunction and alcohol-induced organ injuryand therapeutic interventions. The ULARC investigators come from 13 departments across 6 schools. TheAdministrative Core provides oversight and coordination to the ULARC. The Administrative Core supportsadministrative oversight a tissue handling technician and a biostatistician/bioinformatician. The PI will beassisted by an Associate Director the Steering and Program Advisory committees and a part-time assistant.The Specific Aims of the Administrative Core are to:1) continue the formal governance structure to provide coordination implementation direction and prioritizationof activities including budget issues and resolving any conflicts as they arise ensuring the quality of allfunctions and evaluation progress;2) provide a mechanism to replace any key individuals who may leave;3) provide biostatistical and bioinformatics support for investigators;4) provide chain of custody for tissue/sample handling and storage; and5) disseminate pertinent information to the scientific and lay community.All projects and cores will be using the Administrative Core.

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


application_id: 10833527
project_number: 5P50AA024337-09
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2024-05-10
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
program_official: MURRAY, GARY
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) was created to serve as aregional/national resource to perform interdisciplinary collaborative research on the role of nutrition asa cofactor in alcohol induced organ injury and as a possible therapeutic intervention to prevent/treatthis organ injury. The nutrition and alcohol-induced organ injury theme of the center is unique amongalcohol centers. The approach is highly translational. Our investigators include faculty from 13 departmentsand 6 colleges. The Specific Aims of the ULARC are to:1) perform/facilitate interdisciplinary research on nutrition and alcohol-induced organ injury;2) serve as a regional/national resource for the study of nutrition and alcohol-induced organ injury;3) develop potential therapeutic targets/interventions for alcohol induced organ injury based on themechanistic research of the ULARC; and4) disseminate knowledge/interventions to the scientific and lay communities.We will explore interactions of nutrition and alcohol abuse in the development of alcohol-induced organdysfunction and we will evaluate diverse potential nutritional preventive/therapeutic interventions. Project 1(Kirpich/McClain) evaluates the role of dietary fat in ALD pathogenesis; Project 2 (Barve) evaluates alcohol-induced epigenetic alterations in the gut:liver axis. Project 3 (Chen) will elucidate the mechanisms by whichenhancers mediate ethanol-induced developmental impairment of neural crest cells and teratogenesis andunique exosome treatment for prevention of FASD. Project 4 (Feng) studies the beneficial effects of theprobiotic Lactobacillus rhamnosis GG (LGG)on the gut:liver axis in ALD. Together these projects form a cohesive and interactive approach to investigate the effects of nutrition andnutritional interventions on alcohol-induced organ injury.

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

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


application_id: 10833503
project_number: 5R01AG069909-04
project_title: The role of satellite cells in skeletal muscle hypertrophy with aging
administering_ic: NIA
award_notice_date: 2024-05-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 069909
program_official: BOYCE, AMANDA T
project_start_date: 2021-08-15
project_end_date: 2026-04-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: WEN, YUAN
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe loss of skeletal muscle mass with age is of clinical importance because it is associated with increasedmorbidity and mortality as well as a marked deterioration in the quality of life. There is also a heightenedinterest in the identification of cellular and molecular mechanisms responsible for the lack of an anabolicresponse of aged muscle to hypertrophic stimuli. The use of satellite cells to treat loss of skeletal muscle massis considered a promising therapeutic strategy given their stem cell characteristics and essential role in post-natal muscle growth and regeneration. The results of our studies have prompted us to perform mechanisticanalyses of both of the well-known function of satellite cells; fusion to myofibers to provide additional nuclei forhypertrophic growth to other functional consequences of satellite cell expansion that occurs in response tovarious exogenous stimuli such as exercise as the increase in satellite cell abundance in response tomechanical overload far exceeds myonuclear accretion associated with increased myofiber size. We reportedsatellite cells were necessary for optimal long-term hypertrophic growth of skeletal muscle by regulating theextracellular matrix. Activated satellite cells repressed fibroblast collagen production via extracellular vesicle(EV) delivery of miR-206 revealing a previously unrecognized function of satellite cells in addition to providinga mechanism through which satellite cells communicate with other cells within muscle. We now have in vivosingle-cell (sc)RNA-seq evidence from Pax7-tdT reporter mice of a satellite cell intercellular communicationnetwork in which satellite cells communicate with FAPs/fibrogenic cells and endothelial cells duringhypertrophic growth. Aim 1 will test the hypothesis that aging negatively impacts this communication networkinhibiting proper remodeling of the extracellular matrix thereby inhibiting hypertrophy. We have also developeda novel mouse model that allows us to simultaneously deplete satellite cells and label resident myonuclei Aim2 will use this model and single-myonuclear (smn)RNA-seq to characterize age-dependent changes in theresident myonuclear transcriptome and identify mechanisms that enable short term hypertrophy in the absenceof satellite cells in adult mice which is lost in old age. Aim 3 will use an additional newly developed reportermouse that enables specific and stable labeling of satellite cell nuclei to determine how aging alters thesatellite cell-derived myonuclear transcriptome in response to a hypertrophic stimulus. We hypothesize that inaged muscle satellite cell-derived myonuclei have altered transcriptional output that does not promote ahypertrophic response and that impaired fusion of satellite cells or defective satellite cells may negativelyimpact resident myonuclear transcriptional activity contributing to impaired growth. Defining fusion-dependentand -independent roles of satellite cells and age-associated changes that negatively impact muscle adaptabilitywill identify potential new targets to promote skeletal muscle growth in the face of inactivity during aging and inthe face of muscle wasting diseases.

project_terms:
Ablation;Adult;Affect;Age;Aging;Cell Communication;Cell Nucleus;Cells;Chronic;Clinical;Collagen;Communication;Deterioration;Doxycycline;Elderly;Endothelial Cells;Exercise;Extracellular Matrix;Female;Fibroblasts;Fibrosis;Foundations;Gene Expression;Genes;Genetic Transcription;Grant;Growth;Human;Hypertrophy;Immunohistochemistry;Impairment;In Vitro;Label;Mechanics;Messenger RNA;MicroRNAs;Modeling;Molecular;Mononuclear;Morbidity - disease rate;Mus;Muscle;Muscle satellite cell;Muscular Atrophy;Natural regeneration;Output;Phenocopy;Plantaris muscle;Population;Population Dynamics;Process;Production;Quality of life;Reporter;Reporting;Repression;Rodent;Role;Skeletal Muscle;Stimulus;Systemic disease;Tamoxifen;Testing;Therapeutic;Therapeutic Uses;Time;Transcript;Wasting Syndrome;age related changes;aged;extracellular vesicles;human old age (65+);in vivo;intercellular communication;interest;male;mortality;mouse model;muscle aging;muscle form;muscle hypertrophy;muscle progenitor cell;novel;old mice;patient population;physical inactivity;postnatal;prevent;progenitor;response;sarcopenia;single-cell RNA sequencing;skeletal muscle growth;skeletal muscle wasting;stem cells;stemness;transcriptome;transcriptome sequencing;young adult

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


application_id: 10833471
project_number: 5R01HL152714-05
administering_ic: NHLBI
award_notice_date: 2024-05-03
opportunity_number: PAR-19-274
application_type: 5
activity_code: R01
ic: HL
serial_number: 152714
program_official: BROWN, ALISON GWENDOLYN MARY
project_start_date: 2020-08-01
project_end_date: 2027-04-30
study_section: Dissemination and Implementation Research in Health Study Section[DIRH]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: PHILLIPS, SIOBHAN MARIE
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Implementing an evidence-based mHealth diet and activity intervention: Make Better Choices 2 for rural Appalachians

project_abstract:
ABSTRACTWe propose a type 1 hybrid effectiveness-implementation study to test an adaptedevidence-based intervention and explore critical implementation issues includingfeasibility acceptability and costs that influence scale-up and sustainment. We focusthis adaptation effectiveness and implementation study on rural residents apopulation that maintains extremely high rates of suboptimal diet and sedentarybehaviors placing them at elevated risk for cardiovascular disease obesity diabetescancer and other chronic conditions. Appalachian Kentuckians experience poor healthoutcomes including among the highest rates of morbidity and mortality in the nation.Increasingly however Appalachian residents and other populations are gaining accessto modalities that may be useful in addressing these health challenges including internetconnectivity and nearly ubiquitous cell phone use. Despite this accelerating technologyuse the evidence base on personal technology-associated interventions (mHealth) in arural population remains sparse. We propose finalizing adaptation and testing anevidence-based multicomponent mHealth intervention Make Better Choices 2 (MBC2)a behavioral program consisting of personalized health coaching an appaccelerometer and financial incentives. In a recent randomized controlled trial amongurban adults MBC2 produced large sustained diet and physical activity improvementsby leveraging effective behavior change techniques including goal-setting selfmonitoringaccountability and support. To prepare for the implementation of thissuccessful intervention with a new population with health challenges our team hasengaged in extensive foundational efforts based on the Dynamic Adaptation Processframework. These include: (1) completing focus groups and key informant interviews toassess the feasibility and acceptability for rural Appalachian residents to use the MBC2program; (2) undertaking a comprehensive community inventory to reveal existing andneeded resources; (3) engaging stakeholders in community and academic teammeetings including community forums and CAB meetings; and (4) identifying MBC2programmatic and structural elements in need of adaptation. With this extensivepreliminary activity we now propose a type 1 hybrid effectiveness-implementation trial inwhich we: (1) finalize adaptation by wireframe and usability testing MBC2 with localAppalachian residents; (2) conduct a RCT to test the effectiveness of the adapted MBC2compared to an active control arm; and (3) explore implementation outcomes andcontextual factors with a focus on sustainment. This project aspires to demonstrate thatsystematic adaptation and implementation of an evidence-based intervention can lead tomeaningful and sustained behavioral changes and to prepare for potential scale-up andsustainment of the intervention to maximize its public health impact.

project_terms:
Acceleration;Accelerometer;Accountability;Adaptation research;Address;Adult;Appalachian Region;Behavior;Behavioral;Blood Pressure;Body mass index;Budgets;Cardiovascular Diseases;Cellular Phone;Characteristics;Chronic;Chronic Disease;Clinical;Communities;Consolidated Framework for Implementation Research;Consumption;Data;Devices;Diabetes Mellitus;Diet;Effectiveness;Elements;Equipment and supply inventories;Evidence based intervention;Fatty acid glycerol esters;Focus Groups;Future;Goals;Health;Influentials;Intake;Internet;Intervention;Interview;Leisures;Life Style;Lipids;Malignant Neoplasms;Methods;Modality;Monitor;Morbidity - disease rate;Obesity;Outcome;Participant;Physical activity;Population;Process;Public Health;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research Activity;Resources;Rural;Rural Appalachia;Rural Population;Shapes;Techniques;Technology;Testing;Time;Training Support;Underserved Population;Unhealthy Diet;Uninsured Medical Expense;Vulnerable Populations;acceptability and feasibility;active control;active lifestyle;arm;attentional control;behavior change;cardiovascular disorder risk;contextual factors;cost;design;effectiveness evaluation;effectiveness research;effectiveness study;effectiveness testing;effectiveness trial;effectiveness/implementation study;effectiveness/implementation trial;evidence base;experience;financial incentive;fruits and vegetables;good diet;health equity;health inequalities;hybrid type 1 design;implementation context;implementation evaluation;implementation outcomes;implementation research;implementation science;implementation study;improved;informant;information gathering;insight;intervention cost;intervention delivery;intervention program;iterative design;knowledge base;low socioeconomic status;mHealth;meetings;mhealth interventions;mortality;physical inactivity;poor health outcome;prevent;primary outcome;programs;rural dwellers;rural underserved;scale up;secondary outcome;sedentary;sedentary lifestyle;smartphone application;smartphone based device;stress management;successful intervention;tool;tv watching;usability;virtual;waist circumference

public_health_relevance:
PROJECT NARRATIVEThe increasing use of personal technology with support from trained local healthcoaches offers a new opportunity to improve lifestyle behaviors and ultimately improvehealth for all. A type 1 hybrid effectiveness-implementation trial will contribute to theknowledge base for scalable sustainable solutions to the most prevalent drivers ofmorbidity and mortality suboptimal diet and physical activity.


application_id: 10833287
project_number: 3R01DC019634-02S1
project_title: The fungiform papilla as a multi-sensory end-organ
administering_ic: NIDCD
award_notice_date: 2023-06-17
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: DC
serial_number: 019634
suffix: S1
program_official: SULLIVAN, SUSAN L
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: BREZA, JOSEPH MICHAEL
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
project_abstract:
Project Summary/Parent grant. Our perception of food in the mouth is a multi-modal sensory experienceinvolving taste olfaction and somatosensation. All of these stimuli combine to contribute to the recognition andpalatability of food. The first step leading to the perception of mouth feel in the oral cavity is activation ofperipheral somatosensory neurons. Multiple classes of these trigeminal somatosensory neurons innervate theoral cavity and can be defined by the types of stimuli to which they respond. For example low thresholdmechanoreceptors (LTMRs) carry information concerning touch or mechanical stimuli. In skin at least 7 clearsubtypes of these neurons have been defined by using gene expression to relate the anatomical features ofthese neurons with their functions. We do not know how many specialized neuron subtypes mediate touchsensation in the tongue or their specialized anatomical and functional properties. Understanding the sensationsevoked by a food stimulus requires us to determine the unique anatomical and functional properties of eachLTMR subtype in the tongue. Equally important is how each LTMRs activities are integrated with other oralsensory neuron types (i.e. taste and temperature). Toward these long-term goals we propose to use twogenetic identifiers to examine trigeminal neuron subtypes innervating the fungiform (taste) papillae. Our Aimsspecifically test the following hypotheses: 1) Taste papillae are innervated by a A LTMRs with a smallreceptive field that express the neurotrophin receptor TrkC and that they neurons can further be divided intorapidly adapting and slowly-adapting types based on the presence or absence of Parvalbumin. 2) These ALTMRs project to the to a region of the brainstem immediately adjacent to the primary taste terminal fieldwhere they activate postsynaptic neurons that are responsive to touch. 3) These A LTMRs are capable ofmodulating responses to taste stimuli at the first gustatory synaptic relay. Successful completion of theseexperiments establishes the fungiform papilla as a mechanosensory end organ and provides the genetic toolsto explore the contribution of a specific subtype of LTMR in the integration of sensations produced by the multi-modal food stimulus.

project_terms:
Afferent Neurons;Amyloid beta-Protein;Anatomy;Attention;Award;Behavior;Binding Proteins;Brain Stem;Burning Mouth Syndrome;C Fiber;Cell Nucleus;Central Nervous System;Characteristics;Code;Cream;Data;Electrophysiology (science);Epithelium;Esthesia;Fiber;Food;Fungiform Papilla;Gene Expression;Genes;Genetic;Genetic Identity;Genetic Markers;Goals;Housing;Image;Lateral;Light;Liquid substance;Location;Mechanoreceptors;Mediating;Modality;Mucous Membrane;Mus;Nerve Growth Factor Receptors;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 3;Oral;Oral cavity;Organ;Parents;Parvalbumins;Perception;Peripheral;Peripheral Nervous System Diseases;Potato;Property;Proprioceptor;Research;Rodent;Role;Sensory;Skin;Smell Perception;Stimulus;Structure;Structure of trigeminal ganglion;Surface;Synapses;Taste Buds;Taste Perception;Temperature;Testing;Texture;Thermoreceptors;Tongue;Touch sensation;Trigeminal Nuclei;Trigeminal System;Viral;awake;experience;experimental study;feeding;mechanical stimulus;multimodality;multisensory;nerve supply;olfactory stimulus;optogenetics;oral sensory;parent grant;postsynaptic neurons;receptive field;repaired;response;somatosensory;taste stimuli;tongue papilla;tool

public_health_relevance:
Somatosensory neurons innervating the tongue contribute to numerous perceptual qualitiesincluding texture of food and location of gustatory stimuli. Understanding their role in normalfunction is the first step in determining how they might be repaired when disrupted (peripheralneuropathies and/or burning mouth syndrome).


application_id: 10832634
project_number: 5R34DK132548-03
administering_ic: NIDDK
award_notice_date: 2024-05-22
opportunity_number: RFA-DK-20-032
application_type: 5
activity_code: R34
ic: DK
serial_number: 132548
program_official: BURCH, HENRY B
project_start_date: 2022-05-01
project_end_date: 2026-04-30
study_section: ZDK1-GRB-9(J2)S
contact_pi_person_id: 12349240
contact_pi: LACY, MARY E.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Using Practice Facilitation and Operationalizing Referral Information Technology (UP FOR IT) to Increase DSMES Utilization

project_abstract:
PROJECT SUMMARYThe prevalence of diabetes in Kentucky is ~25% higher than the national average and rural areas withinKentucky face an even higher burden of diabetes and its related complications. Diabetes self-managementeducation and support (DSMES) services are integral to quality diabetes care. Substantial evidence shows thatDSMES participation improves diabetes outcomes and is cost-effective. Despite strong evidence of benefit andclear guidelines from the American Diabetes Association recommending its use <10% of eligible individualscomplete DSMES. Determinants that contribute to low DSMES uptake exist at multiple levels and includeclinician awareness geographic availability cost and reimbursement and referral mechanisms. Although theKentucky Department of Public Health administers a statewide DSMES program that is free to participants andavailable face-to-face in 80/120 counties and by telehealth in all counties DSMES utilization remains lowacross Kentucky. In response to the current RFA seeking to test innovative and pragmatic approaches tofacilitate greater use of DSMES we propose testing and evaluating a clinic-level intervention that implementshealth information technology (automated patient identification and a bidirectional referral system) to reducebarriers related to identification and referral of eligible patients and engages clinical teams in a practicefacilitation collaborative to increase clinician awareness and overcome clinic-level barriers. We will achieve thisthrough three aims: 1) Planning  implementation science-guided evaluation and adaptation of an existing pilotdiabetes clinical quality improvement program; 2) Implementation  of the adapted intervention; and 3)Evaluation - of intervention components using the Practical Robust Implementation and Sustainability Model(PRISM). We will adapt the proposed intervention from a successful pilot project that used health informationtechnology and a collaborative quality improvement approach to increase DSMES utilization at participatingclinics by >100%. We will use a pragmatic cluster randomized study design to evaluate implementationeffectiveness and will use an implementation science framework to guide evaluation of the feasibilityacceptability and sustainability of the intervention. To achieve the study aims we have partnered with theKentucky Department of Public Health (DSMES provider) the Kentucky Regional Extension Cooperative(practice facilitation partner) Kentucky Health Information Exchange (health information technology partner)and two healthcare systems in rural Kentucky. This pilot and feasibility study will provide insight on pragmaticscalable and sustainable strategies to increase DSMES utilization. Findings will generate key preliminary datathat will guide planning of an R01-level dissemination and implementation trial with the goal of reducingdiabetes-related morbidity and mortality.

project_terms:
Address;Adult;American;Appalachian Region;Awareness;Blood Glucose;Caring;Charge;Clinic;Clinical;Communities;Complications of Diabetes Mellitus;County;Data;Diabetes Mellitus;Diagnosis;Disease;Education;Educational process of instructing;Electronics;Eligibility Determination;Evaluation;Face;Feasibility Studies;Geography;Glycosylated hemoglobin A;Goals;Guidelines;Health;Health Care Costs;Health system;Healthcare Systems;Individual;Information Technology;Intervention;Interview;Kentucky;Maps;Morbidity - disease rate;Motivation;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Practical Robust Implementation and Sustainability Model;Prevalence;Process;Provider;Public Health;Public Health Administration;Quality of life;Randomized;Recommendation;Research Design;Rural;Secure;Services;Surveys;System;Testing;care costs;combat;community clinic;cost;cost effective;diabetes self-management;dissemination trial;effectiveness testing;empowerment;evidence base;glycemic control;health disparity populations;health information technology;implementation evaluation;implementation framework;implementation process;implementation science;implementation trial;implementation/effectiveness;improved;innovation;insight;mortality;primary care clinic;primary care clinician;program costs;programs;response;rural area;skills;system-level barriers;telehealth;uptake

public_health_relevance:
PROJECT NARRATIVEDiabetes Self-Management Education and Support (DSMES) is an evidence-based small group educationalprogram that helps people with diabetes better control blood sugar (improved hemoglobin A1c) and reducediabetes-related complications and healthcare costs. DSMES is strikingly underutilized with fewer than 10% ofeligible patients receiving this helpful service due to patient- clinician- and health system-level barriers thatinclude low clinician awareness and lack of integrated referral processes between clinics and community-based DSMES programs. Our project tests a clinic level-intervention that implements an electronic clinic-community referral system and creates a practice facilitation collaborative to empower clinical teams to identifyand address DSMES barriers with the goal of increasing DSMES utilization.


application_id: 10832615
project_number: 5R01CA258751-03
project_title: Combating melanoma resistance by targeting ABL1/2
administering_ic: NCI
award_notice_date: 2024-04-03
opportunity_number: PAR-21-033
application_type: 5
activity_code: R01
ic: CA
serial_number: 258751
program_official: SONG, MIN-KYUNG H
project_start_date: 2022-05-23
project_end_date: 2027-04-30
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: KOLESAR, JILL MARIE;WILSON, MELISSA A
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:
SUMMARYDespite treatment advances over the past decade five-year survival rates for metastatic melanoma remain low(23%). BRAF mutations occur in 50-75% of melanoma and a combination of BRAF and MEK inhibitors (BRAFiMEKi) are effective therapies; however acquired resistance rapidly develops for most patients. Research overthe past decade has identified mechanisms by which melanoma cells develop resistance to BRAF/MEKinhibitors but thus far there are no FDA-approved regimens that reverse BRAFi/MEKi resistance and increasethe 5-year survival rate. Here we demonstrate that the activities of the ABL family of non-receptor tyrosinekinases are potentiated following BRAFi or BRAFi/MEKi resistance and ABL1/2 drive resistance. Moreovertargeting ABL1/2 with an FDA-approved anti-leukemia drug nilotinib dramatically reverses BRAFi/MEKi(dabrafenib/trametinib) resistance in vivo inducing prolonged tumor regression. Based on these excitingfindings the central hypothesis of our proposal is that ABL1/2 are key nodes that activate ERK-dependent or-independent pathways to drive BRAFi/MEKi resistance; thus targeting ABL1/2 may be effective for overcomingresistance and ultimately extending survival for patients with treatment-refractory melanomas. Our long-termtranslational goal is to develop a novel regimen to improve the 5-year survival rate for patients with metastaticmelanoma. We propose a comprehensive hypothesis-driven experimental design and multi-disciplinaryapproach. Aim 1 will define mechanisms by which ABL1/2 drive resistance. To achieve our objectivebiochemical molecular biological and cell biological approaches using parental/resistant melanoma cell linespharmacological inhibitors/RNAi mass spectrometry xenograft GEM PDX and syngeneic in vivo approachesas well as human tissue collected from the clinical trial (Aim 3) will be used to test the hypothesis that ABL1/2drive MAP3K activation of MEK/ERK/MYC (ERK-dependent resistance); induce ERBB2/ERBB3 activation ofPI3K/AKT (ERK-independent resistance); and alter immune cell infiltration. In Aim 2 conditioned medium fromparental/resistant cell lines co-culture experiments using in vitro and in vivo models and serum collected fromanimals and patients will be used to test the prediction that the ABL1/2-driven secretome contributes toBRAFi/MEKi resistance. Finally Aim 3 is a multi-site seamless Phase I/II clinical trial that tests the safety ofcombining nilotinib with dabrafenib+trametinib (BRAFi/MEKi) for treatment-refractory patients. Additionalendpoints include identifying the recommended Phase II dose initial efficacy (PFS) based on Phase II dataPK/PD studies and initial exploratory biomarker development. Results from these studies not only will increaseour understanding for how melanomas resist the effects of BRAFi/MEKi but also will lay the groundwork for alarge multi-center randomized clinical trial.

project_terms:
ABL1 gene;Animal Model;Animals;BRAF gene;Basic Science;Biochemical;Biological;Cell Line;Cells;Cessation of life;Clinical;Clinical Trials;Coculture Techniques;Collaborations;Conditioned Culture Media;Coupling;Data;Dose;Dose Limiting;Drug Kinetics;Drug resistance;ERBB2 gene;ERBB3 gene;Experimental Designs;FDA approved;Family;Flow Cytometry;Genetically Engineered Mouse;Goals;Growth Factor;Hematologic Neoplasms;Immune;Immunotherapeutic agent;Immunotherapy;In Vitro;Incidence;Intervention;Invaded;Kentucky;Link;MAP3K1 gene;MEKs;Maintenance;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Mediating;Melanoma;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Monitor;Mutation;Neoplasm Metastasis;Oncologist;PI3K/AKT;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I/II Clinical Trial;Phase I/II Trial;Phosphotransferases;Protein Family;Protein Secretion;Protein Tyrosine Kinase;Proteomics;Proto-Oncogene Proteins c-akt;Publishing;Qualifying;RELA gene;RNA Interference;Recommendation;Records;Refractory;Regimen;Relapse;Research;Research Personnel;Resistance;Resistance development;Role;Safety;Sampling;Series;Serum;Serum Proteins;Site;Survival Rate;Testing;Toxic effect;Translational Research;Treatment Protocols;Tumor Burden;Xenograft procedure;advanced disease;antileukemic agent;arm;biomarker development;chemokine;cytokine;drug-sensitive;early phase clinical trial;effective therapy;experimental study;gain of function;human tissue;immune cell infiltrate;immunoregulation;improved;in vivo;in vivo Model;inhibitor;innovation;interdisciplinary approach;loss of function;mutant;next generation sequencing;novel;open label;patient subsets;pharmacokinetics and pharmacodynamics;pharmacologic;phase 2 study;prevent;primary endpoint;randomized clinical trials;resistance mechanism;response;safety testing;secondary endpoint;single-cell RNA sequencing;targeted agent;therapy resistant;transcriptome sequencing;translational goal;tumor;tumor-immune system interactions

public_health_relevance:
PROJECT NARRATIVEMetastatic melanoma is one of the deadliest cancers and although immunotherapy and targeted agents extendsurvival some melanomas do not respond to the treatments or develop resistance; thus the 5-year survival rateremains dismal. This proposal examines the mechanism by which ABL family proteins contribute to BRAF/MEKinhibitor resistance and includes a clinical trial to test the safety and initial efficacy of an ABL1/2 inhibitor incombination with BRAF/MEK inhibitors for treating refractory melanomas.


application_id: 10832473
project_number: 5F31NS129159-02
project_title: Role of C. elegans RAPGEF in Synapse Development at the Neuromuscular Junction
administering_ic: NINDS
award_notice_date: 2024-04-30
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: NS
serial_number: 129159
program_official: LEENDERS, MIRIAM
project_start_date: 2023-05-01
project_end_date: 2024-05-15
study_section: Special Emphasis Panel[ZRG1-F03A-E(20)L]
contact_pi_person_id: 78425059
contact_pi: LAMB, REAGAN ELIZABETH MAYFIELD
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/ABSTRACTSynaptic dysfunction is a major contributor towards the development of a large range of neurologicaldisorders. For proper formation synapses require a series of signaling pathways to guide them butnot all of those pathways are well understood. Rap Guanine Exchange Factors or RapGEFs aresignaling proteins that act to accelerate the rate of activation of GTPases that achieve downstreamfunctions. RAPGEF subfamily members are associated with multiple neurological disorders includingschizophrenia. In murine models disruption of RAPGEF6 function results in reduced anxietybehaviors like that observed in patients with schizophrenia and increased long term potentiation. Inaddition they found no changes in gross brain morphology. Although these studies suggest thatRAPGEFs modulate synaptic function the exact mechanism is currently unknown. To addresswhether loss of RapGEF function influences synapses mutations within pxf-1 a C. elegans RapGEForthologue were studied. When exposed to the acetylcholinesterase inhibitor aldicarb pxf-1 mutantsdisplayed decreased sensitivity indicating altered synaptic function. Additionally pxf-1 and rac-2GTPase mutants display decreased synaptic vesicle intensity in cholinergic synapses. Based onthese preliminary findings the central hypothesis is that PXF-1 alters cytoskeletal reorganizationwithin neurons to influence synaptic formation and accomplishes this through activation of RacGTPase signaling. To test this hypothesis this study will use the C. elegans neuromuscular junction.C. elegans are an advantageous model system for the study of neuronal function due to their well-defined genome translucent body for imaging techniques and overall ease of genetic manipulation.The goal of this project is to determine the mechanism of PXF-1 function within the neuromuscularjunction through the following aims. Aim 1. To identify the downstream GTPase that PXF-1 isactivating in this pathway. Aim 2. To investigate whether inhibiting a GAP protein in the PXF-1pathway can restore synaptic development and function. Overall this research will provide insight intothe molecular mechanisms that govern synaptic formation and how their dysregulation may lead todevelopment of disorders. This research will support the development of future treatments forsynaptopathologies.

project_terms:
Acceleration;Acetylcholinesterase Inhibitors;Actins;Address;Affect;Aldicarb;Animals;Appearance;Auxins;Behavior;Biological Assay;Biological Models;Biosensor;Caenorhabditis elegans;Calcium;Cholinergic Receptors;Complementary DNA;Copy Number Polymorphism;Cytoskeletal Modeling;Data;Defect;Development;Disease;Dissociation;Docking;Epilepsy;Exposure to;F-Actin;Fluorescence Microscopy;Functional disorder;Future;GTP Binding;GTPase-Activating Proteins;Genetic Diseases;Genetic Engineering;Genome;Goals;Guanine;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate;Guanosine Triphosphate Phosphohydrolases;Heritability;Homologous Gene;Hydrolysis;Image;Imaging Techniques;Knowledge;Location;Long-Term Potentiation;Malignant Neoplasms;Mammals;Measures;Mediating;Mission;Molecular;Morphology;Mus;Mutation;Nature;Nervous System;Nervous System Disorder;Neuromuscular Junction;Neurons;Organism;Pathway interactions;Patients;Phenotype;Polymers;Population;Presynaptic Terminals;Proteins;Public Health;RAPGEF2 gene;Research;Role;Schizophrenia;Series;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Protein;Stereotyping;Synapses;Synaptic Transmission;Synaptic Vesicles;System;Testing;Therapeutic;Tissues;Transmission Electron Microscopy;United States National Institutes of Health;Vesicle;Work;anxiety reduction;brain morphology;cholinergic synapse;connectome;density;disability;genetic manipulation;in vivo;insight;member;mouse model;mutant;neuronal circuitry;new therapeutic target;non-invasive imaging;polymerization;presynaptic;restoration;synaptic function;therapeutically effective

public_health_relevance:
PROJECT NARRATIVE The proposed research is relevant to public health because synaptic dysfunction is associatedwith many neurological disorders that lack effective therapeutic options. Moreover understanding thesignaling proteins that promote synaptic development will provide significant advances in ourknowledge of how the nervous system is organized. Therefore the proposed research is relevant toNIHs mission to seek fundamental knowledge about living systems and to reduce illness anddisability.


application_id: 10832115
project_number: 5R01ES034389-02
project_title: Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2024-02-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: ES
serial_number: 034389
program_official: NADADUR, SRIKANTH
project_start_date: 2023-05-01
project_end_date: 2028-02-29
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 12651681
contact_pi: SANSBURY, BRIAN EDWARD
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular disease. Although the mechanismsby which PM induces pervasive multi-organ injury are still under investigation evidence strongly implicateschronic inflammation as a primary driver of pathology. Whether exposure to fine PM (PM2.5) specifically impairsthe endogenous pathways that promote the resolution of inflammation is not known. Therefore the long-termgoal of this project is to determine how exposure to PM impacts the resolution of inflammation and whether thiscontributes to PM exposure-exacerbated atherosclerosis. In work in progress we discovered that in miceexposed to concentrated PM (PM2.5) for 30 days circulating erythrocytes expressed markers of premature agingand oxidative damage. In the spleens of these mice there was an expansion of the population of cells responsiblefor erythrocyte disposal red pulp macrophages while pathways related to erythrocyte turnover hememetabolism and iron cycling were upregulated. Additionally we found that several factors related tohematopoiesis were induced in the tissue. These alterations were accompanied by a marked decrease in theabundance of specialized lipid mediators that promote resolution (SPMs) and their receptors. The changes inspleen are particularly critical because the spleen plays a central role in regulating immune response dynamics.It houses an important and distinct reservoir of monocytes which can be rapidly mobilized and deployed inresponse to various insults. In addition to coordinating immune function the spleen acts as a filter to removesenescent and damaged erythrocytes. Though patients survive following splenectomy they are more likely tocontract serious and life-threatening infections and have heightened risk of developing hematologicalmalignancies and coronary artery disease among other disorders. Our preliminary studies suggest that exposureto PM2.5 may disrupt splenic homeostasis with targeted impacts on red pulp macrophages. As macrophages arethe critical facilitators of erythrophagocytosis maintenance of the splenic hematopoietic niche and SPM actionsour central hypothesis is that PM2.5 exposure increases splenic macrophage erythrophagocytosis whichsuppresses SPM production and permits local myelopoiesis thereby enhancing monocyte egress andexacerbating vascular inflammation. To test this hypothesis we will examine the effects of PM2.5 exposure onsplenic macrophages determine the impact of PM2.5 exposure on the splenic hematopoietic niche and delineatethe contribution of splenic myelopoiesis to PM2.5-exacerbated atherosclerosis. This project will elucidate theeffects of PM on the resolution of inflammation and will provide a new mechanism by which exposure to PMestablishes a state of chronic non-resolving inflammation that affects multiple organs and processes.

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

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


application_id: 10832063
project_number: 5R35GM136295-05
project_title: Mechanisms and functions of Shoc2-transduced cellular signals
administering_ic: NIGMS
award_notice_date: 2024-03-18
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 136295
program_official: LEWIS, MECHELLE MAYLEBEN
project_start_date: 2020-05-01
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overall vision of our NIGMS-supported program is to address the molecular mechanisms of theextracellular signal-regulated kinases 1 and 2 (ERK1/2) signal transmission as guided by scaffold proteins.Essential for the normal functioning of the cell the ERK1/2 ability to rewire signaling pathways is a majorproblem for clinical intervention. The rationale for the proposed studies is that a thorough understanding of themechanism by which key regulators such as scaffold protein Shoc2 modify ERK1/2 signaling is essential forunderstanding dysregulated mechanisms in ERK1/2-related diseases and for identifying new drug targets. Ourstudies have raised many exciting questions and the most transformative research will be pursued in the nextfive-year period. Our efforts during the first cycle of NIGMS funding led to the discovery that the ubiquitin machineryregulates the signal transmission of ERK1/2 signals through the Shoc2 scaffolding module and controlsassembly of the proteins in the complex. We identified key enzymes modulating the ability of Shoc2 to transmitERK1/2 signals. We then discovered that organized spatial distribution of the Shoc2 complexes is critical forthe proper transmission of ERK1/2 signals. Our work further revealed a distinct function of the signalstransduced by the Shoc2 scaffold in ERK1/2 in mediating cell adhesion and motility. We also established thatloss of Shoc2 in zebrafish has a systemic effect of on early development recapitulating congenitalmalformations observed in patients with Shoc2 mutations. For MIRA application we propose to define the mechanisms by which endosomal sorting regulates theubiquitin-driven remodeling of the Shoc2 complexes and signaling. The key steps that segregate Shoc2 intothe distinct intracellular sorting pathways will be delineated. The molecular details of how Shoc2-activatedERK1/2 signals promote early developmental stages will be determined. We will use an innovativecomprehensive approach encompassing genetic state-of-the-art microscopy as well as cell-based andbiophysical methodologies. Of note we will use zebrafish as a vertebrate model to investigate the in vivo effectof Shoc2 gene editing on the early stages of development since they offer distinct advantages for studies ofdevelopment including their transparency as well as external and rapid development. The proposed researchis expected to produce an ambitious and comprehensive mechanistic understanding of how Shoc2 is involvedin determining the specificity of ERK1/2 signaling outcomes and has the potential for high impact by laying thegroundwork for future studies on developmental disorders and contributing to the advancement of noveltherapeutic strategies and biomarkers.

project_terms:
Address;Biological Markers;Cell Adhesion;Cell Physiology;Cells;Clinical;Complex;Congenital Abnormality;Development;Disease;Endosomes;Enzymes;Funding;Future;Genes;Genetic;Intervention;MAPK3 gene;Malignant Neoplasms;Mediating;Microscopy;Modeling;Molecular;Mutation;National Institute of General Medical Sciences;Outcome;Pathway interactions;Patients;Proteins;Research;Scaffolding Protein;Signal Pathway;Signal Transduction;Sorting;Spatial Distribution;Specificity;Syndrome;Ubiquitin;Vision;Work;Zebrafish;biophysical techniques;cell motility;cellular transduction;developmental disease;in vivo;innovation;new therapeutic target;novel diagnostics;novel therapeutic intervention;programs;public health relevance;scaffold;segregation;targeted treatment;therapeutic development;transmission process;tumor;virtual

public_health_relevance:
Public Health Relevance Statement Deregulation of the ERK1/2 signaling cascade is found in 30% of all tumors and multipledevelopmental abnormalities. While virtually every component of the cascade is target fortherapeutic development the effective targeting of this pathway in disease relies upon a clearunderstanding of all the intricacies in modulating numerous signaling components. The resultsof this study focused on the non-canonical regulators of the ERK1/2 pathway may lead to thediscovery of new diagnostics as well as new treatments for diseases including Noonan-likeSyndrome and some cancers.


application_id: 10831991
project_number: 5R34MH126965-03
administering_ic: NIMH
award_notice_date: 2024-04-25
opportunity_number: RFA-MH-20-500
application_type: 5
activity_code: R34
ic: MH
serial_number: 126965
program_official: BURSTEIN, MARCY ELLEN
project_start_date: 2022-05-01
project_end_date: 2026-04-30
study_section: ZMH1-ERB-N(03)
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Facing Eating Disorder Fears for Anorexia Nervosa: A Virtual Relapse Prevention Program Targeted at Approach and Avoidance Behaviors

project_abstract:
PROJECT SUMMARY/ABSTRACTAnorexia nervosa (AN) is chronic and disabling; most individuals never achieve full remissioneven after acute treatment and 50% of those who access acute treatment will relapse within 6-months of discharge. AN relapse-prevention treatments are urgently needed that can disrupt thepersistent cycle of admission and discharge from acute treatment. Importantly existingtreatments do not differ from control treatments in the ability to alter cognitive-behavioral ANpathology which is the primary remaining symptomatology at discharge from acute care. Theinability to alter cognitive-behavioral pathology is a function of the limited availability oftreatments that include skills training to promote behavior change in a real-world contextoutside of treatment facilities. As such relapse-prevention treatments should explicitly targetcore cognitive-behavioral pathology to facilitate approach behaviors (e.g. facing fear foods) inthe real-world. Our scientific premise developed from our past work is that the application of avirtual format of Facing Eating Disorder Fears (FED-F) for AN will facilitate engagement inapproach behaviors and minimize avoidance behaviors - improving outcomes enhancing fullrecovery and decreasing the likelihood of relapse. FED-F is a modular treatment that enhancesexposure therapy with psychoeducation and cognitive skills teaching how to face fears of (a)food (b) weight gain (c) interoception/body and (d) social situations. Our study goals are to (1)refine and test the acceptability and feasibility of FED-F delivered post-acute treatment asadjunctive to step-down specialty care (2) test if this treatment outperforms treatment as usual(TAU) and (3) to examine if treatment targets our hypothesized mechanism of action: approachbehaviors. These goals will lead to a highly deployable and accessible virtual treatment targetedat core AN mechanisms that predict relapse. The proposed research uses highly innovativemethods; we will use an all-remote technology-based approach combining a virtual non-therapist assisted treatment with remote behavioral and momentary assessment ofapproach/avoidance behaviors. Specific aims are to (1) refine FED-F into a fully virtual formatwith input from patients and stakeholders and collect preliminary data (N=10) on its feasibilityand acceptability (2) conduct a small pilot RCT of FED-F (n=30) as compared to TAU (n=30)and (3) examine if FED-F targets approach/avoidance behaviors and test if this mechanism isassociated with clinical outcomes. Ultimately this proposal will lead to the creation anddissemination of a highly user-friendly easily accessible and deployable intervention deliveredduring a critical period of care that can prevent AN relapse which will decrease mortalitymorbidity and the high costs associated with chronic treatment.

project_terms:
Acute;Admission activity;Aftercare;Anorexia Nervosa;Anxiety;Behavior;Behavior assessment;Behavioral;Caring;Cessation of life;Chronic;Clinical;Cognitive;Cognitive Therapy;Communities;Data;Disabling;Disease remission;Eating Disorders;Educational process of instructing;Ensure;Environment;Extinction;Face;Feedback;Focus Groups;Food;Fright;Goals;Hospitalization;Hospitals;Individual;Inpatients;Interoception;Intervention;Lead;Literature;Medical;Methods;Morbidity - disease rate;Neurobehavioral Manifestations;Outcome;Outpatients;Pathology;Patient Discharge;Patient Self-Report;Patients;Play;Preparation;Prevention program;Provider;Randomized Controlled Trials;Recovery;Relapse;Research;Role;Service delivery model;Services;Stimulus;Symptoms;System;Technology;Testing;Time;Translating;Translations;United States National Institutes of Health;Weight;Weight Gain;Work;acceptability and feasibility;acute care;approach behavior;approach/avoidance behavior;avoidance behavior;behavior change;care systems;clinical efficacy;cognitive benefits;cognitive function;cognitive skill;cost;cost outcomes;critical period;evidence base;experience;feasibility testing;habituation;hospital readmission;improved outcome;innovation;medical specialties;mortality;outpatient facility;prevent;psychoeducation;public health relevance;relapse prediction;relapse prevention;remote technology;skills training;social;social situation;symptomatology;therapy design;treatment as usual;treatment center;user-friendly;virtual;virtual delivery;virtual platform;virtual therapy;weight restoration

public_health_relevance:
PROJECT NARRATIVEThis project will refine the Facing Eating Disorder Fears (FED-F) for anorexia nervosa (AN)relapse-prevention treatment designed to prevent relapse after discharge from acute treatment.We will assess the feasibility acceptability clinical efficacy and target engagement of thistreatment versus treatment as usual. The proposed research has significant public healthrelevance as it will directly lead to a highly accessible and deployable treatment that candecrease AN relapse and the high societal burden associated with AN. The proposed researchis relevant to NIHs strategic aim 4.3 as it will lead to the creation of an innovative evidence-based service delivery model using technology that can be easily disseminated to communitiesin need during a critical period of transition of care.


application_id: 10831101
project_number: 5F30NS124136-03
administering_ic: NINDS
award_notice_date: 2024-04-30
opportunity_number: PA-21-050
application_type: 5
activity_code: F30
ic: NS
serial_number: 124136
program_official: MATTHEWS, MARGUERITE
project_start_date: 2022-05-08
project_end_date: 2025-07-07
study_section: Special Emphasis Panel[ZRG1-F03A-T(20)L]
contact_pi_person_id: 15915830
contact_pi: SHADE, LINCOLN
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-08
project_title:
Elucidating Shared Risk of Brain Arteriolosclerosis and Related Pathologies with Multiple 'omics Modalities

project_abstract:
Abstract Brain arteriolosclerosis (B-ASC) is a cerebrovascular disease characterized by pathological thickening ofthe arterioles in the brain. Non-Alzheimers disease brain pathologies including B-ASC are increasinglyrecognized as important contributors to cognitive decline in aged individuals. In autopsy cohorts B-ASC isfound in over 50% of participants aged eighty years or older at death. B-ASC is associated with multiple otherneuropathologies including hippocampal sclerosis. Despite its clinical importance the pathophysiology of brainarteriolosclerosis and its mechanistic relationship to other pathologies are not well understood. We haveaggregated and harmonized genotype and autopsy data between four high-quality neuropathology cohorts: theNational Alzheimers Coordinating Center (NACC) the Religious Orders Study and the Memory and AgingProject (ROSMAP) the Adult Changes in Thought Study (ACT) and the Alzheimers Disease NeuroimagingInitiative Neuropathology Cohort (ADNI). In preliminary genetic association and functional genomic studiesusing NACC participants we identified multiple B-ASC risk loci that replicated in at least one independentcohort and established a framework for genetic studies of neuropathological endophenotypes (NPE). In Aim 1we hypothesize that analyses employing gene expression and DNA methylation will further characterizegenomic risk factors for B-ASC pathology. We will investigate the relationship between B-ASC geneexpression and DNA methylation in the dorsolateral prefrontal cortex using ROSMAP. These analyses will befollowed by computational approaches that will estimate the contribution of different cell types and predict geneexpression from genotype data in other cohorts. In Aim 2 we hypothesize that B-ASC shares genomic risk withassociated NPE. We will first use our established analytic pipeline to perform genetic association studies ofNPE comorbid with B-ASC. We will then use statistical methods to quantify and localize shared genetic riskbetween B-ASC and other NPE. Findings from these studies will provide a rigorous characterization of B-ASCrisk factors and relevant biological pathways. Our cross-trait analyses will help clarify B-ASCs place in thecomplex web of mixed brain pathologies common in aged individuals. The mentors and collaborators I haverecruited comprise an experienced and multidisciplinary team that includes two biostatisticians a geneticepidemiologist and an experimental neuropathologist. This NIH F30 fellowship will provide the requisiteexperience knowledge and skills necessary as preparation to the next stage in my career as a clinicalresearcher.

project_terms:
Adult;Age;Aging;Alzheimer's Disease;Architecture;Autopsy;Bioinformatics;Biological;Biological Assay;Brain;Brain Pathology;Cells;Cerebrovascular Disorders;Cerebrovascular system;Cessation of life;Chromosomes;Clinical;Clinical Research;Cognitive;Complex;DNA Methylation;Data;Data Set;Dementia;Development;Diabetes Mellitus;Disease;Epidemiologist;Fellowship;Functional disorder;Gene Expression;Generations;Genetic;Genetic Risk;Genetic study;Genomics;Genotype;Hypertension;Impaired cognition;Internet;Knowledge;Memory;Mentors;Methods;Methylation;Modality;Molecular;Multiomic Data;Outcome;Participant;Pathologic;Pathology;Pathway interactions;Phenotype;Pilot Projects;Prefrontal Cortex;Preparation;Process;Research;Research Personnel;Resources;Risk;Risk Factors;Sampling;Source;Statistical Methods;Testing;Training Programs;Translating;United States National Institutes of Health;Update;aged;aging population;arteriole;brain arteriolosclerosis;career;case control;cell type;clinical risk;cohort;comorbidity;design;endophenotype;experience;functional genomics;genetic association;genetic risk factor;genome wide association study;genome-wide;hippocampal sclerosis;human old age (65+);insight;molecular phenotype;multidisciplinary;multiple omics;neuroimaging;neuropathology;new therapeutic target;recruit;religious order study;risk sharing;risk variant;skills;therapeutic target;trait;translational genomics

public_health_relevance:
Project Narrative Brain arteriolosclerosis (B-ASC) the pathologic thickening of small blood vessels in the brain is a commoncontributor of cognitive decline in aged individuals but the genetic risk factors are poorly understood. Thisproject will identify multi-omic risk factors of B-ASC and identify the shared genetic risk between B-ASC andassociated neuropathologies. Findings will provide mechanistic insight into B-ASC and identify potentialtherapeutic targets.


application_id: 10831064
project_number: 5R01HL163712-02
project_title: Inflammatory Injury Caused by Silica Exposure
administering_ic: NHLBI
award_notice_date: 2024-05-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163712
program_official: VUGA, LOUIS J
project_start_date: 2023-05-01
project_end_date: 2027-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMore than 2 million people in the US are exposed to respirable crystalline silica at work. Inhalationof dust containing respirable crystalline silica causes silicosis which is characterized by chronicinflammation and pulmonary fibrosis. Silica exposure also increases the risk of developingautoimmune diseases and cancer. Silicosis patients have a median survival of 6 years afterdiagnosis. The pathophysiology of silicosis has not been fully understood. Currently there is noeffective treatment against this devastating disease. It has been reported that the dysregulationof alveolar macrophages plays an important role in the pathogenesis of silicosis. The depositionof fine silica particles in alveoli and the ingestion of silica particles by alveolar macrophages triggerpro-inflammatory and pro-fibrotic responses. However molecular mechanisms of thedysregulated alveolar macrophage responses remain elusive. Using a mouse model of silicosisour preliminary studies indicate that myeloid HDAC6 plays an essential role in the pathogenesisof silicosis. In the proposed studies we will test the hypothesis that myeloid HDAC6 is a keymediator of pro-inflammatory and pro-fibrotic responses in silicosis. We will investigate thespecific role of myeloid HDAC6 in silicosis and evaluate the therapeutic potential of HDAC6 as atarget to treat silicosis.

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

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


application_id: 10830964
project_number: 5R01HL163977-03
project_title: Data-driven optimization of therapy for heart failure
administering_ic: NHLBI
award_notice_date: 2024-04-24
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163977
program_official: SHANBHAG, SUJATA MADHUKAR
project_start_date: 2022-05-01
project_end_date: 2026-04-30
study_section: Modeling and Analysis of Biological Systems Study Section[MABS]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: LEE, LIK CHUAN ;WENK, JONATHAN F
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:
ABSTRACTThis collaborative project integrates concepts from engineering artificial intelligence computer modelingphysiology and clinical cardiology to explore new therapeutic strategies for patients who have heart failure. Themoonshot goal is a simulation framework that can predict how a patient's heart will grow and remodel during apotential therapeutic intervention. Once the framework has been validated with patient data it could be deployedto compare the outcomes predicted for different treatments. A clinician could then use the predictions to guidetheir choice of therapy.This project seeks to advance computational cardiology and move the field closer to a randomized clinical trialthat tests whether patients treated with model-optimized therapies have better outcomes than patients whoreceived standard clinical care.The multidisciplinary research team consists of 3 scientists (Ken Campbell PhD; Jonathan Wenk PhD; Lik-Chuan Lee PhD) and 2 cardiologists (Emma Birks MD/PhD; Gaurang Vaidya MD). Together their skillsetsrange from molecular biophysics through computer modeling and engineering to clinical care and VentricularAssist Devices.The plan has 3 Aims: 1) Develop PyMyoVent as a testbed for implementing baroreflex control and myocardial growth. 2) Use MyoFE to create and validate patient-specific biventricular finite element models that incorporate growth and functional remodeling. 3) Deploy personalized MyoFE models to predict optimal therapies for patients who have heart failure.The plan is highly innovative reward and makes intelligent use of clinical data collected as part of normal carefrom 100 patients who are enrolled in a research registry at the University of Kentucky. These data will includepressure signals transmitted wirelessly from patients who have had a CardioMEMS device inserted around theirpulmonary artery. Fundamental contributions include the creation of finite element models that are controlled bya baroreflex and grow and adapt in response to physiological signals including myofilament stress and cellularenergy use.

project_terms:
Algorithm Design;Algorithms;Area;Artificial Intelligence;Atrial Fibrillation;Baroreflex;Biophysics;Cardiac;Cardiology;Cardiovascular system;Caring;Circulation;Clinical;Clinical Data;Computer Models;Computer software;Data;Development;Devices;Dimensions;Doctor of Philosophy;EFRAC;Echocardiography;Elements;Engineering;Enrollment;Foundations;Future;Geometry;Goals;Growth;Heart;Heart failure;Interdisciplinary Study;Intervention;Kentucky;Left ventricular structure;Machine Learning;Magnetic Resonance Imaging;Manuscripts;Microfilaments;Modeling;Molecular;Myocardial;Myosin ATPase;Paper;Patient-Focused Outcomes;Patients;Physiological;Physiology;Positioning Attribute;Pulmonary artery structure;Recommendation;Reflex action;Registries;Research;Research Personnel;Rewards;Running;Science;Scientist;Signal Transduction;Stress;Structure;Swarm intelligence;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Thick;Time;Universities;Ventricular;algorithm development;algorithm training;blood pressure control;blood pump;clinical care;computer program;constriction;gradient boosting;improved;innovation;laptop;novel therapeutic intervention;optimal treatments;outcome prediction;pressure;random forest;randomized clinical trials;research vision;response;simulation;skills;standard care;success;therapeutic evaluation;treatment optimization;ventricular assist device;wireless transmission

public_health_relevance:
NARRATIVEThis project develops computer programs that can predict how different potential therapies change the waythat a patient's heart will grow and adapt. The long-term goal is to create software that cardiologists can use tooptimize therapies for patients who have heart failure.


application_id: 10830470
project_number: 5R35GM141478-04
project_title: Relative adrenal insufficiency as a risk factor and an endotype for sepsis
administering_ic: NIGMS
award_notice_date: 2024-04-16
opportunity_number: PAR-19-367
application_type: 5
activity_code: R35
ic: GM
serial_number: 141478
program_official: ZHAO, XIAOLI
project_start_date: 2021-05-01
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1-CB-T(55)R]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
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:
SummarySepsis is a major health issue with a mortality rate of 30%. Sepsis induces huge stressresponses including a 5-10 fold induction in glucocorticoid (GC) production in adrenalgland however the function of this inducible GC (iGC) remains poorly understood.Importantly 25-60% of septic patients suffer relative adrenal insufficiency  insufficientiGC production in response to stress. Given the potential complications of adrenalinsufficiency GC therapy is often used for septic shock patients. However the truecontribution of adrenal insufficiency to sepsis and the efficacy of GC therapy are highlycontroversial. While a number of factors contribute to the debate a lack of a relativeadrenal insufficiency animal model has limited our capacity to address these issues.Toward a solution scavenger receptor BI (SR-BI) a well-established high densitylipoprotein (HDL) receptor was first identified in our laboratory as a critical protectivefactor in sepsis. A number of laboratories including ours recently reported that SR-BInull mice fail to produce iGC in response to ACTH stimulation establishing SR-BI nullmice as a relative adrenal insufficiency model. Using this unique model wedemonstrated that mice with relative adrenal insufficiency are susceptible to septicdeath and more importantly supplementation of GC rescued mice with relative adrenalinsufficiency but surprisingly caused more death in mice without relative adrenalinsufficiency. Our findings demonstrate that relative adrenal insufficiency is a risk factorand an endotype of sepsis. Our findings also provide a proof of concept to support aprecision medicine approach to guide the use of GC for sepsis therapy specificallyselectively using GC therapy for a subgroup of septic patients with relative adrenalinsufficiency. In this R35/MIRA application we propose to use our newly developedadrenal-specific SR-BI null mice as a unique relative adrenal insufficiency animal modelto understand why relative adrenal insufficiency is a risk factor for sepsis and why GCtherapy benefits mice with relative adrenal insufficiency but harms those without. Thetranslation of this study will improve the overall efficacy of sepsis therapy and savelives.

project_terms:
Address;Adrenal Glands;Adrenal gland hypofunction;Animal Model;Cessation of life;Corticotropin;Death Rate;Glucocorticoids;Goals;Health;Knockout Mice;Laboratories;Modeling;Mus;Patients;Predisposition;Production;Reporting;Risk Factors;SR-BI receptor;Sepsis;Septic Shock;Stress;Subgroup;Supplementation;biological adaptation to stress;high density lipoprotein receptor;improved;precision medicine;protective factors;response;septic;septic patients;translational study

public_health_relevance:
Project NarrativeThe goal of this application is to investigate the contribution of relative adrenalinsufficiency to sepsis. Accomplishment of this study will improve our understanding ofsepsis and provide a proof of concept to support a precision medicine approach todirect the use of glucocorticoid for sepsis therapy.


application_id: 10830360
project_number: 5R01CE003513-03
project_title: RFA-CE-22-010 Evaluation of Kentucky Access to Recovery Linkage Strategy
administering_ic: NCIPC
award_notice_date: 2024-06-27
opportunity_number: RFA-CE-22-010
application_type: 5
activity_code: R01
ic: CE
serial_number: 003513
project_start_date: 2022-09-30
project_end_date: 2025-09-29
study_section: ZCE1-MLW(10)R
contact_pi_person_id: 7931539
contact_pi: BUNN, TERRY LEE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-30
project_abstract:
The CDC National Center for Health Statistics (NCHS) estimates that for the 12-month period endingSeptember 2021 in the United States (US) there were 99543 drug overdose deaths. Kentucky had the 2ndhighest age-adjusted drug overdose fatality rate (51.5 deaths/100000 persons) in the US in 2020. Toaddress the high numbers of drug overdose fatalities effective strategies are needed to link persons in SUDtreatment or those with illicit SUD not yet in treatment with recovery support services (RSSs) to build andmaintain recovery and reduce resumption of illicit substance use and drug overdoses. Access to Recovery(ATR) is a linkage strategy supported by Substance Abuse and Mental Health Services Administration(SAMHSA) that was implemented by Kentucky in 2019 to link vulnerable populations with opioid and/orstimulant SUDs to RSSs using a voucher system and re-link clients to RSSs following resumption ofsubstance use. The Kentucky ATR (KATR) strategy is a 25-county program that links county residents at orbelow the 200% national poverty level who have illicit SUDs and are in treatment or early recovery toevidence-based RSSs such as recovery housing and to other RSSs. Priority KATR clients set by KATR arejustice-involved veteran pregnant/ postpartum and parenting populations. To address the gap inaccessibility of RSSs that often occurs in vulnerable populations the KATR linkage approach usesvouchers as a linkage strategy for individuals in SUD treatment who have no other funding options toacquire critical RSSs. As such KATRs linkage through vouchers is a last resort approach for linking toRSSs. The purpose of this proposal is to perform a rigorous process and outcome evaluation of this lastresort voucher strategy of linking by accomplishing the following specific aims: Specific Aim 1: Conduct aprocess evaluation of the KATR linkage strategy to determine whether the KATR strategy is acceptable andaccessible to vulnerable populations with illicit SUD who are linked to RSSs; identify barriers and facilitatorsto KATR implementation; and assess the extent to which the KATR strategy was implemented as designed.Specific Aim 2: Conduct an outcome and impact evaluation of the KATR linkage strategy. Specific Aim 3:Evaluate the long-term effectiveness of implementing vouchers as a linkage strategy in a populationrequiring RSSs when no other funding sources are available. A within-subjects design will be used to testthe effectiveness of the KATR voucher linkage approach to reducing the risk of nonfatal and fatal overdosesby increasing an individuals recovery capital; reducing resumption of illicit substance use; and promotingrelinking to RSSs if illicit substance use is resumed. Study results may enhance current state ATRs thatserve individuals experiencing similar SUD health access disparities.

public_health_relevance:
Project NarrativeRigorous evaluation of the KATR linkage strategy has the potential to inform and enhance public health policysuch as enhancing state ATR programs to address SUD health disparities experienced by individuals inunderserved areas with incomes at or below the 200% poverty level individuals with prior criminal-justiceinvolvement veterans and pregnant and parenting populations with illicit SUD which are all the uniquecharacteristics of the KATR study population. As individuals with illicit SUD and these specific demographiccharacteristics are not unique to the geographic region of Kentucky we believe that if results are significantthey may be generalizable to populations with those characteristics in other states. One aspect of the KATRlinkage strategy evaluation that will be crucial is determining RSS utilization and RSS combinations that areassociated with long-term recovery capital and recovery maintenance success.


application_id: 10830350
project_number: 5R01AG068330-06
project_title: The metabolic interplay of sleep and Alzheimer's disease
administering_ic: NIA
award_notice_date: 2024-05-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 068330
program_official: SARE, RACHEL
project_start_date: 2020-08-01
project_end_date: 2026-04-30
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8504528
contact_pi: MACAULEY-RAMBACH, SHANNON L
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTA bidirectional relationship exists between Alzheimers disease and sleep where disrupted sleep increasesamyloid-beta (A) and tau pathology and conversely A and tau aggregation disrupt sleep. The sleep/wakecycle is a master regulator of metabolic and neuronal activity where daily oscillations in activity are coupled tothe production and clearance of A and tau. Although modulating neuronal activity alters both sleep/wake cyclesand A/tau release less is known about how fluctuations in glucose metabolism drive changes in sleep andAlzheimers disease related pathology. Therefore the goal of this proposal is to determine whether changes inmetabolic activity lead to changes in neuronal activity to disrupt sleep in Alzheimers disease and whethermetabolic dysfunction can serve as a novel therapeutic target to rescue sleep and Alzheimers pathology. Usinghippocampal biosensors coupled with EEG/EMG recordings this proposal will investigate how glycemicvariability and peripheral glucose intolerance affect sleep and Alzheimers disease in rodent models ofAlzheimers related pathology. Moreover we will establish whether normalizing peripheral glucose homeostasisthrough treatment with the diabetic medication metformin is sufficient to preserve and restore sleep architecturein the setting of Alzheimers disease.

project_terms:
Abeta clearance;Acute;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease risk;Amyloid beta-Protein;Biosensor;Blood Glucose;Brain;Cause of Death;Cerebrum;Chronic;Coupled;Electroencephalography;Glucose;Glucose Intolerance;Goals;Hippocampus;Human;Hyperglycemia;Hypoglycemia;Impairment;Individual;Insulin Resistance;Intervention;Lead;Maintenance;Measures;Metabolic;Metabolic dysfunction;Metabolism;Metformin;Modeling;Mus;Nerve Degeneration;Neurons;Pathogenesis;Pathology;Peripheral;Pharmaceutical Preparations;Pharmacological Treatment;Process;Production;Rodent Model;Role;Sleep;Sleep Architecture;Sleep Deprivation;Sleep Disorders;Sleep Wake Cycle;Sleep disturbances;United States;Wakefulness;Wild Type Mouse;Work;abeta accumulation;beta amyloid pathology;blood glucose regulation;diabetic;euglycemia;glucose metabolism;glucose tolerance;mouse model;neuronal metabolism;new therapeutic target;novel;pharmacologic;preservation;prevent;response;restoration;synergism;tau Proteins;tau aggregation;tau function

public_health_relevance:
PROJECT NARRATIVEAlzheimers disease is the 6th leading cause of death in the United States and is expect to triple by 2050.Individuals with Alzheimers disease suffer from sleep disturbances and sleep disorders are associated with anincreased risk for Alzheimers disease. Since sleep/wake cycles are a dynamic interplay between metabolismand neuronal activity the goal of this project is to understand how changes in metabolism impact the relationshipbetween sleep and Alzheimers disease and whether metabolic dysfunction is a novel therapeutic target fortreating Alzheimers disease and sleep.


application_id: 10828855
project_number: 5R01NS127974-02
administering_ic: NINDS
award_notice_date: 2024-03-11
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 127974
program_official: YIN, XILING
project_start_date: 2023-04-15
project_end_date: 2028-03-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 15196532
contact_pi: HARP, JORDAN PATRICK
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
Predictors and Biomarkers for VCID versus Cognitive Recovery after Stroke Thrombectomy in Rural Appalachia

project_abstract:
Vascular cognitive impairment and dementia (VCID) is present in 25-30% of stroke patients and it is difficult topredict at the time of stroke who those patients will be. The National Plan to Address Alzheimers Disease andthe NHLBI-NINDS VCID Workshop called for increased research on VCID prediction especially in underservedpopulations. The proposed research will identify predictors of cognitive recovery in rural underserved patientsafter mechanical thrombectomy for emergent large vessel occlusion (ELVO) stroke. These predictors will targetpatients that would benefit from intensive rehabilitation. Our novel biologic sample registry was used to identifyproteins in systemic blood samples taken during thrombectomy as independent predictors of cognitiveperformance at post-stroke discharge and 90-day follow-up. The hypothesis is that these proteins will provideincremental predictive validity for cognitive impairment including dementia over and above clinicalcharacteristics social determinants of health and traditional ADRD plasma biomarkers. The proposed study willprospectively enroll 225 patients collecting systemic arterial blood at the time of thrombectomy and analyzeprotein expression. Using a retention strategy tailored to underserved rural participants neurocognitive test dataand venous blood samples for longitudinal protein expression will be collected from 3 months to 2 years post-thrombectomy. The study site located in the US Stroke Belt with some of the most medically underserved ruralcounties in the nation will contribute to the NIH priority focus on health disparities. Specific Aim 1: Test thehypothesis that increased patient home county rurality predicts worse cognitive outcomes post-strokeboth acutely and chronically. Generalized estimating equation models will test the main effect of home countyrurality and other social determinants of health on cognitive status (normal cognitive impairment no dementiadementia) the main effect of time on cognitive performance across time points and the interaction of rurality andtime on cognitive status across time points. Associations among rurality comorbidities and time-of-thrombectomyblood protein expression will be auxiliary analyses. Specific Aim 2: Test the hypothesis that ADRDbiomarkers in systemic blood at time of thrombectomy are biomarkers for acute post-stroke cognitiveimpairment and chronic VCID two years later. Blood samples will be assessed for known proteomicbiomarkers for cognition at the UKY Biomarker Center. Specific Aim 3: Test the hypothesis that novelbiomarkers in systemic blood at time of thrombectomy predict chronic VCID including dementia overand above the effects of ADRD markers. Proteomic analysis will be conducted on time-of-thrombectomy bloodsamples to measure the expression of inflammatory-related proteins. Hierarchical generalized estimatingequation models will assess the incremental improvement in prediction of cognitive status over time added bythese addition markers. Analyses will use LASSO methods and split-sample cross-validation to create apredictive model based on both ADRD and novel biomarkers that predict cognitive outcomes.

project_terms:
Acute;Address;Affect;Alzheimer's Disease;Alzheimer's disease related dementia;Biological;Biological Markers;Blood;Blood Proteins;Blood specimen;Brain;Caregiver Burden;Caring;Catchment Area;Characteristics;Chronic;Clinical;Coagulation Process;Cognition;Cognitive;County;Data;Death Rate;Dementia;Development;Early Diagnosis;Educational workshop;Enrollment;Equation;Excision;Goals;Health Services Accessibility;Home;Home visitation;Impaired cognition;Inflammation;Inflammatory;Joints;Life;Long term disability;Machine Learning;Measures;Mechanics;Medical History;Medical Records;Methods;Modeling;National Heart Lung and Blood Institute;National Institute of Neurological Disorders and Stroke;Outcome;Participant;Patients;Plasma;Positioning Attribute;Procedures;Proteins;Proteomics;Registries;Rehabilitation therapy;Research;Rural;Rural Appalachia;Rural Population;Sampling;Signal Pathway;Site;Statistical Models;Stroke;Stroke Belt;Suburban Population;Testing;Thrombectomy;Time;Travel;Underserved Population;United States National Institutes of Health;Validation;Venous blood sampling;Work;acute stroke;barrier to care;care delivery;cognitive impairment no dementia;cognitive performance;cognitive recovery;comorbidity;disability burden;follow-up;functional improvement;health care availability;health disparity;improved;medical complication;medically underserved;neurocognitive test;novel;novel marker;novel therapeutic intervention;novel therapeutics;outcome prediction;patient population;post stroke;post stroke cognitive impairment;precision medicine;predictive marker;predictive modeling;programs;prospective;protein biomarkers;protein expression;retention rate;rural counties;rural underserved;rurality;social health determinants;stroke cognitive outcome;stroke patient;success;underserved area;urban health disparities;vascular cognitive impairment and dementia

public_health_relevance:
Thrombectomy is a life-saving procedure that removes clot from the brain during stroke but it is difficult topredict which patients will recover cognitively and which will have persistent cognitive impairment or decline(VCID: vascular contributions to cognitive impairment and dementia)and it is particularly difficult to predictthese outcomes in rural underserved patients who tend to have more complicated medical histories andbarriers to care. Using a retention strategy tailored to the needs of rural underserved participants theproposed study will test how well certain proteins in blood collected at the time of thrombectomy predict thelong-term cognitive outcomes of stroke patients in one of the most rural and medically underserved regions inthe U.S. Stroke Belt. Study success would address a major rural-urban health disparity and also benefit strokepatients at large by making available the first long-term cognitive profiles of thrombectomy patients byimproving the assignment to proper care using the earliest possible blood markers for VCID versus cognitiverecovery and by opening the door to development of new therapeutics based on blood protein signalingpathways that affect cognitive outcomes.


application_id: 10828853
project_number: 5R21NS128749-02
project_title: Development of a Novel Animal Model for Spinal Cord Injury with Sepsis
administering_ic: NINDS
award_notice_date: 2024-04-03
opportunity_number: PA-21-219
application_type: 5
activity_code: R21
ic: NS
serial_number: 128749
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2023-04-15
project_end_date: 2025-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11775081
contact_pi: PATEL, SAMIRKUMAR
other_pis: SAITO, HIROSHI
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:
Summary AbstractSepsis is a predominant life-threatening secondary complication following traumatic spinal cord injury (SCI).Several predisposing factors such as polytrauma prolonged/repeated hospital stay pressure ulcer andindwelling catheters make SCI patients more susceptible to microbial infections that can lead to sepsis. Sepsisis a leading cause of death after spinal trauma and is associated with poor functional outcomes among survivors.Depending on the time of onset there are two sepsis types. Sepsis diagnosed within 48hr of initial injury istermed primary sepsis and when its onset occurs after 48hr it is known as secondary sepsis. Though sepsiswith SCI is a serious condition leading to diminished life expectancy and quality of life this combined medicalissue has not been well studied. This is mainly due to lack of an appropriate animal model. Accordingly the goalof proposed study is to develop and validate a novel clinically relevant rodent model that closely mimics the long-term dysfunction of survivors of sepsis after SCI. This model will be validated with six parameters: 1) survivalrate 2) infection severity 3) inflammatory cytokines 4) locomotor score 5) muscle force and 6) histopathology.Our team has developed a clinically relevant rodent sepsis model consisting of polymicrobial abdominal sepsisby cecal slurry (CS) injection followed by a delayed but repeated ICU-like resuscitation procedure with fluids andantibiotics; this refined model allows us to investigate long-term physical dysfunction among sepsis survivors.Our main approach is to combine this long-term sepsis survivor model with rat spinal contusion model to mimiceither primary (Aim 1) or secondary (Aim 2) sepsis after SCI. Our central hypothesis is that the cumulativeeffects of sepsis plus SCI will impair spontaneous motor recovery limit spinal cord tissue sparing exacerbateskeletal muscle weakness and increase mortality. Two specific Aims are designed to test this hypothesis. InAim 1 we will induce sepsis immediately after SCI to mimic primary sepsis by CS injection followed by ICU-like resuscitation initiated at 8 hrs. To mimic secondary sepsis in Aim 2 we will induce sepsis at 6 weeks afterSCI by CS injection and resuscitation initiated at 8hrs after sepsis induction. SCI animals in Aim 1 will undergoweekly locomotor testing for 6 weeks and in Aim 2 for a total of 12 weeks (6 weeks before sepsis induction and6 weeks after) to assess spontaneous recovery. After final locomotor assessments survivors will be subjectedto ex vivo muscle force testing histological examination and mitochondrial function analyses to assess muscleweakness. Spinal cord tissue will be used for quantitative histology of spared gray and white matter as well aslesion volume that will be correlated with locomotor recovery. Successful development of this model will allowus to investigate detailed molecular/physiological mechanisms of sepsis following SCI with a long-term goal ofdeveloping therapeutic strategies to improve quality of life in the afflicted population. Success of this project isassured by our strong multi-disciplinary team including Drs. Patel (MPI SCI researcher) Saito (MPI sepsisresearcher) Butterfield (Co-I muscle researcher) and Stromberg (Co-I biostatistician).

project_terms:
Abdomen;Acute;Address;Affect;Animal Model;Animals;Antibiotics;Biochemical;Blood;Body System;Cause of Death;Clinical;Complication;Contusions;Development;Diagnosis;Functional disorder;Goals;Histologic;Histology;Histopathology;Hospitalization;Impairment;Individual;Indwelling Catheter;Infection;Inflammatory;Injections;Injury;Left;Length of Stay;Lesion;Life;Life Expectancy;Liquid substance;Locomotor Recovery;Medical;Mitochondria;Modeling;Molecular;Multiple Trauma;Muscle;Muscle Weakness;Outcome Measure;Phase;Physiological;Population;Predisposing Factor;Predisposition;Procedures;Quality of life;Rattus;Recovery;Recovery of Function;Research Personnel;Research Proposals;Resuscitation;Rodent;Rodent Model;Secondary to;Sensory;Sepsis;Severities;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Spleen;Sports;Survival Rate;Survivors;Testing;Therapeutic;Time;Tissues;Trauma;Violence;catheter associated UTI;clinically relevant;cytokine;decubitus ulcer;design;falls;functional outcomes;gray matter;improved;inflammatory marker;innovation;microbial;model development;mortality;motor recovery;multidisciplinary;novel;skeletal muscle weakness;success;vehicular accident;white matter;young adult

public_health_relevance:
NARRATIVESepsis is a predominant secondary complication that affects quality of life and reduces life expectancy in spinalcord injury (SCI) populations. Although sepsis after SCI is an existing clinical condition this medical issueunfortunately is understudied due to lack of good animal models. Accordingly the current innovative proposal isdesigned to develop for the first time a novel rat model of sepsis survivors following SCI to study compromisedfunctional recovery as well as damage to various tissue/organ system(s) due to the compounding effects of SCI-sepsis.


application_id: 10828381
project_number: 5R01AI153275-05
administering_ic: NIAID
award_notice_date: 2024-04-16
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 153275
program_official: DUPUY, LESLEY CONRAD
project_start_date: 2020-05-21
project_end_date: 2026-04-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 10849785
contact_pi: SOKOLOSKI, KEVIN JOSEPH
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
budget_start_date: 2024-05-01
project_title:
Comprehensive Definition of the Critical Role(s) of the Alphaviral Noncapped Genomic RNAs to Infection and Pathogenesis

project_abstract:
Alphaviruses are vector-borne pathogens that have proven capable of causing significant outbreaks of clinical disease. Currently there is an absolute lack of safe and approved antiviral therapies / vaccines. Thus research which defines the molecular basis of infection is essential and critically important to not only understanding alphaviral pathogenesis but to the development of innovative antiviral strategies. The overarching research objective of this proposal is to define the mechanism by which a novel alphavirus RNA species impacts infection and pathogenesis. The scientific premise and rationale supporting this objective are based upon a wealth of preliminary evidence which indicates that the production of noncapped genomic RNAs (ncgRNAs) is essential for alphaviral infection as evidenced by studies involving Sindbis virus (SINV) and Ross River virus. Nonetheless the extent to which the ncgRNAs impact viral infection is unknown and represents a critical gap in the knowledge base. Thus we propose the following specific aims- i) To determine the mechanism with which the noncapped genomic vRNAs impact infection and ii) To define the impact of the noncapped genomic vRNAs on viral pathogenesis. To accomplish the first aim we will undertake an exhaustive molecular analysis of SINV infection to determine the mechanism by which the ncgRNAs effect viral infection. Specifically we will determine whether or not ncgRNA function is linked to its translatability via a novel IRES-based approach. In addition we will determine which viral process is negatively affected by ncgRNA reduction; and determine the molecular interactions required for ncgRNA function. The second aim uses a combinatorial approach of in vivo studies and IFN-competent tissue culture models to comprehensively define the contribution of the ncgRNAs to SINV pathogenesis. Briefly the contribution of the ncgRNAs to the induction of a detrimental neuroinflammatory response will be evaluated in depth histologically and at the transcriptomic and proteomic levels. Moreover the consequences of increasing and decreasing alphaviral capping efficiency on the host innate immune response will also be defined in highly tractable tissue culture models of infection. The proposed work is highly significant in that it seeks to characterize and define the molecular importance of a novel viral RNA species. Moreover the proposed research is conceptually and technically innovative as state-of-the-art techniques approaches and models of infection are used to delineate the contributions of the novel ncgRNA species to molecular infection and pathogenesis. The successful completion of this work will fundamentally expand the knowledgebase by eliminating the critical gap in understanding described above; in addition the proposed research has a high likelihood of leading to the identification of novel antiviral strategies.

project_terms:
Address;Affect;Alpha Virus;Alphavirus Infections;Anti-viral Agents;Anti-viral Therapy;Arthritis;Attenuated;Binding;Biology;Brain;Cell Line;Cessation of life;Chikungunya virus;Clinical;Cytoplasm;Defect;Development;Disease;Disease Outbreaks;Environment;Event;Failure;Gene Expression;Genomics;Growth;Histologic;Immune response;Impairment;In Vitro;Individual;Infection;Innate Immune Response;Integration Host Factors;Interferons;Internal Ribosome Entry Site;Invertebrates;Joints;Kinetics;Link;Modeling;Molecular;Molecular Analysis;Morbidity - disease rate;Nature;Nucleocapsid;Pathogenesis;Pathologic;Process;Production;Proteins;Proteomics;Public Health;RNA;RNA chemical synthesis;Reporting;Research;Role;Ross river virus;Sindbis Virus;Structure;Techniques;Testing;Therapeutic;Vaccines;Venezuelan Equine Encephalitis Virus;Viral;Viral Encephalitis;Viral Genes;Viral Pathogenesis;Virion;Virulence;Virus Diseases;Virus Replication;Wild Type Mouse;Work;combinatorial;defined contribution;effective therapy;expectation;genomic RNA;improved;in vivo;innovation;knowledge base;knowledgebase;mortality;mutant;neuroinflammation;novel;particle;pathogen;response;tissue culture;tissue/cell culture;transcriptomics;vaccine strategy;vector-borne pathogen;viral RNA

public_health_relevance:
Alphaviruses such as Sindbis virus Chikungunya virus and Venezuelan Equine Encephalitis virus are significant threats to public health. Alphaviral infection in otherwise healthy individuals may result in severe disease- including persistent severe multi-joint arthritis viral encephalitis and death. This proposal seeks to characterize the importance of a novel noncapped viral RNA in regards to the establishment of viral infection and pathogenesis for the purpose of improving the understanding of alphaviral biology to identify innovative therapeutic strategies.


application_id: 10828309
project_number: 5K22CA258678-03
project_title: Admixture mapping of mosaic copy number alterations for identification of cancer drivers
administering_ic: NCI
award_notice_date: 2024-03-11
opportunity_number: PAR-18-467
application_type: 5
activity_code: K22
ic: CA
serial_number: 258678
program_official: JAKOWLEW, SONIA B
project_start_date: 2022-04-15
project_end_date: 2025-09-30
study_section: ZCA1-RTRB-R(J1)
contact_pi_person_id: 12387511
contact_pi: JAKUBEK SWARTZLANDER, YASMINKA ALEKSANDRA
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:
PROJECT SUMMARY/ABSTRACTBackground: Somatic mosaicism arises due to the clonal expansion of a cell with an acquired mutation whichleads to genetically distinct sub-populations of cells in an organism derived from a single zygote. As a cloneproliferates its subclones can accumulate further molecular changes that seed cancer. A better understandingof acquired point mutations and copy number changes in these clonal expansions can help elucidate theearliest stages of cancer development. Studies of tissues from healthy individuals have found that those withclonal mosaicism in blood specifically copy number alterations (CNAs) have a ~10-fold higher risk ofdeveloping hematological malignancies thus underscoring the translational potential of mosaicism studies forthe development of improved risk assessment and cancer prevention strategies. Research up to now hasmainly focused on persons of European ancestry. My own preliminary results show differences in the genomiclandscape of CNAs between individuals of African American or Latino ancestry when compared withEuropeans. Understanding these differences and the underlying molecular mechanisms is critical in order toinclude these still under-researched populations in translational mosaicism studies for early detection andprevention of hematological and potentially other cancers. Proposed Research: Aim 1 is to address the greatneed for comprehensive studies of mosaicism in American minority populations through a large-scale analysesof CNAs in African American and Latino whole genome sequencing (WGS) data sets. This approach willenable a robust comparison of mosaicism profiles across populations; WGS will allow for joint analysis ofCNAs and somatic point mutations to gain insights into mechanisms that underlie different rates and subtypesof hematological malignancies across populations. Aim 2 is to develop novel methods to combine CNA andhaplotype level ancestry data for detection of variants associated with increased mosaicism rates. I will usethese methods to identify genetic variants that are associated with mosaicism and with increased cancer risk inLatinos and African Americans. Candidate: I have led projects to discover and analyze acquired CNAs inthousands of non-malignant tissues  first of their kind studies for pathologically normal and premalignanttissues  as well as in cancer tissues that complement these. This expertise and my established track record inthe development of computational methods for human/cancer genomics will ensure the successful completionof these aims. As larger volumes of normal tissues are molecularly profiled I will be able to extend methodsdeveloped in Aim 2 to additional normal tissue types and conduct integrative omics analyses. I will follow upthis work and the associated publications with an R01 proposal focused on translational applications of mosaicmutations in normal tissues as markers for cancer risk assessment early detection and prognosis. The K22award will be fundamental as I launch my independent investigator career offering management and grantwriting training helping to hone my skills as a mentor/PI and establish a long-term funded research program.

project_terms:
Address;Admixture;African;African American;African American population;African ancestry;American;Blood;Cell Fraction;Cells;Cessation of life;Clonal Expansion;Complement;Computing Methodologies;DNA Sequence Alteration;Data;Data Set;Development;Disease;Early Diagnosis;Ensure;European;European ancestry;Frequencies;Funding;Genes;Genetic;Genetic Population Study;Genetic Variation;Genetic study;Genomic Segment;Genomics;Germ Lines;Goals;Grant;Haplotypes;Hematologic Neoplasms;Hematology;Human;Incidence;Individual;Inherited;Japanese;Japanese Population;Joints;K22 Award;Latino;Latino Population;Link;Loss of Heterozygosity;Malignant Neoplasms;Maps;Mentors;Methodology;Methods;Minority Groups;Modeling;Molecular;Molecular Profiling;Mosaicism;Mutation;Non-Malignant;Normal tissue morphology;Organism;Paint;Pathologic;Pattern;Persons;Point Mutation;Population;Population Genetics;Prevention;Prevention strategy;Prognosis;Proliferating;Publications;Recurrence;Reporting;Research;Research Personnel;Risk Assessment;Sampling;Screening for cancer;Single Nucleotide Polymorphism;Statistical Methods;Testing;Tissues;Training;Translations;Underrepresented Populations;Variant;Work;Writing;admixture mapping;ancestry analysis;cancer biomarkers;cancer genomics;cancer prevention;cancer risk;cancer seeding;career;detection method;follow-up;genetic variant;genome sequencing;genome wide association study;genomic variation;high risk;improved;innovation;insight;leukemia;method development;mosaic;mosaic analysis;mosaic variant;multi-ethnic;novel;premalignant;programs;skills;translational applications;translational potential;variant detection;whole genome;zygote

public_health_relevance:
PROJECT NARRATIVEClonal mosaicism in the blood has not been comprehensively investigated in African American and Latinopopulations. We will assess this biomarker of cancer risk in these populations through the development ofnovel methodology that will enhance integrative analysis of mosaic mutations germline variation and ancestry.A better understanding of mosaicism in these under-studied populations will allow for more targeted cancer riskassessment and early detection.


application_id: 10827922
project_number: 5R01AG068215-05
project_title: Sleep Fragmentation and Alzheimers Disease
administering_ic: NIA
award_notice_date: 2024-05-22
opportunity_number: PAR-18-497
application_type: 5
activity_code: R01
ic: AG
serial_number: 068215
program_official: SARE, RACHEL
project_start_date: 2020-08-01
project_end_date: 2026-04-30
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BACHSTETTER, ADAM D;DUNCAN, MARILYN J.;O'HARA, BRUCE FREDERICK;SUNDERAM, SRIDHAR
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Chronic sleep disruption resulting from work schedules noise exposure family obligations sleep disorders orlifestyle choices is a pervasive feature of contemporary life. Sleep problems affect up to 40% of AD patientsmay precede cognitive impairments by more than a decade and worsen as the disease progresses. As well asaffecting mood and well-being sleep disruption may drive the development of AD neuropathology for instanceby reducing clearance of amyloid- (A) and by promoting a neurotoxic proinflammatory state involvingastrocytes and microglia. Sleep disruption can include reduced total sleep (sleep restriction [SR]) loss of deepsleep (also known as slow-wave sleep [SWS] marked by large amplitude low frequency electrical activity)and fragmentation of sleep (SF) into shorter bouts. Fragmentation of the daily sleep-wake rhythm is associatedwith greater risk of incident AD and earlier cognitive decline in older humans. In spite of these correlativestudies whether or how chronic SF impacts the progression of AD has not been experimentally investigated.SF may be a better model of the sleep disruption associated with AD than the traditional approach of SR. Ourstudies of AD mouse models show that spontaneously occurring SF is associated with more severe Aaccumulation and that experimentally-induced SF leads to A accumulation and neuroinflammation. BesidesSF loss of SWS may exacerbate AD and improving SWS may be beneficial in mild cognitive impairment(MCI) or even in AD. Since sleep disruption adversely affects the development of AD-related neuropathology itis surprising that sleep enhancement (SE) strategies to consolidate sleep and increase SWS have not beenadequately explored to slow or reverse these effects. Our overall working hypothesis is that a change in thequality of sleep especially sleep fragmentation and loss of SWS is more important than the quantity of sleep.Further we hypothesize that the mechanism underlying these effects is primarily neuroinflammation at least inpart mediated by A peptide deposition. We will use a unique well-characterized mouse model that exhibitsAD-related A pathology neuroinflammation and cognitive deficits. This project has three specific aims: (1)that SF will accelerate (and SE decelerate) AD progression; (2) that increases in A accumulation mediatesSF-induced neuroinflammation neuropathology and cognitive decline; and (3) that increases inneuroinflammation mediate SF-induced neuropathology and cognitive decline. We will use multiple novelapproaches including thermoneutral temperature manipulation and a unique anti-inflammatory compound thathas recently entered early stage clinical trials. Thus these studies will elucidate the underlying mechanisms bywhich sleep disruption is linked to AD and will lay the groundwork for new therapeutic strategies.

project_terms:
Abeta clearance;Acceleration;Address;Affect;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Attenuated;Biological;Brain;Chronic;Cognition;Cognitive deficits;Correlative Study;Deceleration;Dementia;Demographic Factors;Deposition;Development;Disease;Disease Progression;Exhibits;Family;Frequencies;Human;Impaired cognition;Impairment;Inflammation;Inflammatory;Knock-in Mouse;Life;Life Style;Light;Link;Mediating;Mediator;Medical History;Microglia;Modeling;Moods;Mus;Nerve Degeneration;Noise;Pathology;Personal Satisfaction;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Process;Rest;Risk;Role;Schedule;Sleep;Sleep Deprivation;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Societies;Synapses;System;Temperature;Testing;Time;Work;abeta accumulation;age related;beta amyloid pathology;circadian;circadian pacemaker;design;improved;improvement on sleep;middle age;mild cognitive impairment;mouse model;neuroinflammation;neuropathology;neurotoxic;noise exposure;novel;novel strategies;novel therapeutic intervention;pharmacologic;pre-clinical;prevent;response;sleep quality;sleep quantity

public_health_relevance:
Age-related dementia is a significant and growing burden on our society  the most well known of which isAlzheimer's disease (AD)  and chronic sleep disruption is a pervasive feature of contemporary life that isassociated with and exacerbated in AD. This project will examine the idea that sleep quality is more importantthan sleep quantity and will investigate the underlying biological mechanisms of this process as well asexplore novel strategies for improving sleep and treating deleterious inflammation in the brain.


application_id: 10827917
project_number: 5T35DK072923-19
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2024-05-01
opportunity_number: PA-20-162
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: CASTLE, ARTHUR
project_start_date: 2006-05-01
project_end_date: 2026-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:This is a competing renewal application for a T35 short term medical student summer training program inendocrine research that has been funded by NIDDK for 15 years. The 2 Specific Aims are 1) To providehands-on training in basic and clinical Endocrine-related research to medical students in a structured mentoredenvironment; 2) To provide an interactive educational experience that introduces medical students thefundamental skills necessary for basic translational and clinical Endocrine-related research. The program hassupported the training of 6 second year medical students in endocrine research topics including diabetes  witha particular focus on diabetic kidney disease endocrine malignancies pituitary regulation of peptide hormoneexpression non-alcoholic fatty liver disease cardiovascular complications of diabetes and obesity hormonalregulation of metabolism and stem cell biology. Trainees are selected from the first year class at University ofLouisville School of Medicine (SOM) applying for the summer research scholar program (SRSP). A successfuleffort has been made to recruit students from underrepresented minorities and disadvantaged backgrounds.Students review the available projects submitted by 28 faculty research mentors and enter their 1st-3rd choicesallowing matching of trainees with mentors. In-person meetings between trainees and mentors assures the fitin the middle of the Spring semester. During the 10 week summer training students work with mentors onresearch projects in clinical or laboratory settings complete training in the Responsible Conduct of Researchincluding managing scientific data fabrication and falsification of data plagiarism publication practices andresponsible authorship mentorship stewardship and conflict of interest. Trainees working with humansubjects complete human subject and IRB training. Trainees who use vertebrate animals in mentors labscomplete and pass IACUC training courses. All trainees attend a weekly Summer Endocrine ResearchTraining Class to introduce clinical/translational research in endocrinology. An essential component well-integrated into this class by T35 faculty mentors is discussion of methods for enhancing reproducibility. TheClass culminates with each trainee presenting his/her research project to peers and mentors. Trainees alsopresent their research results as posters at a SOM-wide week-long celebration of Research!Louisville.Winners from the poster contest have the opportunity to attend the National Student Research Forum thefollowing Spring. Trainees may choose to continue research as part of the Distinction in Research (DIR) trackenrichment program that provides research experiences throughout the medical school curriculum including inthe third and fourth years toward the goal of developing clinician-researchers. Student trainees have publishedin peer reviewed journals and/or presented their research in national or international forums and many havereceived the DIR notation on their medical school diplomas. Trainee career outcomes are tracked to assessthe impact of this T35 program on careers as physician-scientists.

project_terms:
Authorship;Cardiovascular system;Clinical;Complications of Diabetes Mellitus;Conflict of Interest;Data;Diabetes Mellitus;Diabetic Nephropathy;Education;Educational Curriculum;Endocrine;Endocrinology;Environment;Funding;Goals;IACUC;Institutional Review Boards;International;Journals;Laboratories;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Metabolism;Methods;National Institute of Diabetes and Digestive and Kidney Diseases;Obesity;Outcome;Peer Review;Persons;Physicians;Pituitary Gland;Plagiarism;Publications;Publishing;Regulation;Reproducibility;Research;Research Personnel;Research Project Grants;Research Training;Scholars Program;Scientist;Structure;Student recruitment;Students;Training;Training Programs;Training Support;Translational Research;Universities;Vertebrates;Work;career;disadvantaged background;experience;fabrication;faculty mentor;faculty research;hormone regulation;human subject;medical schools;meetings;non-alcoholic fatty liver disease;peer;peptide hormone;posters;programs;responsible research conduct;skills;stem cell biology;summer research;summer student;underrepresented minority student

public_health_relevance:
Understanding the aberrant hormonal and genetic regulation of cellular homeostasis is the key to unravelingchronic and emerging disease and to develop new treatment strategies. The major goal of this project is toprovide medical students who have completed at least one year of medical school with a hands-on summerresearch experience in NIDDK-focused research on endocrine-related health concerns to stimulate theirinterest in a clinical-research career.


application_id: 10826270
project_number: 1R01EY035885-01
project_title: The role of plasticity in loss of vision caused by retinitis pigmentosa
administering_ic: NEI
award_notice_date: 2023-12-12
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: EY
serial_number: 035885
program_official: WRIGHT, CHARLES BAKER
project_start_date: 2024-01-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1 ICN-Y (02)]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: MCCALL, MAUREEN A
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:
AbstractRetinitis pigmentosa (RP) is the most common group of inherited retinal disorders associated with progressiveloss of vision. RP is typically diagnosed in adulthood following the onset of night blindness and impairedperipheral vision. Longitudinal studies of patients with RP reveal that their loss of visual acuity is significantlyslower than the deterioration of their photoreceptor function. How the visual system sustains acuity despite theprogressive loss of photoreceptors is unclear.Our hypothesis is that flexibility within the circuits of the visual system engage with the progressive loss of visualoutput to impair acuity. We will test our hypothesis by first characterizing the deficit in acuity and related functionalcharacteristics in visual cortex and retina in using the rhodopsin P23H/+ (rho P23H/+) mutant mouse model.These mice have similar declines in retinal function and are a good model of human RP. Then we will evaluatewhether enhancing or reducing experience-dependent plasticity affects the trajectory of the progressive loss ofvision of rho P23H/+ mice by then characterizing the deficit in acuity and related functional characteristics invisual cortex and retina in using the rhodopsin P23H/+ (rho P23H/+) mutant mice that also lack a gene that limitsplasticity in adult visual circuitry (nogo-66 receptor ngr1) or that is required for visual plasticity (activity-regulatedcytoskeleton-associated protein ARC). Mice lacking ngr1 (ngr1 -/-) display greater visual plasticity than adultwild-type mice while mice lacking ARC (ARC -/-) exhibit reduced visual plasticity.

project_terms:
Acceleration;Adult;Affect;Age Months;Amblyopia;American;Behavioral;Blindness;Brain region;Calcium;Cessation of life;Characteristics;Cytoskeleton;Darkness;Deterioration;Diagnosis;Electroretinography;Exhibits;Frequencies;Functional disorder;Gene Modified;Genes;Histology;Human;Image;Immediate-Early Genes;Impairment;Individual;Inherited;Knock-in Mouse;Knowledge;Learning;Life;Light;Longitudinal Studies;Measures;Mission;Mus;Mutant Strains Mice;Neurons;Night Blindness;North America;Output;Patients;Peripheral;Persons;Photoreceptors;Point Mutation;Property;Proteins;Public Health;Research;Retina;Retinal Cone;Retinal Diseases;Retinitis Pigmentosa;Rhodopsin;Role;Testing;United States National Institutes of Health;V1 neuron;Vertebrate Photoreceptors;Vision;Visual;Visual Acuity;Visual Cortex;Visual System;Visual impairment;Water;Wild Type Mouse;area striata;autosome;calcium indicator;constriction;excitatory neuron;experience;experimental study;flexibility;human model;mouse model;mutant;mutant mouse model;novel therapeutic intervention;preservation;receptor;recruit;response;rho;sensory cortex;sight restoration;therapeutic evaluation;visual plasticity

public_health_relevance:
Project NarrativeRetinitis pigmentosa causes progressive loss of vision including night blindness and poor acuity. The proposedresearch is relevant to public health because understanding how flexibility in the visual system circuit engagesdeteriorating retinal function to accelerate the loss of vision may lead to new therapeutic interventions to preserveand/or restore vision in RP. The proposed research is relevant to the mission of the NEI/NIH to prolong andprotect vision of the American people


application_id: 10824707
project_number: 1R01AA030775-01A1
project_title: Influence of Orexin Antagonism on Motivation for Alcohol
administering_ic: NIAAA
award_notice_date: 2024-03-13
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: AA
serial_number: 030775
suffix: A1
program_official: KUMAR, SHAILESH
project_start_date: 2024-03-15
project_end_date: 2027-02-28
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTAlcohol use disorder (AUD) is an unrelenting public health concern. Despite great strides in understanding theneurobiological underpinnings of problem alcohol use in preclinical models a limited amount of research hastranslated those findings into clinical populations. Such translation is crucial to identify neurobiological circuitsthat contribute to the problems posed by AUD and to guide treatment based on those clinical neurosciencefindings. One area of intense interest in preclinical research is the role of the orexin system in addiction.Through extrahypothalamic transmission the orexin system plays a key part in motivation for maladaptiverewards like drugs of abuse. In preclinical studies exogenous administration of orexin peptides increasesalcohol self-administration. Conversely pharmacological antagonism of the orexin system reduces effortfulresponding maintained by alcohol (e.g. on a progressive-ratio schedule) and alcohol-seeking behavior relativeto vehicle. Pharmacological antagonism of orexin receptors also ameliorates sleep disruptions caused bychronic alcohol exposure. Preclinical findings further indicate administration of orexin antagonists generallydoes not affect responding for non-alcohol rewards. Taken together these preclinical findings suggest orexinsystem antagonism selectively reduces motivation for alcohol as well as other maladaptive alcohol-associatedbehaviors. Although a robust preclinical literature indicates a key role of the orexin system in motivation foralcohol along with alcohols other pharmacodynamic effects this area remains essentially unstudied inhumans except for some observational studies showing altered peripheral orexin levels during alcoholwithdrawal. The overarching goal of this project is thus to translate promising preclinical findings into clinicalpopulations thereby demonstrating the orexin system plays a key role in motivation for alcohol in humans. Thisproject will also determine the influence of orexin antagonism on other pharmacodynamic effects of alcoholincluding subjective response performance physiological response and sleep. The research proposed herewill directly translate findings from preclinical research and provide the initial clinical evidence that orexinantagonism reduces motivation for alcohol and other alcohol-associated maladaptive behaviors in individualswith AUD. This study will also provide basic science information about the orexinergic mechanisms underlyingthe pharmacodynamic effects of alcohol in humans. As such the outcomes will contribute to our understandingof the clinical neurobiology of AUD. Overall the proposed work seeks to expand the scope of current clinicalneuroscience research on AUD by focusing on orexin which has strong preclinical evidence supporting itscritical role in addiction but remains largely unstudied in humans.

project_terms:
Acute;Adaptive Behaviors;Affect;Alcohol abuse;Alcohol consumption;Alcohol withdrawal syndrome;Alcohols;American;Area;Basic Science;Behavior;Cessation of life;Chronic;Clinical;Clinical Research;Cognitive;Dose;Eating;Economic Burden;Electroencephalography;Fatty acid glycerol esters;Food;Goals;Heart Rate;Human;Hypothalamic structure;Individual;Laboratories;Laboratory Study;Lateral;Literature;Maintenance;Measures;Motivation;Neurobiology;Neuropeptides;Neurosciences;Neurosciences Research;Observational Study;Oral;Outcome;Peptides;Performance;Peripheral;Persons;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Play;Polysomnography;Population;Pre-Clinical Model;Public Health;Research;Rewards;Role;Sampling;Schedule;Self Administration;Sleep;Sleep disturbances;Study Subject;System;Task Performances;Testing;Time;Translating;Translations;Withdrawal;Work;addiction;alcohol effect;alcohol exposure;alcohol measurement;alcohol seeking behavior;alcohol use disorder;antagonist;drug maintenance;drug of abuse;hypocretin;interest;maladaptive behavior;non-drug;pharmacologic;pre-clinical;pre-clinical research;preclinical study;receptor;reinforcer;response;sleep regulation;transmission process

public_health_relevance:
PROJECT NARRATIVEThe orexin system is increasingly being recognized for its key role in motivation to engage in maladaptivebehaviors including alcohol self-administration in preclinical models. No clinical neuroscience research hasadvanced these preclinical findings limiting our ability to determine whether the orexin system also contributesto alcohol use in humans. The proposed research will fill that gap by determining how administration of an orexinantagonist suvorexant impacts motivation for alcohol and other abuse-related effects of alcohol.


application_id: 10824301
project_number: 5R01HL168294-02
administering_ic: NHLBI
award_notice_date: 2024-04-23
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: HL
serial_number: 168294
program_official: BAIZER, LAWRENCE
project_start_date: 2023-04-10
project_end_date: 2028-03-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
Neuromodulatory rehabilitation for respiratory motor function in individuals with chronic spinal cord injury

project_abstract:
Project Summary/AbstractRespiratory motor control deficit is the leading cause of morbidity and mortality in patients with spinal cordinjury. The long-term goal of this research is to develop a rehabilitation strategy for respiration in patients withspinal cord injury as a standard of care. Our previous findings demonstrate that respiratory function in patientswith chronic spinal cord injury can be improved by using our original inspiratory-expiratory pressure thresholdrespiratory training protocol. However the effectiveness of this intervention is limited to the amount offunctional capacity preserved below the neurological level of injury. Our preliminary data obtained for thisproposal demonstrate that electrical spinal cord stimulation applied non-invasively to target spinal respiratorycircuits in combination with respiratory training can activate and re-organize spinal motor networks forrespiration. We propose to investigate respiratory motor control-related responses to transcutaneous spinalcord stimulation alone and in combination with respiratory training. By characterization of respiratory muscleactivation patterns using surface electromyography in association with pulmonary functional and relatedcardiovascular measures we expect to determine specific stimulation parameters needed to increase spinalexcitability below level of injury to enhance responses to the input from supraspinal centers that remain afterinjury and to promote the neural plasticity driven by the respiratory training. This hypothesis will be tested bypursuing two Specific Aims: 1) Evaluate the acute effects of transcutaneous spinal cord stimulation onrespiratory functional and motor control properties; and 2) Evaluate the effectiveness of transcutaneous spinalcord stimulation combined with respiratory training.

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

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


application_id: 10823336
project_number: 5R21EB032515-03
administering_ic: NIBIB
award_notice_date: 2024-05-20
opportunity_number: PAR-20-084
application_type: 5
activity_code: R21
ic: EB
serial_number: 032515
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2022-08-01
project_end_date: 2026-04-30
study_section: Emerging Imaging Technologies and Applications Study Section[EITA]
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-05-01
project_title:
Non-destructive optical spectroscopic assay for high-throughput metabolic characterization of in vitro cell models  and patient-derived organoids

project_abstract:
AbstractTo maximize cancer patients survival rate post-therapy in vitro immortal cancer cell models and newlydeveloped patient-derived organoids are widely used to study the role of tumor metabolism reprogramming intumor growth and survival under therapeutics stresses. Although conducting longitudinal metabolicmeasurements on the same tumor sample during a course of therapy is critical for therapeutic studies thereare surprisingly few techniques that can provide a systems-level view of tumor metabolism on in vitro cancermodels or organoids non-destructively. Several metabolic tools such as Seahorse Assay and Metabolomicsprovide standardized metabolic measurements but often require destructive sample preparation. Relying onthe non-invasive nature of optical technique this proposal seeks to fill the critical technical gap by developingan optical spectroscopic assay that will enable non-destructive high-throughput metabolism measurement on invitro cancer models and organoids for cancer research. Specifically we will develop a novel multi-channelfluorescence spectroscopic assay and a machine learning de-convolution algorithm to quantify the keymetabolic parameters of in vitro cancer models (Aim 1). As there is a significant unmet clinical need for breastcancer (BC) radiotherapy (RT) sensitivity evaluation prior to treatment we will demonstrate our non-destructiveassay for early prediction of BC radiation responses within the decision-making window via longitudinalmetabolic characterization of patient-derived organoids under radiation stresses (Aim 2). Our technology fillsan important gap that exists between Seahorse Assay (in vitro cells) and Metabolomics (in vitro cells and exvivo tissue) by providing a novel approach for non-destructive metabolism measurement on in vitro cancermodels and patient-derived organoids. Our innovative RT sensitivity prediction model will directly impact BCpatients by providing a novel paradigm for patients RT sensitivity prediction during the decision-makingwindow. Once we demonstrate the proof-of-concept of our optical technique and the RT sensitivity predictionmodel we will move our study to a large-scale trail in clinics with a goal of providing individualized RT for BCpatients in our future R01 plan.

project_terms:
4T1;Algorithms;Biological Assay;Biological Markers;Biomedical Research;Breast Cancer Model;Breast Cancer Patient;Cancer Model;Cancer Patient;Cell Line;Cell model;Cells;Clinic;Clinical;Control Groups;Convulsions;Decision Making;Evaluation;Fatty Acids;Fiber;Fluorescence;Future;Genus Hippocampus;Goals;In Vitro;Incubated;Light;Machine Learning;Malignant Breast Neoplasm;Matrix Metalloproteinases;Measurement;Measures;Membrane Potentials;Metabolic;Metabolism;Modeling;Nature;Optics;Organoids;Outcome;Patients;Performance;Preparation;Radiation;Radiation Tolerance;Radiation therapy;Reader;Regimen;Role;Sampling;Siblings;Source;Specimen;Spectrum Analysis;Standardization;Stress;Survival Rate;System;Techniques;Technology;Testing;Therapeutic;Therapeutic Studies;Time;Tissues;Update;Work;anti-cancer research;cancer cell;cancer radiation therapy;cancer therapy;experience;experimental group;fluorophore;glucose uptake;high throughput screening;improved;in vivo;indexing;innovation;machine learning algorithm;metabolomics;mitochondrial membrane;new technology;novel;novel strategies;pilot test;pre-clinical;preclinical study;predictive modeling;programs;radiation response;radioresistant;tool;tumor;tumor growth;tumor metabolism;uptake

public_health_relevance:
PROJECT NARRATIVEThe goal of this program is to develop a high-throughput optical assay that enables non-destructive metaboliccharacterization of in vitro cell models and organoids for biomedical applications. We will demonstrate ourassay for early prediction of breast cancer radiation sensitivity within the decision-making window vialongitudinal metabolic characterization of patient-derived organoids under radiation stresses. The proposedwork will impact the biomedical research by providing a novel tool for non-destructive metabolic measurementof cell and organoid models and a novel paradigm for cancer patients radiotherapy sensitivity prediction.


application_id: 10821706
project_number: 1R43HL172484-01
project_title: A novel mobile phone technology to improve access for preeclampsia and hypertension detection
administering_ic: NHLBI
award_notice_date: 2024-09-20
opportunity_number: PA-22-176
application_type: 1
activity_code: R43
ic: HL
serial_number: 172484
program_official: VARAGIC, JASMINA
project_start_date: 2024-09-20
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 HSS-J (10)]
contact_pi_person_id: 78826114
contact_pi: WOLFSON, DAVID
other_pis: HEIRONIMUS, JOHN CONRAD;HUECKER, MARTIN RICHARD
congressional_district: 03
department: Unavailable
primary_uei: CHJ8YC513988
uei: CHJ8YC513988
fips: US
organization_id: 10072316
organization_name: TELE-STETHOSCOPE INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40207
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-09-20
budget_end_date: 2026-08-31
project_abstract:
Project Summary / AbstractPreeclampsia is a complication affecting 2  8% of all pregnancies and results in significantmaternal and neonatal morbidity and mortality. The invention to be researched in this grantdetects preeclampsia and hypertension in patients with the phones that they already own. Itimproves outcomes by increasing access to care among underserved populations andmonitoring frequency among high risk patients. Patients record themselves using their ownphones which takes only a few minutes. The long term objective is to commercialize a productwhich enables any of 7 billion phones to assist in preeclampsia or gestational hypertensiondetection.The invention is intended to be used at home by patients via a phone app with results sent tothe prescribing obstetrician (OB). The purpose is to alert the OB if immediate physicalexamination is needed and to initiate possible preeclampsia management protocol. In thesesituations there are no other comparable testing options.The invention includes both improvements to clinical practice and to science. Current clinicalpractice standard of care requires patients to be examined in an OB office. The inventionallows preeclampsia and hypertension to be detected via patient self-examination fromlocations outside the OB office. This improves upon current technology such as home bloodpressure cuffs and in-office dipstick urinalysis. In terms of improvements to science theinvention consists of both a Universal Translator (UT) and Deductive Intelligence (DI). UTallows for any mobile phone to capture body acoustic data. DI is a novel physics basedapproach to creating classifier algorithms from passively received time series data such asmobile phone recordings received from the UT. The invention analyzes hemodynamics andextracts pertinent physics based features from which a classifier algorithm is based.This will be the third large scale human study that demonstrates classification of cardio -pulmonary functionality. It follows a published study on COVID detection as well as a studyunder peer review on the ability to reproduce echocardiogram estimates of ejection fraction.The echocardiogram study establishes the protocol to be used in the proposed research. Ina recent preliminary study 46 pregnant women were recorded at the aortic site. The resultingmodel was able to determine which patients had high blood pressure and to accuratelydetermine which patients had complications. These studies support our hypothesis thatacoustic hemodynamic data captured by OEM phone microphones at the aortic auscultationsite and at the upper arm can be used to identify patients who have preeclampsia and/orhypertension.The study has two primary aims. The first is to demonstrate proof of concept that the inventionenables ordinary mobile phones to reproduce physicians diagnosis of pre-eclampsia. Thesecond aim is to demonstrate proof of concept that the invention enables ordinary mobilephones to reproduce cuff measurements of blood pressure and to detect hypertension. Theapproach is based on recruitment from both outpatient clinics and inpatient hospital settings.Patients already labeled with preeclampsia or high blood pressure will be enrolled as well ascontrol patients without disease conditions. Patients will be recorded by clinicians with acustom phone app. Algorithms will be developed based on these recordings using UT andDI. Results will be tested and analyzed using AUC sensitivity/specificity accuracy as welladj RSQ for the linear regression analysis.The team consists of a broad range of talent including the inventor of the technology theMaternal Fetal Medicine Division Director at the hospital the research director of emergencymedicine for the hospital running the tests statistical expertise and project management.

project_terms:
Acoustics;Affect;Algorithms;Ambulatory Care Facilities;American;Aorta;Auscultation;Black race;Blood Pressure;COVID-19 detection;Cardiopulmonary;Cause of Death;Cellular Phone;Classification;Complication;Computer software;Country;Custom;Data;Death Rate;Detection;Devices;Diagnosis;Diagnostic;Disease;Drops;EFRAC;Early Intervention;Echocardiography;Emergency Medicine;Enrollment;Evaluation;First Pregnancy Trimester;Frequencies;Grant;Health;Health Care Costs;Health Services Accessibility;Home;Hospitals;Hypertension;Improve Access;Inpatients;Intelligence;Label;Left;Linear Regressions;Location;Logistic Regressions;Machine Learning;Maternal-fetal medicine;Mathematics;Measurement;Medicaid;Medical;Medical Imaging;Modeling;Monitor;Neonatal;Nigeria;Nonlinear Dynamics;Office Visits;Patients;Peer Review;Performance;Physical Examination;Physicians;Physics;Pre-Eclampsia;Pregnancy;Pregnant Women;Process;Protocols documentation;Provider;Publishing;Regression Analysis;Research;Research Support;Running;Rural;Sampling;Science;Self-Examination;Sensitivity and Specificity;Series;Site;Slice;Somatotype;Talents;Technology;Telephone;Testing;Time;Training;Underserved Population;Uninsured;Upper arm;Urinalysis;Variant;arm;classifier algorithm;clinical practice;commercialization;comorbidity;cost;demographics;hemodynamics;high risk;human study;improved;improved outcome;innovation;invention;maternal morbidity;microphone;mortality;neonatal morbidity;neural network;novel;predictive modeling;pregnancy hypertension;recruit;remote monitoring;rural patients;stability testing;standard of care;technology development

public_health_relevance:
The research supports development of technology that allows ordinary mobile phones to be usedto detect preeclampsia and hypertension in patients remotely. The intent is to improve access tocare as well as the ability to increase monitoring frequency. The technology is scientificallyimportant in that it uses a novel hemodynamics based approach in creating classifier algorithmsfrom passively received time series data.


application_id: 10821327
project_number: 5R01HL163818-03
project_title: Systematic identification of cardiotoxic e-cigarette flavorants
administering_ic: NHLBI
award_notice_date: 2024-03-25
opportunity_number: RFA-OD-21-002
application_type: 5
activity_code: R01
ic: HL
serial_number: 163818
program_official: POSTOW, LISA
project_start_date: 2022-04-22
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-E(56)R]
contact_pi_person_id: 11702638
contact_pi: CARLL, ALEX PERROW
other_pis: NYSTORIAK, MATTHEW A
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe use of e-cigarettes (e-cigs) has increased substantially since they were first introduced in 2003. E-cigdevices aerosolize e-liquids that typically consist of humectants with variable levels of nicotine and flavoringchemicals. Although there are thousands of commercially available flavor mixtures they routinely overlap inindividual flavor chemicals (flavorants) which are far fewer in number. Many of these flavorants belong tocommon chemical classes and are generally recognized as safe for ingestion. However their direct and indirectcardiac effects following heating and inhalation particularly in combination with nicotine remain mostly unknown.Direct exposure to nicotine alone distinctly affects the cardiac action potential waveform potentially contributingto the high incidence of arrhythmias and sudden cardiac death among smokers. Recent evidence also suggeststhat nicotine in e-cigs may similarly promote adverse cardiac outcomes. Yet the influence of flavorants on thecardiac effects of e-cig aerosols remains untested. In our ongoing work we found that exposure to nicotine-containing e-cig aerosols of various flavors acutely and differentially altered the electrocardiogram (ECG) in micevariably inducing QT interval prolongation increasing heart rate and evoking arrhythmia. As well two separatee-liquids with the same characterizing flavorant consistently increased ventricular arrhythmias. Furthermore weobserved in cardiomyocytes that treatment with several flavorants common to e-cigs directly altered contractilityrhythmicity and action potential duration. Nonetheless it remains unknown how individual flavorants in e-cigaerosols exert direct or indirect cardiac effects in vivo. Considering the growing popularity of e-cigarettes andthe urgent need for studying the in vivo toxicological profile of constituents in these products we propose to testthe hypothesis that e-cigarette flavorants modify the effects of e-cig aerosol exposures on cardiacelectrophysiology leading to arrhythmias and functional remodeling of the heart. To test this we willsystematically identify both acute and long-term effects of flavorant exposure on cardiac electrophysiology usinga combination of state-of-the-art in vivo in vitro and ex vivo approaches. Specifically we will: 1) Identify theacute effects of flavored e-cig aerosol inhalation on cardiac electrophysiology in vivo 2) Examine thedirect impact of flavorants on cardiac electrophysiology in vitro and ex vivo and 3) Elucidate deleteriousimpacts of acute and chronic flavorant aerosol exposure on cardiac electrophysiology structure andfunction. These studies which are responsive to the research priorities of the FDA/CTP will provide new datashowing how different flavor chemicals affect cardiac excitability and potentially promote arrhythmogenesis.Such results would aid in formulating policies regulating the manufacture distribution and marketing of flavorede-cigarettes.

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


application_id: 10820746
project_number: 1F31DC021084-01A1
project_title: Anatomy and Function of a Fungiform Specific Mechanoreceptor
administering_ic: NIDCD
award_notice_date: 2023-08-22
opportunity_number: PA-21-052
application_type: 1
activity_code: F31
ic: DC
serial_number: 021084
suffix: A1
program_official: SCHURMAN, JACLYN REBECCA
project_start_date: 2024-03-01
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZDC1 SRB-Y (55)]
contact_pi_person_id: 77801859
contact_pi: MYERS, THOMAS ALEXANDER
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractSomatosensory innervation of the oral cavity enables us to detect the various texturestemperatures and chemicals of the foods we consume. The combination of these featureselicits the perception called mouthfeel which plays an essential role in food choice. Theneuron subtypes which play a role in this perception have not been identified. I am speculatingthat the tongue is innervated by subtypes of mechanically sensitive neurons each having aunique sensitivity morphology receptive field size and adaptation properties. Here I will use agenetic label to fully characterize one such neuron subtype innervating the tongue. This geneticlabel can then be used to gain a better understanding of the relationship between geneticsanatomy and function of oral sensory neurons mediating touch. The goals of this proposal are:1) to determine if parvalbumin (Pvalb+) is a genetic label for a mechanosensory subtype; 2) tofurther characterize Pvalb+ neurons by determining if they are myelinated and if they overlapwith other labels; 3) to determine the receptive field size and ending morphologies of Pvalb+neurons; and 4) to determine the functional characteristics of Pvalb+ neurons. To accomplishthis I will use a combination of immunohistochemistry single cell electrophysiology andcalcium imaging. Together these experiments will test the hypothesis that Pvalb+ neuronsidentify a myelinated rapidly adapting fast-conducting subtype of touch neuron that primarilyinnervates single fungiform papillae with basket like endings. If so these neurons would begood at indicating the location of a food on the tongue surface. This is the first step towardfuture studies designed to examine the central circuity and behavioral contributions of Pvalb+neurons innervating the oral cavity.

project_terms:
Afferent Neurons;Aging;Amyloid beta-Protein;Anatomy;Axon;Behavior;Behavioral;Biological Markers;Burning Mouth Syndrome;C Fiber;Calcium;Calcium-Binding Proteins;Cells;Characteristics;Chemicals;Complex;Data;Detection;Electrophysiology (science);Epithelium;Fiber;Food;Food Preferences;Fungiform Papilla;Future;Genetic;Genetic Identity;Goals;Image;Immunohistochemistry;Individual;Ion Channel;Label;Location;Mechanics;Mechanoreceptors;Mediating;Modality;Morphology;Movement;Myelin Basic Proteins;Nature;Nerve;Neurons;Oral cavity;Parvalbumins;Pattern;Perception;Peripheral Nervous System Diseases;Piezo 2 ion channel;Play;Population;Property;Research Design;Role;Sensory;Skin;Smell Perception;Stimulus;Structure;Surface;Tactile;Taste Buds;Taste Perception;Temperature;Testing;Texture;Tongue;Touch sensation;Transgenic Mice;experimental study;food consumption;in vivo;mouse genetics;nerve supply;neurofilament;optogenetics;oral sensory;pressure;receptive field;receptor;response;somatosensory;tongue papilla;tongue root

public_health_relevance:
Project NarrativeSomatosensory neurons innervating the tongue contribute to numerous perceptual qualitiesincluding texture of food and location of gustatory stimuli. Here I am determining the relationshipbetween genetic expression anatomy and function of a specific touch neuron subtype. This isthe first step in determining how/if this neuron type is disrupted in peripheral neuropathiesaging and/or burning mouth syndrome.


application_id: 10820287
project_number: 1F31EY034730-01A1
project_title: Optimizing c-Met signaling to enhance corneal epithelial homeostasis
administering_ic: NEI
award_notice_date: 2024-04-04
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: EY
serial_number: 034730
suffix: A1
program_official: AGARWAL, NEERAJ
project_start_date: 2024-04-04
project_end_date: 2027-04-03
study_section: Special Emphasis Panel[ZRG1 F05-Q (20)]
contact_pi_person_id: 15999666
contact_pi: TARVESTAD LAISE, KATE
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 SummaryThe proposed research is relevant to public health because corneal blindness is the 4th leading cause ofblindness globally and is often preventable with proper healthcare. Blindness arises due to damaged integrity ofthe corneal epithelium as the result of physical chemical or thermal trauma and/or as a consequence ofdiseases surgery or anti-cancer drugs. Regardless of the cause disruption of the epithelial layer is extremelypainful due to the dense sensory nerve innervation makes the eye vulnerable to infection and can result inblindness. Despite the widespread incidence and the array of medical problems associated with epithelialdamage there are no FDA-approved drugs that promote corneal wound healing or epithelial homeostasis. It iswell-established that proteins of the receptor tyrosine kinase (RTK) family can induce cell proliferation migrationsurvival and differentiation of epithelial cells. We are investigating the signaling axis of one of these proteins c-Met and its cognate ligand hepatocyte growth factor (HGF). c-Met activity can not only promote the woundhealing/re-epithelialization phenotypes stated previously but can also prevent transformation of keratocytes tofibroblasts and promote neuronal growth. However c-Met is limited for therapeutic reasons in that RTKs havetransient activation and are desensitized following ligand stimulation. We hypothesize that extending c-Metreceptor activity by disrupting its downregulation will help restore corneal homeostasis followingwounding. This hypothesis will be tested through the following aims: Aim 1: Determine if ubiquitylation of the c-Met receptor limits its signaling in corneal epithelial cells in vitro. We hypothesize that inhibiting negativeregulation of c-Met signaling will prolong receptor activity and accelerate healing. We will test this by blocking c-Met ubiquitylation in vitro by genetic knockout of CBL genes from immortalized human corneal epithelial cellsand measuring receptor phosphorylation trafficking in vitro wound healing and cell migration and proliferation.Aim 2: Determine effect of CBL knockout and c-Met activation in corneal wound healing murine models in vivo.We hypothesize that HGF-induced c-Met signaling will not only aid in re-epithelialization but also will decreasefibrotic markers in the stromal layer and promote axonal outgrowth of corneal nerves. We will test this by usingcorneal epithelial-specific inducible CBL knockout murine models. We will wound the corneas and monitor grosscorneal morphology and homeostasis re-epithelialization fibrosis and inflammatory markers and nerverestoration. These studies are innovative because we will manipulate c-Met signaling regulation to extendsignaling and promote healing of all layers of the cornea. The proposed research is relevant to the National EyeInstitutes mission of eliminating vision loss and improving quality of life through research.

project_terms:
Acceleration;Anatomy;Anterior;Antineoplastic Agents;Autoimmune Diseases;Axon;Back;Binding;Biochemical;Biological Assay;Biology;Blindness;Brain;CBL gene;Cell Line;Cell Proliferation;Chemicals;Cicatrix;Complication;Comprehension;Cornea;Corneal Injury;Corneal Opacity;Cytokine Receptors;Descemet's membrane;Diabetes Mellitus;Disease;Down-Regulation;Dryness;Endothelium;Environment;Epithelial Cells;Epithelium;Eye;FDA approved;Family;Fibroblasts;Fibrosis;Foreign Bodies;Genetic;Goals;Growth;Growth Factor;HGF gene;Health;Healthcare;Homeostasis;Human;Human body;In Vitro;Incidence;Infection;Infectious Agent;Inflammation;Inflammation Mediators;Inflammatory;Intervention;Knock-out;Knockout Mice;Ligands;Light;Measures;Medical;Mission;Modeling;Molecular;Monitor;Morphology;National Eye Institute;Nerve;Nerve Fibers;Nerve Regeneration;Nutrient;Operative Surgical Procedures;Oxygen;Pain;Patients;Peripheral Nerves;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Phosphorylation;Physiology;Process;Proliferating;Proteins;Public Health;Quality of life;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Recurrence;Regulation;Research;Research Support;Retina;Role;Sensory;Signal Pathway;Signal Transduction;Structure;System;Tamoxifen;Temperature;Testing;Therapeutic;Tissues;Trauma;Trigeminal nerve structure;Vision;afferent nerve;axon growth;cell motility;corneal epithelial wound healing;corneal epithelium;corneal regeneration;cytokine;desensitization;epithelial injury;epithelium regeneration;expectation;healing;improved;in vivo;in vivo Model;inflammatory marker;innovation;intraepithelial;migration;mouse model;nerve supply;neuronal growth;pathogen;pharmacologic;preservation;prevent;re-epithelialization;receptor;response;restoration;side effect;therapy development;trafficking;transmission process;ubiquitin-protein ligase;wound;wound healing

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because the integrity of the corneal epithelium is frequentlycompromised as the result of trauma surgery side-effects of anti-cancer drugs and as a complication of multiplediseases including diabetes and autoimmune disorders. Identifying the molecular mechanisms that regulate theintegrity of the corneal epithelium is the first step in developing therapies that promote the homeostasis andregeneration of the corneal epithelium before vision becomes jeopardized. This project is relevant to the NEIsmission to support research with respect to the molecular basis of visual function and the preservation of sight.


application_id: 10820144
project_number: 6U01CE003394-02M002
administering_ic: NCIPC
award_notice_date: 2023-03-29
opportunity_number: RFA-CE-21-006
application_type: 6
activity_code: U01
ic: CE
serial_number: 003394
suffix: M002
project_start_date: 2021-09-30
project_end_date: 2025-09-29
study_section: ZCE1-MLW(06)R
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-09-30
project_title:
RCT to evaluate Bystander-informed See it Stop it (BiSiSi) to Prevent Child Sex Trafficking in Kentucky Middle Schools

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

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


application_id: 10820082
project_number: 1R41AG085737-01
project_title: Trans Spinal Delivery of a Targeted Nanoformulation of Curcuminoids to Treat AD
administering_ic: NIA
award_notice_date: 2024-09-20
opportunity_number: PAS-22-197
application_type: 1
activity_code: R41
ic: AG
serial_number: 085737
program_official: MARTIN, ZANE
project_start_date: 2024-09-25
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 AN-P (11)]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Technical Abstract Neurodegenerative disorders affect over 40 million people worldwide and most if not all are mediated byinflammation. Even though several drugs are approved by the FDA for treating neurological disorders such asAlzheimers disease (AD) their efficacy as AD therapeutics has not been realized as extremely low levels of thedrug reach the brain. The goal of this Phase I project is to develop an effective targeted delivery system for thebioactive curcuminoids curcumin (CUR) and bisdemethoxycurcumin (BDMC) to mitigate AD and potentially otherneuroinflammatory diseases. We will apply our extensive experience in exosomes drug delivery planttherapeutics and inflammatory responses for efficient targeted delivery of bioactive curcuminoids to themicroenvironment of the brain where progressive increase in inflammation amyloid plaque formation andneurofibrillary tangles ultimately leads to manifestation of AD. We hypothesize that the combined administrationof CUR and BDMC will be highly effective at ameliorating neuroinflammation and aberrant AD-related geneexpression returning these biomarkers to pre-disease levels due to synergistic action via different mechanisms.We also hypothesize that folic acid (FA)-functionalized exosomal formulations administered using a novel topicaltrans-spinal (t.s.) route will provide enhanced targeting to AD-related regions of the brain including the cortex andhippocampus. Exosomes cross the BBB efficiently and areas of the brain associated with AD have high levels offolate receptors (FRs). Thus t.s.-administered FA-ExoCUR/BDMC will deliver higher payload to the brain vs.conventional routes. Our hypotheses are supported by 1) effective drug loading of curcuminoids onto bovinecolostrum exosomes 2) higher levels (~5-fold brain) of curcuminoids in rodent tissues after oral treatment withExo-curcuminoids than free curcuminoids 3) FA-exosomes can increase drug delivery to the brain which containshigh expression of FR4) reduced NFB accumulation and decreased abundance of phosphorylated Tau (pTau)and amyloid precursor protein (APP) expression in brain lysates of mice treated orally with ExoCUR/BDMC inconcurrence with increased expression of brain-derived neurotrophic factors (BDNF) comparable to levels in age-matched untreated WT mice while free CUR/BDMC was ineffective and 5) higher brain accumulation of exosomesin mice treated via t.s. route vs. the traditional i.v. route. Investigators experienced in exosomes drug deliveryplant bioactives and animal models leveraging extensive experience of Dr. Robert Friedland in AD research willpursue the following specific aims: Aim 1. Optimize ExoCUR/BDMC formulations and determine biodistributionand toxicity in WT mice. Aim 2. Determine efficacy of FA-functionalized ExoCUR/BDMC formulations in AD mice.This project will provide proof-of-principle for the effectiveness of t.s.-delivered FA-ExoCUR/BDMC on themodulation of key molecular targets and cognitive function behavioral tests with AD progression. In Phase II wewill conduct dose-finding and longer-term early and late intervention studies using multiple rodent AD modelsimmunotoxicity etc. The t.s.-brain delivery could ultimately lead to the development of t.s. patches for AD.

project_terms:
3xTg-AD mouse;AD transgenic mice;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease therapeutic;Alzheimers disease biomarker;Amyloid beta-Protein Precursor;Animal Model;Anti-Inflammatory Agents;Area;Attenuated;Biodistribution;Biological Availability;Biological Markers;Brain;Brain region;Brain-Derived Neurotrophic Factor;Cattle;Clinical;Clinical Research;Cognitive;Colostrum;Curcumin;Data;Development;Disease;Disease Progression;Dose;Drug Delivery Systems;Dryness;Effectiveness;Electrophoretic Mobility Shift Assay;FDA approved;Folic Acid;Formulation;Gene Expression;Goals;Hepatic;Hippocampus;Human;Immunoassay;In Vitro;Inflammation;Inflammation Mediators;Inflammatory Response;Intervention Studies;Label;Lead;Mediating;Metabolism;Microglia;Minor;Molecular Target;Mus;Nervous System Disorder;Neuroblastoma;Neurodegenerative Disorders;Neurofibrillary Tangles;Oral;Persons;Pharmaceutical Preparations;Phase;Plants;Powder dose form;Progress Reports;Property;Reporting;Research;Research Personnel;Rodent;Route;SIRT1 gene;Senile Plaques;Spinal;Standardization;System;Testing;Therapeutic;Tissues;Toxic effect;Transgenic Mice;abeta accumulation;behavior test;beta-site APP cleaving enzyme 1;blood-brain barrier crossing;brain tissue;cognitive function;cyanine;demethoxycurcumin;donepezil;drug standard;efficacy evaluation;exosome;experience;folate-binding protein;immunotoxicity;nanoformulation;nanoparticle;neuroblastoma cell;neuroinflammation;neuroprotection;novel;preclinical study;protein expression;public health relevance;receptor;reduce symptoms;small molecule;targeted delivery;tau-1;treatment response

public_health_relevance:
Narrative (Public Health Relevance Statement) In the proposed project we will use a novel nano formulation of curcuminoids to mitigateneuroinflammation and attenuate neurological diseases with emphasis on Alzheimers disease (AD). In ourapproach curcuminoids known for their potent anti-inflammatory activity and activities inhibiting early brainmarkers of AD including neurofibrillary tangles and amyloid plaque formation will be sequestered in exosomes(natural nanoparticles) isolated from standardized bovine colostrum powder to increase bioavailability. Theexosomes will be decorated with folic acid whose receptors are expressed in high levels in the brain to targetthe brain sub tissues such as cortex and hippocampus and the formulation is delivered by a novel trans-spinal(t.s.) topical route for efficient brain delivery and the efficacy assessed using transgenic mouse model of AD.


application_id: 10819137
project_number: 5R01CA259580-04
project_title: Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2024-03-20
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 259580
program_official: WATSON, JOANNA M
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
N-methyltransferase (NNMT) a key enzyme in the NAD+ salvage pathway with unclear functions isexpressed highly and specifically in basal-like breast cancer (BLBC). We found that NNMT is robustlyelevated when BLBC cells detach from a matrix and grow in suspension. Knockout (KO) of NNMT not onlyinhibits anchorage-independent growth in vitro but also suppresses tumor growth and metastasis in animalmodels. Using an unbiased CRISPR-Cas9 library screening we identified the FOXC1-CARM1 complex asbeing responsible for NNMT upregulation in BLBC. Importantly inhibition of NNMT by either KO or use of aninhibitor increases the proapoptotic effects mediated by chemo-drugs. We thus hypothesize that NNMT is acritical gatekeeper that maintains NAD+ homeostasis for BLBC progression and metastasis; this homeostasisboosts the cellular antioxidative defense machinery and prevents surges of ROS that BLBC cells encounterduring metastasis. The objective of this proposal is to (1) characterize NNMT function in regulating NAD+homeostasis in tumor progression and metastasis; (2) delineate the transcriptional regulation of NNMT bythe FOXC1-CARM1 complex; and (3) explore the clinical value of NNMT as a prognostic biomarker and adruggable target for BLBC. Guided by strong preliminary data we will test this hypothesis by pursuing threespecific aims: (1) to determine the critical roles of NNMT in BLBC; (2) to delineate NNMT transcription by theFOXC1-CARM1 complex; and (3) to define the roles of NNMT in the development of mammary gland andbreast cancer metastasis. Our proposal is innovative and significant because NNMT represents the achillesheel of BLBC; targeting this metabolic vulnerability offers an effective therapeutic option against metastaticBLBC.

project_terms:
Acetylation;Aging;Anchorage-Independent Growth;Animal Model;Apoptotic;Brain;Breast Cancer Cell;CRISPR library;Cancer Biology;Cancer Cell Growth;Cell Nucleus;Cell model;Clinical;Code;Complex;Cytoplasm;Data;Development;Diabetes Mellitus;Diagnosis;Disease;Drug resistance;Endowment;Environment;Enzymes;Event;Exhibits;Extravasation;FOXC1 gene;Family;Gatekeeping;Genetic Transcription;Goals;Homeostasis;Human;In Vitro;Knock-out;Lung;Malignant Breast Neoplasm;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methyltransferase;Mitochondria;NADH;NADP;Neoplasm Metastasis;Niacinamide;Nicotinamide N-Methyltransferase;Nicotinamide adenine dinucleotide;Oncogenic;Oxidation-Reduction;Oxidative Stress;Pathologist;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;Prognosis;Prognostic Marker;Proliferating;Property;Reactive Oxygen Species;Regimen;Regulation;Rejuvenation;Research;Respiration;Rodent;Role;Shapes;Signal Pathway;Site;Specimen;Suspensions;Talents;Testing;Therapeutic;Transcriptional Regulation;Tumor Promotion;Up-Regulation;Vertebral column;Xenograft Model;arginine methyltransferase;breast cancer metastasis;breast cancer progression;coactivator-associated arginine methyltransferase 1;druggable target;experimental study;extracellular;in vivo;inhibitor;innovation;knock-down;mammary gland development;metabolomics;mouse model;multidisciplinary;novel therapeutic intervention;oxidative damage;patient derived xenograft model;prevent;screening;stemness;success;synergism;therapeutically effective;therapy resistant;transcription factor;tumor growth;tumor progression;uptake

public_health_relevance:
Nicotinamide N-methyltransferase (NNMT) a key enzyme in the NAD+ salvage pathway with unclear functionsis expressed highly and specifically in basal-like breast cancer (BLBC). We propose that NNMT which isregulated by the FOXC1-CARM1 complex is a critical gatekeeper to promote tumor progression metastasisand drug-resistance in BLBC. Our systematic and complementary analyses will lead to a major advance in theunderstanding of breast cancer biology and the development of novel therapeutic strategies for metastaticBLBC.


application_id: 10818773
project_number: 3K01ES033289-02S1
project_title: Evaluating mechanisms of sex differences in environmentally-induced metabolic diseases
administering_ic: NIEHS
award_notice_date: 2023-07-27
opportunity_number: PA-20-272
application_type: 3
activity_code: K01
ic: ES
serial_number: 033289
suffix: S1
program_official: SCHUG, THADDEUS
project_start_date: 2022-06-03
project_end_date: 2025-05-31
study_section: ZES1(K1)
contact_pi_person_id: 14294360
contact_pi: WAHLANG, BANRIDA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Mechanistic studies pertaining to sex-based differences in metabolic syndrome (MetS) are currently insufficientto explain and prevent the higher prevalence of certain MetS symptoms in women versus men andhigher prevalence of other symptoms such as hyperlipidemia in men versus women. MetS describes aconstellation of risk factors such as abdominal adiposity hypertension glucose intolerance/hyperglycemiaand dyslipidemia leading to diabetes and cardiovascular morbidity. High-caloric intake and sedentary lifestylehabits are among key players shown to induce symptoms of MetS. However exposures to environmentalchemicals such as persistent organic pollutants (POPs) often dictated by socio-economic status andeducation levels have been increasingly identified as additional key players leading to MetS consequences.Previous studies showed that exposures to POPs such as organochlorine pesticides (OCPs) andpolychlorinated biphenyls (PCBs) in in-vivo models and human studies were associated with diabetes obesityand non-alcoholic fatty liver disease which are hallmarks for MetS development. Furthermore using in-vitro models and diet-induced obesity mouse models we had previously demonstrated that the liver wasthe predominant target organ of toxicity to POPs including PCBs and mechanism(s) of toxicity wereprimarily through activation of hepatic receptors leading to metabolic disruption. The liver has long beenestablished as a sexually dimorphic organ and it is therefore important to address POPs toxicity in term ofbiological differences or sex. Additionally POPs such as OCPs are endocrine disrupting chemicals having theability to interact with androgen or estrogen receptors and potentially promoting variable effects in men andwomen. However most epidemiologic studies demonstrating associations between POPs exposure with livertoxicity/metabolic diseases including diabetes either focused on agricultural workers who were mostly men oradjusted for sex; but POPs exposures occur in both men and women and thus their health risks may vary.POPs exposures today is primarily through ingestion of contaminated food and water and serum levels canvary depending on sex and gender. Hence it is relevant to examine exposures to POPs such as OCPs basedon environment-sex-gene interactions to better address such discrepancies.

project_terms:
Address;Agricultural Workers;Androgen Receptor;Authorization documentation;Biological;Cardiovascular system;Development;Diabetes Mellitus;Dyslipidemias;Educational Status;Endocrine Disruptors;Energy Intake;Environment;Environmental Health;Estrogen Receptors;Exposure to;Food Contamination;Future;Gender;Glucose Intolerance;Grant;Habits;Health;Health Care Costs;Hepatic;Hepatotoxicity;High Prevalence;Human;Hyperglycemia;Hyperlipidemia;Hypertension;Ingestion;Knowledge;Liver;Metabolic;Metabolic Diseases;Metabolic syndrome;Morbidity - disease rate;Obesity;Organ;Outcome;Polychlorinated Biphenyls;Population;Predisposition;Reporting;Risk;Risk Factors;Serum;Sex Differences;Socioeconomic Status;Symptoms;Therapeutic;Toxic effect;Water;Woman;abdominal fat;authority;design;diet-induced obesity;environmental chemical;epidemiology study;gene interaction;in vitro Model;in vivo Model;men;mouse model;non-alcoholic fatty liver disease;organochlorine pesticide;persistent organic pollutants;prevent;receptor;sedentary lifestyle;sex;sex disparity;sexual dimorphism

public_health_relevance:
Mechanistic studies pertaining to sex-based differences in the metabolic syndrome are currently insufficient toexplain and prevent the higher prevalence of certain metabolic conditions in women versus men and higherprevalence of other symptoms such as hyperlipidemia in men versus women. In addition epidemiologicstudies have reported that exposure to environmental chemicals such as persistent organic pollutantsincluding organochlorine pesticides yield different health outcomes in men and women and therefore thecurrent project aims to evaluate the underlying cellular mechanisms impacted by sexual dimorphism thatpotentially drive such differences. The concepts and information that will be gained from this grant will betteraddress sex disparities in environmental health as well as provide health authorities with furtherknowledge to identify metabolic syndrome-related factors in susceptible populations and design sex-specific therapeutic strategies to better control future health care costs.


application_id: 10818680
project_number: 3R01CA237643-05S2
project_title: Targeting Epigenetic Heterogeneity to Improve Lung Cancer Immunotherapy Response
administering_ic: NCI
award_notice_date: 2023-08-16
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: CA
serial_number: 237643
suffix: S2
program_official: SOMMERS, CONNIE L
project_start_date: 2019-07-01
project_end_date: 2025-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. Our central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing immunogenic PD-L1 expressing cellsand by depleting immunosuppressive tumor associated neutrophils. The overarching goal of the proposedstudy is to validate combining EZH2 inhibition with PD1/PD-L1 targeted immunotherapy and learn the molecularmechanisms when the treatment is successful as well as when it is not successful. In Aim 1 we will use both mouse models and human patient derived organoid cultures to examine NGFRCXCL9/10/11 PD-L1 and MHC expression in lung SCC cells after EZH2 inhibitor treatment. The epigenetic andtranscriptional consequences of EZH2 inhibition on squamous and bronchiolar lung tumor cells will be assessedby ChIP-seq and RNA-seq. In Aim 2 we will focus on the tumor associated neutrophils (TANs). We will compareTANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migration capacityand ability to suppress T cells. We will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 we will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. We will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. We will also develop tumoroid multi-cultures containing tumor cellsmesenchymal cells T cells and myeloid cells to be able to test responses of systems to EZH2 inhibition and anti-PD1 inhibition ex vivo. Completion of these aims will solidify the efficacy of a promising therapeutic combinationand uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2 inhibitorsin squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibition with anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.

project_terms:
Affect;CXCL9 gene;Cancer Etiology;Cancer Patient;Cells;Cessation of life;ChIP-seq;Clinical;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Flow Cytometry;Gene Expression;Genes;Genetic Transcription;Genotype;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Major Histocompatibility Complex;Malignant neoplasm of lung;Mesenchymal;Methyltransferase;Molecular;Mus;Myeloid Cells;NGFR gene;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;System;T-Lymphocyte;Testing;Therapeutic;Tumor stage;Update;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;cancer immunotherapy;cell type;clinically relevant;combinatorial;conditional knockout;cytokine;effector T cell;immunogenic;improved;in vivo;inhibitor;migration;mouse model;neoplastic cell;neutrophil;parent grant;programmed cell death ligand 1;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
PI: Brainson Christine FillmorePROJECT NARRATIVELung cancer is the leading cause of cancer-related deaths worldwide and is a very complex disease withdifferent cell types that comprise each tumor. Immunotherapy is ground-breaking because it is able to cure somepatients with late stage tumors but the number of patients that have this great response is still low. In thisproposal we will test the combination of a second drug with immunotherapy to increase the likelihood thatsquamous lung tumors will respond to treatment.


application_id: 10818585
project_number: 5R01CA279748-02
project_title: Immunotherapeutic targeting of MIF-dependent chaperone activity
administering_ic: NCI
award_notice_date: 2024-03-11
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 279748
program_official: FORRY, SUZANNE L
project_start_date: 2023-04-01
project_end_date: 2028-03-31
study_section: Special Emphasis Panel[ZRG1-TIO-D(01)Q]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Immunotherapeutic targeting of MIF-dependent chaperone activity Metabolic reprogramming that favors mitochondrial respiration plays an important role in controllingdifferential gene expression patterns in myeloid lineage cells. Our recent findings have identified a novel proteinchaperone-dependent pathway that indirectly controls mitochondrial homeostasis and metabolic programmingthat are needed to drive maximal intratumoral myeloid cell immune suppressive phenotypes. Our hypothesispredicts that small molecule inhibition of this chaperone activity carried out by the multifunctional cytokine MIFinduces spontaneous Cu/Zn superoxide dismutase (SOD1) misfolding and aberrant mitochondrial bindingleading to metabolic reprogramming and subsequent phenotypic reversion of intratumoral myeloid cell immunesuppressive phenotypes into immune stimulatory phenotypes. Studies proposed in this application will: 1)Delineate the mechanisms of action of 4-IPP-based MIF chaperone inhibitors in the context of MIF/SOD1-dependent TAM/MDSC polarization; 2) Determine the relative contribution of hypoxia as a physiologic ERstressor that exacerbates myeloid wt SOD1 misfolding in the context of MIF and 4-IPP and 3) Evaluate thetherapeutic potential of lead MIF chaperone antagonists as individual and combinatorial modalities againstestablished metastatic melanoma.

project_terms:
ALS patients;Acute;Antibody Therapy;Binding;Biological Assay;Biological Availability;CTLA4 gene;Cell Lineage;Cell surface;Cells;Clinic;Clinical;Communities;Cuprozinc Superoxide Dismutase;Data;Disease Progression;Disease Resistance;Drug Targeting;Effector Cell;Functional disorder;Future;Gene Expression Profile;Genetic Transcription;Homeostasis;Human;Hypoxia;Immune;Immune checkpoint inhibitor;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In complete remission;Individual;Induced Neurons;Innate Immune Response;Laboratories;Lead;Lesion;Macrophage;Malignant - descriptor;Malignant Neoplasms;Melanoma;Melanoma patient;Metabolic;Metastatic Melanoma;Migration Inhibitory Factor;Mitochondria;Modality;Molecular Chaperones;Monoclonal Antibodies;Myelogenous;Myeloid Cell Activation;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Oral;Pathway interactions;Patients;Phenocopy;Phenotype;Physiological;Play;Proteins;Respiration;Role;Solid;Solid Neoplasm;Stromal Cells;Structure-Activity Relationship;Suicide;Superoxide Dismutase;T-Lymphocyte;Testing;Therapeutic;Tissue-Specific Gene Expression;Transgenic Organisms;Tumor-associated macrophages;analog;angiogenesis;antagonist;anti-CTLA4;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;cancer immunotherapeutics;cancer therapy;combinatorial;cytokine;endoplasmic reticulum stress;immune checkpoint blockade;immunogenic;immunoregulation;improved;inhibitor;mitochondrial dysfunction;monocyte;mouse model;mutant;neovascularization;neurotoxicity;novel;overexpression;partial response;polarized cell;prevent;programmed cell death protein 1;protein folding;receptor;response;small molecule;small molecule inhibitor;stressor;tumor;tumor microenvironment;tumor progression;tumorigenic

public_health_relevance:
NARRATIVE Immunotherapeutic targeting of MIF-dependent chaperone activity Despite some very encouraging improvements in response rates and overall survival in late-stagemelanoma patients receiving anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB) immunotherapies anunacceptably high percentage of treated patients remain unresponsive to these therapies. Studies proposed inthis project application will investigate a unique metabolic transcriptional programming pathway that is governedby MIF-dependent chaperone activity. When therapeutically inhibited with a suicide antagonist discovered by ourlaboratory highly immune suppressive myeloid lineage cells are converted to highly immune stimulatory myeloidcells in the tumor microenvironment which is sufficient to induce tumor rejection and increased survival.


application_id: 10818353
project_number: 5R01NS116058-05
administering_ic: NINDS
award_notice_date: 2024-03-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 116058
program_official: YIN, XILING
project_start_date: 2020-04-01
project_end_date: 2026-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)

project_abstract:
Alzheimer's disease (AD) is the most common cause of cognitive impairment but diseases of cerebral bloodvessels particularly the small blood vessels that supply all cells of the brain are also major contributors. Noeffective therapies exist and innovative approaches are needed. The proposed study introduces two conceptualinnovations to identify novel therapeutic strategies. First the study focuses on cerebral small vessel ischemicdisease (SVID) induced by dyshomeostasis of amylin an endocrine hormone that participates in the centralregulation of satiety and also known to form pancreatic amyloid in patients with type-2 diabetes. Recent empiricalfindings advanced in part by our group suggest that axonal degeneration and maladaptation of small vesselssuch as gliosis are linked by vascular deposits of amylin. Our preliminary data also show that amylin depositionin brain capillaries correlates with accumulation of amylin in red blood cells. Working in non-AD rats we showedthat pancreatic expression of human amylin (rat amylin is non-amyloidogenic) promotes vascular amylindeposition leading to microhemorrhages axonal degeneration and late-life onset neurological deficits. Secondthe study introduces a new paradigm that amylin dyshomeostasis modulates brain amyloid composition. Severallaboratories (including ours) report the presence of mixed amylin- amyloid (A) plaques in brains of individualswith pathological AD. To study the amylin-A interaction in vivo we crossed AD rats with human amylin-expressing rats. Our preliminary data indicate that human amylin-expressing AD rats have accelerated agingand behavioral changes whereas genetic or pharmacological suppression of amylin is protective. Here wepropose to test these hypotheses by using red blood cell lysates cerebrospinal fluid samples and clinical datafrom the MarkVCID study along with mechanistic studies and amylin-centric therapeutic interventions in ratmodels of amylin dyshomeostasis-related dementia. Data derived from the proposed specific aims can directlylead to human clinical translational studies for the prevention and treatment of vascular cognitive impairmentand/or mixed pathologic disease states that currently lack effective treatments.

project_terms:
Acceleration;Acids;Adherence;Adhesions;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimers disease biomarker;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Arteries;Behavioral;Blood;Blood Vessels;Blood capillaries;Brain;Cardiovascular system;Carrying Capacities;Cerebral small vessel disease;Cerebrospinal Fluid;Cerebrovascular Circulation;Cerebrovascular system;Cerebrum;Clinical Data;Data;Dementia;Deposition;Development;Diabetes Mellitus;Disease;Disease Marker;Endocrine;Enrollment;Enzymes;Epoxide hydrolase;Erythrocytes;Feasibility Studies;Genetic;Gliosis;Glucose;Hemoglobin;Hemorrhage;Hormone Antagonists;Hormones;Human;Hypersensitivity skin testing;Hypoxia;Hypoxic-Ischemic Brain Injury;Impaired cognition;Individual;Insulin;Ischemia;Isomerism;Laboratories;Link;Magnetic Resonance Imaging;Measures;Mediating;Mediator;Metabolic dysfunction;Microspheres;Modeling;National Institute of Neurological Disorders and Stroke;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pancreas;Participant;Pathologic;Pathologic Processes;Pathology;Patients;Phenotype;Prevention;Prevention strategy;Proteins;Rattus;Regulation;Reporting;Research Project Grants;Sampling;Satiation;Senile Plaques;Signal Pathway;Skin;Techniques;Testing;Therapeutic Intervention;Vascular Cognitive Impairment;Vascular Endothelial Cell;age acceleration;axonal degeneration;beta amyloid pathology;brain cell;brain dysfunction;cerebral capillary;cerebrovascular;clinical translation;cohort;comorbidity;effective therapy;hypoxic ischemic injury;in vivo;inhibitor;innovation;islet amyloid polypeptide;late life;mild cognitive impairment;neuroinflammation;novel therapeutic intervention;pharmacologic;protective pathway;skin biopsy;tau Proteins;tool;translational study;vascular cognitive impairment and dementia

public_health_relevance:
Most patients with late-life onset Alzheimer's disease (AD) have cerebral small vessel ischemic disease;currently there is no treatment or effective prevention strategies. We will focus on a specific endocrine hormonewhich when hypersecreted causes diabetes and interaction with AD pathology. If our study demonstrates thatthe specific hormone we are studying causes cerebral small vessel disease then new inhibitors of this hormoneshould help protect the brain in aging and diabetes.


application_id: 10818203
project_number: 3R01CA237643-05S1
project_title: Targeting Epigenetic Heterogeneity to Improve Lung Cancer Immunotherapy Response
administering_ic: NCI
award_notice_date: 2023-08-15
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: CA
serial_number: 237643
suffix: S1
program_official: SOMMERS, CONNIE L
project_start_date: 2019-07-01
project_end_date: 2025-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. Our central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing immunogenic PD-L1 expressing cellsand by depleting immunosuppressive tumor associated neutrophils. The overarching goal of the proposedstudy is to validate combining EZH2 inhibition with PD1/PD-L1 targeted immunotherapy and learn the molecularmechanisms when the treatment is successful as well as when it is not successful. In Aim 1 we will use both mouse models and human patient derived organoid cultures to examine NGFRCXCL9/10/11 PD-L1 and MHC expression in lung SCC cells after EZH2 inhibitor treatment. The epigenetic andtranscriptional consequences of EZH2 inhibition on squamous and bronchiolar lung tumor cells will be assessedby ChIP-seq and RNA-seq. In Aim 2 we will focus on the tumor associated neutrophils (TANs). We will compareTANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migration capacityand ability to suppress T cells. We will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 we will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. We will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. We will also develop tumoroid multi-cultures containing tumor cellsmesenchymal cells T cells and myeloid cells to be able to test responses of systems to EZH2 inhibition and anti-PD1 inhibition ex vivo. Completion of these aims will solidify the efficacy of a promising therapeutic combinationand uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2 inhibitorsin squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibition with anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.1

project_terms:
Affect;CXCL9 gene;Cancer Etiology;Cancer Patient;Cells;Cessation of life;ChIP-seq;Clinical;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Flow Cytometry;Gene Expression;Genes;Genetic Transcription;Genotype;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Major Histocompatibility Complex;Malignant neoplasm of lung;Mesenchymal;Methyltransferase;Molecular;Mus;Myeloid Cells;NGFR gene;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;System;T-Lymphocyte;Testing;Therapeutic;Tumor stage;Update;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;cancer immunotherapy;cell type;clinically relevant;combinatorial;conditional knockout;cytokine;effector T cell;immunogenic;improved;in vivo;inhibitor;migration;mouse model;neoplastic cell;neutrophil;parent grant;programmed cell death ligand 1;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
PI: Brainson Christine FillmorePROJECT NARRATIVELung cancer is the leading cause of cancer-related deaths worldwide and is a very complex disease withdifferent cell types that comprise each tumor. Immunotherapy is ground-breaking because it is able to cure somepatients with late stage tumors but the number of patients that have this great response is still low. In thisproposal we will test the combination of a second drug with immunotherapy to increase the likelihood thatsquamous lung tumors will respond to treatment.


application_id: 10817995
project_number: 1R25ES036039-01
administering_ic: NIEHS
award_notice_date: 2024-02-19
opportunity_number: PAR-21-168
application_type: 1
activity_code: R25
ic: ES
serial_number: 036039
program_official: HUMBLE, MICHAEL C
project_start_date: 2024-03-01
project_end_date: 2028-12-31
study_section: Special Emphasis Panel[ZES1 BWD-W (25)]
contact_pi_person_id: 8531285
contact_pi: NEAL, RACHEL ELIZABETH
other_pis: ABOLINS-ABOLS, MIKUS ;CORBITT, CYNTHIA
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-03-01
project_title:
KEEP: Kentucky Environmental Education Pipeline A program to retain a diverse and equitable scientific trainee pipeline

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

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

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


application_id: 10817933
project_number: 5R01GM070559-17
project_title: Epigenetic regulation of hormone action in Tribolium and Aedes
administering_ic: NIGMS
award_notice_date: 2024-03-19
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: PHILLIPS, ANDRE W
project_start_date: 2005-02-01
project_end_date: 2027-03-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThere has been a continuous demand for development of insect control methods that are target-specific.Juvenile hormone (JH) and ecdysteroids (20-hydroxyecdysone 20E is the most active form) are the majorhormones that regulate many physiological and developmental processes in insects. Since these hormonesare not present in vertebrates they represent attractive targets for development of insect control methods.Hindering this effort is the lack of understanding on the molecular basis of action of these hormones. There hasbeen excellent recent progress in understanding the molecular basis of 20E and JH action. Key playersincluding receptors co-activators response elements and target genes involved in the action of thesehormones have been identified. Non-steroidal ecdysone agonists and JH analogs have been discovered andcommercialized for the control of pests and disease vectors. Research supported by this program showed thatepigenetic modifications especially acetylation levels of histones regulated by histone acetyltransferases(HAT) and histone deacetylases (HDAC) modulate JH and 20E action. Hormone action requires multiple layersof regulation because the same circulating levels of hormones exert diverse functions in different tissues andunder different physiological conditions. Based on the published literature and preliminary data included in thisapplication we hypothesize that epigenetic regulators HDACs HATs histone lysine methyltransferases(HKMT) and histone demethylases (HDM) modulate JH and 20E action in the regulation of postembryonicdevelopment and reproduction. The main goal of this proposal to test this hypothesis by studying themechanisms of action of epigenetic modifiers in JH and 20E action using T. castaneum TcA cells Ae. aegyptiand Aag2 cells as model systems. The two Specific Aims of the proposal are 1. To identify and characterizeepigenetic modifiers required for 20E and JH regulation of postembryonic development and femalereproduction and 2. To study mechanisms of action of epigenetic modifiers required for 20E and JH regulationof postembryonic development and female reproduction. In the first Specific Aim RNAi CRISPR/Cas9genome editing methods RNA sequencing bioinformatics RT-qPCR enzyme assays and cell cultureapproaches will be used to identify and characterize HATs HDACs HKMTs and HDMs required forpostembryonic development and female reproduction in T. castaneum and Ae. aegypti. In the second SpecificAim the mechanisms of action of 10-12 epigenetic modifiers will be studied using western blots and ChIPreporter Two-hybrid and pull-down assays and mass spectrometry approaches. Results from the proposedresearch will impact medicine by providing information for the development of vector control methods. Thisinformation could help in understanding epigenetics of human diseases such as cancer. The results from theproposed research may help to transform our understanding of endocrinology of disease vectors.

project_terms:
Acetylation;Adult women;Aedes;Agonist;Animals;Antibodies;Binding;Bioinformatics;Biological Assay;Biological Metamorphosis;Biological Models;CRISPR/Cas technology;Cell Culture Techniques;Cells;Complex;Culicidae;Data;Deacetylation;Development;Developmental Process;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ecdysterone;Embryonic Development;Endocrinology;Ensure;Environment;Enzymes;Epigenetic Process;Female;Food;Friends;Genes;Goals;Growth;Histone Deacetylase;Histone-Lysine N-Methyltransferase;Histones;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insect Hormones;Insecta;Insecticides;Juvenile Hormones;Knowledge;Laboratories;Life;Ligands;Literature;Livestock;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Medicine;Methods;Methoprene;Methylation;Modeling;Modification;Molecular;Pathway interactions;Pest Control;Physiological;Physiological Processes;Plants;Play;Postembryonic;Principal Investigator;Process;Proteins;Publishing;RNA Interference;Regulation;Reporter;Reproduction;Reproductive Process;Research;Research Support;Response Elements;Role;Steroid Receptors;Testing;Tissues;Tribolium;Vertebrates;Western Blotting;chromatin immunoprecipitation;commercialization;demethylation;ecdysone receptor;enzyme activity;epigenetic regulation;experimental study;gene product;genome annotation;genome editing;histone acetyltransferase;histone demethylase;histone modification;hormone analog;hormone regulation;hormone response element;human disease;insect disease vector;mass spectrometer;programs;promoter;receptor;receptor binding;response;success;transcription factor;transcriptome sequencing;transmission process;vector control;yeast two hybrid system

public_health_relevance:
Project Narrative Mosquitoes transmit deadly diseases. The research proposed in this application will provideinformation of potential importance for development of insecticides for vector control. The proposed studieswill reveal functions and mechanisms of action of epigenetic marks which will help in understandingepigenetics of human diseases such as cancer.


application_id: 10817710
project_number: 5P30ES030283-05
project_title: PILOT PROJECT
administering_ic: NIEHS
award_notice_date: 2024-03-14
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6994
contact_pi_person_id: 8957618
contact_pi: LEBLANC, AMANDA JO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Center for Integrated Environmental Health Science (CIEHS) will promote research toward understanding how lifestyle factors interact with exposure to environmental toxicants in human health and disease. The CIEHS Pilot Project Program will further this overall goal by providing support for short-term projects leading to data collection enabling new external grant applications. In this way the Pilot Project Program will enhance capacity for novel research in environmental health science at the University of Louisville. The Program will publicize the availability of pilot project funds solicit and coordinate the review of pilot project applications make funding recommendations monitor the progress of research projects assess usage of center cores by pilot projects and track deliverables. A mix of investigators will be targeted including new early stage investigators community partners and established researchers who can apply their expertise in novel ways relevant to environmental health. Results obtained through pilot projects will be disseminated via the annual Research!Louisville event that showcases research to the university local and regional communities. Because the ultimate goal is to develop new self-sustaining research projects an emphasis will be placed on facilitating and improving the quality of new grant applications pertaining to environmental exposures/lifestyle factors. Strategies for this include obtaining feedback from CIEHS members regarding pilot project findings and experimental design as well as performing rigorous internal review of grant proposals. Thus the Program will assist investigators throughout the pilot project life cycle from initial idea to extramurally funded project and is expected to generate significant new research funding and enhance the capacity for research in the environmental health sciences at the University of Louisville.

project_terms:
Accountability;Applications Grants;Area;Award;Benchmarking;Categories;Collaborations;Communication;Communities;Data Collection;Disease;Eligibility Determination;Environmental Exposure;Environmental Health;Event;Experimental Designs;Exposure to;Extramural Activities;Feedback;Fostering;Funding;General Population;Goals;Grant;Grant Review;Health;Human;Individual;Life Cycle Stages;Malignant Neoplasms;Mentors;Monitor;National Institute of Environmental Health Sciences;Organ;Pilot Projects;Publications;Recommendation;Reporting;Research;Research Peer Review;Research Personnel;Research Project Grants;Research Support;Technology;Toxic Environmental Substances;Toxicology;Translational Research;Universities;Work;career;career development;citizen science;community engagement;community partners;design;improved;lifestyle factors;meetings;member;novel;programs;stem;success;symposium


application_id: 10817709
project_number: 5P30ES030283-05
project_title: Omics and Exposures Facility Core
administering_ic: NIEHS
award_notice_date: 2024-03-14
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8049
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Center for Integrated Environmental Health Sciences (CIEHS) goals are to understand how lifestyle factors interact with exposure to environmental toxicants in human health and disease and toenhance the capacity for environmental health research at the University of Louisville (UofL). UofLshared resource facility cores offer cutting edge scientific services enabling access to high-endequipment advanced techniques and specialized expertise that would typically be inaccessible for aninvestigator. It is essential for the modern environmental health scientist to understand the numerousavailable shared resource facility cores; in terms of accessibility effective experimental design dataacquisitionand -analyses. The Integrated Toxicomics and Environmental Measurement Facility Core(ITEMFC) will create a central resource for CIEHS members allowing them to understand access andeffectively use environmental omics resources. The ITEMFC will coordinate activities between CIEHSmembers and the existing UofL shared resource facility cores. The ITEMFC will be comprised of sixdiscrete technology-centric components: genomics/ transcriptomics proteomics metabolomicsmetallomics metagenomics and controlled inhalation exposure studies. The ITEMFC will focus itsefforts on advising investigators on study design facilitating shared resource facility cores use andeducating Center members and trainees on these technologies. Additionally the ITEMFC will facilitatethe transfer of omics data to the Biostatistics and Informatics Facility Core (BIFC). It will accomplishthese goals through the following specific aims: Aim 1. Increase access and facilitate use of UofLshared resource facility cores. ITEMFC will serve our members by (a) explaining the various cores andhow they operate (b) establishing direct interactions with the right shared resource director to selectthe appropriate technology. We will aid in experimental design and closely collaborate with all FacilityCores to streamline sample handling and data analysis. The ITEMFC will also supplement the cost ofmember studies. Aim 2. Cultivate awareness interest and understanding of the ITEMFC sharedresource facility cores. The ITEMFC will support CIEHS members by (a) drawing attention to theshared resource facility cores (b) suggesting how the ITEMFC may enhance their approach inanswering their research questions and (c) support educating the next generation of environmentalscientists in the various technologies. Aim 3. Facilitate submission of CIEHS members grantapplications proposing to use ITEMFC Resources. The ITEMFC will support CIEHS members in theirgrant applications that include omics-based aims. The integrated services and expertise of the ITEMFCare essential to achieve CIEHS goals and to make progress with regard to understanding the diversepathological consequences of exposure to environmental toxicants together with lifestyle factors.

project_terms:
Applications Grants;Attention;Award;Awareness;Biometry;Cells;Chronic Disease;Collaborations;Communities;Core Facility;DNA;Data;Data Analyses;Disease;Environmental Health;Equipment;Event;Experimental Designs;Exposure to;Faculty;Funding;Genomics;Goals;Grant;Health;Health Sciences;Human;Informatics;Inhalation;Inhalation Exposure;Institution;Interest Group;Investments;Laboratories;Life Style;Malignant Neoplasms;Measurement;Measures;Metabolic;Metagenomics;Metals;Modernization;National Institute of Environmental Health Sciences;Organ;Pathologic;Pilot Projects;Pollution;Proteins;Proteomics;RNA;Research;Research Design;Research Personnel;Resource Sharing;Resources;Running;Sampling;Scientist;Services;Suggestion;Techniques;Technology;Tissues;Toxic Environmental Substances;Toxicogenetics;Toxicology;Universities;Work;citizen science;community engagement;cost;environmental toxicology;health science research;interest;lifestyle factors;medical schools;member;metabolomics;neurodevelopment;next generation;programs;shared attention;toxicant interaction;transcriptomics


application_id: 10817708
project_number: 5P30ES030283-05
project_title: Biostatistics and Informatics Facility Core
administering_ic: NIEHS
award_notice_date: 2024-03-14
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8048
contact_pi_person_id: 14867184
contact_pi: PARK, JUW WON
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long-term objective of the Center for Integrated Environmental Health Sciences (CIEHS) is to build aframework that integrates studies on the interactions between combined exposure to pollutants and life stylefactors) in order to understand their role in human health and disease risk at various life stages and asmodified by gender. The Biostatistics and Informatics Facility Core (BIFC) plays a vital role in supportingCIEHS research by providing state-of-the-art statistical and bioinformatics support and training to all CIEHSmembers. The BIFC is an essential resource for designing systematic acquisition and deposition of preclinicaland clinical data as well as for providing intellectual input required for rigorous data analysis. Building theframework to integrate translational basic science research on pollution and lifestyle cofactors influencingchronic disease risk requires sophisticated statistical support. The BIFC addresses this need by using state-of-art techniques related to statistics and informatics as it serves CIEHS members during all phases of theirstudies. The BIFC provides seamless infrastructure and support to CIEHS member research includingpreclinical-basic science patient-oriented clinical research (e.g. the diagnosis prevention and therapy ofenvironmentally-related disorders) public health/population-based research and community-engaged /community-led research. The aims of the BIFC are: 1. Provide state-of-the-art statistical support in designanalysis and dissemination of findings of a range of basic science translational clinical population health andenvironmental epidemiology studies; 2. Provide support for the integration of multi-omics data from both animaland human studies; 3. Facilitate integration of exposure data with lifestyle factors to identify effect modifiersand mediators of the health effects of environmental exposures; 4. Educate center investigators staff andtrainees in new methods related to statistics/omics approaches applicable to their research activities. Areas ofspecial interest include repeated measures models measurement error spatio-temporal methodscomputational biology statistical genetics clinical informatics and Bayesian methods. Several CIEHSmembers currently use the statistical support services of the BIFC Director and staff demonstrating both needand productive interactions. An IDeA grant to the Kentucky Biomedical Research Infrastructure Network andINBRE provides partial support for some BIFC bioinformatics personnel and access to a variety ofbioinformatics and statistical tools. By leveraging and building upon existing resources at UofL the BIFC isable to facilitate access and use of these resources by CIEHS members and expand statistical andbioinformatics support in a more cost efficient manner.

project_terms:
Address;Animals;Area;Basic Science;Bayesian Method;Big Data;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Centers of Research Excellence;Chronic Disease;Clinical;Clinical Data;Clinical Informatics;Clinical Research;Communities;Computational Biology;Consultations;Core Facility;Data;Data Analyses;Dedications;Deposition;Diagnosis;Disease;Environment;Environmental Epidemiology;Environmental Exposure;Environmental Health;Exposure to;Funding;Gender;Genetic;Goals;Grant;Health;Human;Human Resources;Informatics;Infrastructure;Kentucky;Life;Life Style;Measurement;Measures;Mediator;Methods;Modeling;Multiomic Data;National Institute of Environmental Health Sciences;Network Infrastructure;Phase;Play;Pollution;Population Research;Population Study;Prevention;Productivity;Public Health;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Science;Services;Strategic Planning;Superfund;Techniques;Toxic Environmental Substances;Training;Universities;alcohol research;bioinformatics tool;cofactor;community based participatory research;community engagement;cost efficient;data infrastructure;design;disorder risk;epidemiology study;health science research;interest;lifestyle factors;member;patient oriented;pollutant;population health;pre-clinical;spatiotemporal;statistics;tool


application_id: 10817706
project_number: 5P30ES030283-05
project_title: Integrated Health Science Facility Core
administering_ic: NIEHS
award_notice_date: 2024-03-14
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8047
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overarching objective of the Integrated Health Sciences Facility Core (IHSFC) of the Center for IntegratedEnvironmental Health Sciences (CIEHS) is to translate basic research on pollution and lifestyle factorsinfluencing human health and chronic diseases. The multi-disciplinary IHSFC provides infrastructure facilitatingtranslational human subjects EHS research for the CIEHS university and community. The ultimate goal is toimprove public health and clinical practice. The IHSFC supports patient-oriented clinical research; group andpopulation-based research; and community engaged/led research. The IHSFC is comprised of two interactingsubunits: the Research Administration and Planning Subunit (RAPS) and the Research ImplementationSubunit (RIS). The IHSFC interacts with other CIEHS cores and the Research Interest Groups (RIGs) to (i)provide access to state-of-the-art instrumentation and technologies; (ii) increase multidisciplinary collaboration;and (iii) enhance partnerships with community-based organizations. The IHSFCs first specific aim is toadminister the IHSFC and plan translational human subjects EHS research. This aim is performed by RAPS.RAPS provides IHSFC access to CIEHS members trainees and the community. RAPS solicits applications forhuman subjects research; and then reviews prioritizes and financially subsidizes supported applications.RAPS defines IHSFC research in the context of the NIEHS Translational Research Framework. Community-proposed research ideas are assigned to an appropriate CIEHS member for development and execution.RAPS provides translational research training/education; and tracks and reports performance metrics to theAdministrative Core for evaluation. RAPS provides scientific study design and community engagementconsultation through linkages to the RIGs and other CIEHS cores. These consultations ensure that all IHSFC-supported studies: (i) are rigorously designed and powered; (ii) are consistent with CIEHSs theme andresearch interests; and (iii) consider the involvement of community organizations impacting this research. TheIHSFCs second specific aim is to implement IHSFC research. This aim is performed by the RIS. RIS provideshuman subjects research services and access to state-of-the-art bio-analytic instrumentation and technologiesthrough linkage to the Integrated Toxicomics & Environmental Measurement Facility Core (ITEMFC). In turnITEMFC measures exposure and omics-based disease biomarkers. RIS leverages UofLs adult Clinical TrialsUnit (CTU) the Kosair Charities Pediatric Clinical Research Units (KCPCRU) and existingcohorts/biorepositories to obtain human subjects data and biological samples. Next RIS provides linkage toother CIEHS cores for biomarker measurement data analysis and knowledge dissemination. Based on thecombination of physician-scientists engaged in EHS research and clinical research units found nowhere elsethe IHSFC has the unique capacity to conduct impactful translational EHS research including biomarkerstudies and interventional clinical trials.

project_terms:
Adult;Affect;Basic Science;Biological;Biological Markers;Biometry;Charge;Charities;Childhood;Chronic Disease;Clinical;Clinical Research;Clinical Trials;Clinical Trials Unit;Communities;Consent;Consultations;Core Facility;Data;Data Analyses;Development;Disease;Doctor of Medicine;Early Diagnosis;Ensure;Environment;Environmental Health;Evaluation;Fee-for-Service Plans;Goals;Health;Health Sciences;Health Services Accessibility;Human;Human Resources;Human Subject Research;Informatics;Infrastructure;Interdisciplinary Study;Interest Group;Intervention;Knowledge;Life;Measurement;Measures;Metagenomics;Metals;National Institute of Environmental Health Sciences;Nature;Performance;Pharmaceutical Preparations;Physicians;Pilot Projects;Pollution;Population Research;Prevention;Program Evaluation;Proteomics;Public Health Practice;Randomized;Reporting;Research;Research Design;Research Personnel;Research Support;Retrieval;Sampling;Scientist;Services;Technology;Therapeutic Intervention;Time;Training and Education;Translating;Translational Research;Universities;biobank;clinical practice;cohort;community engagement;community involvement;community organizations;cost effective;design;experience;follow-up;human data;human subject;improved;innovation;instrument;instrumentation;interest;lifestyle factors;member;metabolomics;multidisciplinary;patient oriented;programs;recruit;response;sample collection;sex;transcriptomics;volatile organic compound


application_id: 10817704
project_number: 5P30ES030283-05
project_title: COMMUNITY ENGAGEMENT
administering_ic: NIEHS
award_notice_date: 2024-03-14
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8046
contact_pi_person_id: 12053538
contact_pi: HUNTINGTON-MOSKOS, LUZ G
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Center for Integrative Environmental Health Sciences (CIEHS) will promote the translation of research onpollution and lifestyle factors to understand their role in human health and diseases. The CIEHS CommunityEngagement Core (CEC) vision is to develop and sustain community-academic partnerships that enhance thehealth of south-central and western Kentucky residents by empirically addressing pollution and lifestyle factorsinfluencing chronic diseases. The aims of the CEC are to: (1) facilitate and support multi-directionalinteractions among residents community agencies and the CIEHS to assess community needs and priorities;(2) facilitate and support multi-directional interactions to increase community awareness and understanding ofCIEHS research and resources; 3) cultivate environmental literacy among identified audiences; and (4) buildcapacity for community-led and community-engaged environmental health research. The approach to engagethe identified audiences has three tiers: (1) engage community residents via housing agencies to assessenvironmental health needs and community priorities; (2) involve healthcare providers to impact the healthcaresystem as it relates to environmental health needs; (3) share environmental health knowledge with communityyouth as a catalyst to promote environmental health literacy within families. In Aim 1 the CEC will work directlywith residents and community partners across south-central and western Kentucky to assess their uniquecommunity needs and priorities. Based upon the needs identified the CEC will translate and disseminateenvironmental health information to our targeted audience including CIEHS research findings (Aim 2). We willcommunicate with communities using multiple traditional (e.g. newspapers factsheets) and non-traditionalformats (e.g. social media platforms). With Aim 3 the CEC will leverage its community engagement efforts toincrease environmental health literacy in a three-tiered staggered approach in the four University of LouisvilleArea Health Education Center (AHEC) regions of south-central and western Kentucky. Outreach andengagement efforts will involve community members healthcare providers and community youth. Establishedresources from the EPA and NIEHS will be accessed including the Partnerships for Environmental PublicHealth. In Aim 4 the CEC will collaborate with the Pilot Projects Program the Stakeholders Advisory Boardand other community organizations to develop and implement through the Integrated Health Sciences FacilityCore (IHSFC ) community-led environmental health research. Aim 4 will also include working closely with theIHSFC to facilitate investigator-initiated community-engaged environmental health studies. The four targetedUofL AHEC areas include smaller urban areas multiple townships and rural areas. Residents in these ruralareas are exposed to diverse environmental exposures from industry (e.g. rural distilleries; urban/smalltown/rural manufacturing) 12 superfund sites and urban and rural agriculture. The CEC is an integral corewithin the CIEHS structure with direct impact on CIEHS research direction and decision-making.

project_terms:
Address;Agriculture;Area;Area Health Education Centers;Awareness;Chronic Disease;Collaborations;Communication;Communities;Core Facility;Decision Making;Diabetes Mellitus;Disease;Ensure;Environmental Exposure;Environmental Hazards;Environmental Health;Exposure to;Family;Gender;Goals;Health;Health Personnel;Health Resources;Health Sciences;Healthcare Systems;Housing;Human;Huntington Disease;Hypertension;Industry;Kentucky;Knowledge;Leadership;Life;Malignant Neoplasms;National Institute of Environmental Health Sciences;Newspapers;Obesity;Pilot Projects;Pollution;Public Health;Research;Research Personnel;Resources;Role;Rural;Structure;Toxic Environmental Substances;Translating;Translational Research;Translations;Universities;Vision;Work;Youth;burden of illness;catalyst;community academic partnership;community engaged research;community engagement;community involvement;community organizations;community partners;experience;health assessment;health knowledge;health literacy;health science research;household environmental exposure;lifestyle factors;literacy;manufacture;member;outreach;programs;research faculty;rural area;social media;superfund site;urban area


application_id: 10817702
project_number: 5P30ES030283-05
project_title: ADMINISTRATIVE CORE
administering_ic: NIEHS
award_notice_date: 2024-03-14
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2026-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 8044
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisvilles (UofL) Center for Integrative Environmental Health Science (CIEHS) is building aframework to study the integration of the interactions of pollutants and lifestyle factors in order to betterunderstand the impact on human health and disease risk across life stages and how these interactions aremodified by genetics and gender with the overall goal of improving the health of the Louisville RegionalCommunity. We will achieve this goal by fostering unique translational research on pollution and lifestyle as co-determinants that influence disease risk and facilitating transformative interdisciplinary research on preventionand/or mitigation of disease resulting from exposure to these cofactors at various life stages while consideringgenetics and gender as significant modifiers of outcomes. The CIEHS is designed to leverage existingresources to enhance trans-disciplinary environmental health research at UofL. The Administrative Core is anessential component of CIEHS that will provide scientific leadership and vision coordinate all CIEHSprogrammatic activities maintain open communication among the Cores monitor program progress andmember productivity and provide good stewardship of resources to maximize member productivity. In additionthe Administrative Core facilitates an active Community Engagement program that educates healthcareproviders serving an underprivileged patient population and the community members focusing on youthgroups. The Administrative Core also mentors junior and mid-level faculty through a Career DevelopmentProgram. The Administrative Core coordinates activity between the Community Engagement Core theIntegrated Health Sciences Facility Core the Biostatistics and Informatics Facility Core the IntegratedToxicomics and Environmental Measurement Facility Core and the Research Interest Groups to ensure multi-directional communication between CIEHS scientists and community groups to keep CIEHS research focusedon community needs. The Specific Aims are: 1. Provide leadership in coordinating and integrating Centercomponents and activities; 2. Cultivate and recruit junior and mid-level investigators to enhance careers andresearch programs in environmental health sciences; 3. Assess productivity effectiveness andappropriateness of CIEHS activities and cores; 4. Determine CIEHS membership assess scientificopportunities and areas for collaboration among CIEHS members; 5. Organize CIEHS activities such asretreats invitation of consultants meetings and focus groups; 6. Provide recordkeeping of meeting minutesand measures of success including use of CIEHS facilities publications pilot project awards and new grantapplications resulting from preliminary data enabled by the CIEHS; 7. Organize Internal and External AdvisoryCommittees; 8.Interact with other Environmental Health Science Core Centers (EHSCC) the NIEHS andother appropriate individuals groups organizations.

project_terms:
Advisory Committees;Applications Grants;Area;Award;Biometry;Collaborations;Communication;Communities;Core Facility;Data;Disease;Effectiveness;Electronic Mail;Ensure;Environmental Health;Evaluation;Exposure to;Faculty;Focus Groups;Fostering;Gender;Genetic;Goals;Grant;Health;Health Personnel;Health Sciences;Human;Individual;Informatics;Interdisciplinary Study;Interest Group;Lead;Leadership;Life;Life Style;Measurement;Measures;Mediating;Mentors;Mentorship;Methods;Monitor;National Institute of Environmental Health Sciences;Outcome;Output;Pilot Projects;Pollution;Prevention;Process;Productivity;Program Development;Publications;Recruitment Activity;Reporting;Research;Research Personnel;Resources;Schedule;Scientist;Societies;Telephone;Toxic Environmental Substances;Toxicology;Translational Research;Translations;Universities;Vision;Youth;candidate identification;career;career development;cofactor;community engagement;design;disorder risk;health science research;improved;interest;lifestyle factors;meetings;member;patient population;pollutant interaction;programs;recruit;repository;success;symposium


application_id: 10817512
project_number: 3R01CA251663-03S1
project_title: Targeting Mitochondrial Redox Capacity to Overcome Cancer Subtype that Regrowth After Radiation
administering_ic: NCI
award_notice_date: 2023-09-11
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: CA
serial_number: 251663
suffix: S1
program_official: PRASANNA, PAT G
project_start_date: 2023-08-01
project_end_date: 2026-03-31
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT (R01CA251663)Radiation therapy (RT) is widely used to treat localized prostate cancer (PCa). However cancer cells oftendevelop resistance to RT through unknown mechanisms resulting in cancer recurrence. To improve RT thereis a dire need to uncover cellular events that cause cells to become resistant. We previously demonstrated thatPCa heterogeneity particularly in prostate cancers with an abundant mitochondria subpopulation often surviveand regrow after RT (termed radiation resistant prostate cancer or RR-PCa). Elevation of mitochondrial massnumber reactive oxygen species (ROS) and biogenesis markers is acquired in RR-PCa cells. We furtherdemonstrated that knockdown of the mitochondrial biogenesis regulator TFAM (transcription factor Amitochondrial) significantly restored the sensitivity of RR-PCa cells to RT. Hence our overarching hypothesis isthat RT-activated mitochondrial biogenesis via ROS is an acquisition mechanism that drives PCa survival post-RT a premise that will undergo stringent examination in the proposed studies. ROS are known to directly andindirectly regulate mitochondrial homeostasis through fusion fission mitophagy and biogenesis. We screenedFDA-approved drugs in search of compounds that are nontoxic to normal cells and have the ability to raise thelevel of mitochondrial hydrogen peroxide (mtH2O2) in PCa cells while blocking mitochondrial protein translation.We found azithromycin (AZM) a macrolide antibiotic to be an effective prototype compound that possessesboth properties. We further demonstrated that AZM combined with RT enhances the death of PCa cells with anabundant mitochondrial subpopulation compared to AZM or RT alone. Thus we propose to advance our findingsand identify the mechanism(s) that effectively inhibit the survival of post-irradiated cancer cells to improve RTefficacy. The specific aims are: 1) to define the molecular mechanism(s) by which RT-activated mitochondrialbiogenesis promotes cell survival and metabolic adaptations of PCa cells with abundant mitochondria both invitro and in vivo; 2) to determine if overloading mtH2O2 to target inherent mitochondria and RT-acquiredmitochondria while blocking mitochondrial protein translation in RT-acquired mitochondria enhancesradiosensitivity of RR-PCa cells and 3) to improve RT using a mtH2O2 generator and a mitochondrial proteintranslation inhibitor AZM as prototype in an orthotopic mouse xenograft model and a patient-derived xenograftmodel of PCa with activated mitochondrial biogenesis. This study uses state-of-the-art platforms includingreverse phase protein array stable isotope-resolved metabolomics total internal reflection fluorescencemicroscopy with Imaris software TEMPOL-enhanced MRI imaging and a high resolution O2k-FluoRespirometer.The proposed studies are expected to uncover novel molecular insights by which concurrently targetingmitochondrial redox capacity and mitochondrial biogenesis improve RT efficacy in the treatment of RR-PCa.

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


application_id: 10817400
project_number: 3P30ES030283-04S1
project_title: University of Louisville Center for Integrative Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2023-03-31
opportunity_number: PA-21-071
application_type: 3
activity_code: P30
ic: ES
serial_number: 030283
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The University of Louisvilles (UofL) Center for Integrative Environmental Health Science (CIEHS) bringstogether a multidisciplinary group of investigators working together to develop a framework to understand thecomplexities of and to integrate the interactions between environmental toxicants life style factors life stagegenetics and gender and their roles in human health and disease. The CIEHS is uniquely positioned to buildtransdisciplinary teams to tackle these problems by virtue of the multidisciplinary expertise of its members andits geographic location. The Louisville Regional Community composed of Metropolitan Louisville and thecounties of western Kentucky is a unique mix of urban and rural environments with industrial and agriculturalexposures that is a microcosm of the United States. The region is plagued by rates of chronic disease (e.g.cardiovascular diabetes cancer etc.) all with environmental etiologies that are among the highest in thenation. The CIEHS facilitates research and training focused on: (1) exposure to industrial chemicals present inthe urban and rural KY environments (metals VOCs PCBs vinyl chloride etc.) (2) lifestyle factors (dietalcohol socioeconomic stressors obesity etc.) and the modifications to response by life stage genetics andgender in development of chronic adult diseases. CIEHS is organized into three multi-disciplinary researchinterest groups (multi-organ toxicology cancer and neurodevelopmental toxicology). The Integrated HealthScience Facility Core promotes translation of basic science including assistance with both adult and pediatricclinical trials. The Community Engagement Core promotes multi-directional communication between CIEHSinvestigators and community groups with special focus on rural health care providers and youth groups. ThePilot Project Program provides resources supporting new environmental health investigators collaborationsbetween CIEHS members and established investigators bringing new skill sets to environmental healthproblems new avenues of environmental health research by CIEHS members and community-engaged andcommunity-led research in collaboration with CIEHS members. A Career Development Program providesmentorship and support to new junior as well as mid-level investigators. These activities are supported by twofacility cores (biostatistics and informatics and integrated toxicomics and environmental measurements). TheCIEHS provides leadership in environmental health research promotes investigation of the interactions ofchronic exposure to environmental toxicants and lifestyle factors in pathogenesis and develops the nextgeneration of environmental health researchers. Our studies utilize model systems in the laboratory the largerecosystem by investigation of pollution effects on wildlife and the human laboratory provided by the LouisvilleRegional Community in collaboration with community partners.

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

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


application_id: 10817135
project_number: 5R21AG082081-02
project_title: Olfactory Epithelium Responses to Human APOE Alleles
administering_ic: NIA
award_notice_date: 2024-03-13
opportunity_number: PAR-22-094
application_type: 5
activity_code: R21
ic: AG
serial_number: 082081
program_official: ST HILLAIRE-CLARKE, CORYSE
project_start_date: 2023-04-01
project_end_date: 2026-09-30
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
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:
Project Summary:Deficits in olfaction were recognized decades ago as early symptoms in people with incipient AlzheimersDisease. However these discoveries have had less impact than hoped on the study diagnosis and treatmentof this disease. Though central nervous system olfactory pathways suffer the plaques and/or tangles that arecharacteristic of late-stage disease these symptoms do not set the olfactory system apart from other foci ofresearch into Alzheimers Disease. Perhaps because the regenerative capacity of the olfactory epitheliumobscured the vulnerability of olfactory sensory neurons to Alzheimers Disease especially the early eventsleading to the neurodegeneration characteristic of the disease study of how the olfactory epithelium isimpacted by Alzheimers Disease languished. Clear evidence that the olfactory sensory neurons in theepithelium are susceptible to factors that cause or increase risk of Alzheimers Disease has recently emergedhowever. These findings demonstrate that the olfactory epithelium is a worthy model of how risk factors forAlzheimers Disease affect neurons and their supporting cells. Thus far the data correlate well with effects inthe brain evidence that the olfactory epithelium may be a bellwether for events transpiring in the centralnervous system. The accessibility of the olfactory epithelium for biopsy to assess disease progression inindividuals and to drugs that cannot pass the blood brain barrier further elevates the significance of theolfactory epithelium as a model. This project investigates the effects of a critical risk factor for AlzheimersDisease APOE genotype on the olfactory epithelium and its olfactory sensory neurons. The experimentsfocus on identifying early events and the strength of their effects on phenotype and function. It uses mousemodels of the disease including established genetic models previously used to investigate effects in the brainand a novel model that allows switching at will from a neurodegenerative genotype to a neuroprotectivegenotype. The latter allows testing of whether cellular and molecular events associated with vulnerability toAlzheimers Disease can be prevented or reversed by in vivo genetic manipulation outcomes that would informand inspire further work towards curing this disease.

project_terms:
Adult;Affect;Age;Alleles;Alzheimer associated neurodegeneration;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Apolipoprotein E;Autopsy;Biopsy;Blood - brain barrier anatomy;Brain;Cells;Central Nervous System;Characteristics;Chronic;Complex;Data;Data Correlations;Development;Diagnosis;Disease;Disease Progression;Early identification;Epithelium;Event;Foundations;Gene Expression;Genetic;Genetic Models;Genotype;Glucose;Goals;Human;Human Amyloid Precursor Protein;Immune response;Individual;Intervention;Late Onset Alzheimer Disease;Learning;Link;MAPT gene;Measures;Messenger RNA;Metabolic dysfunction;Microglia;Modeling;Molecular;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurons;Olfactory Epithelium;Olfactory Pathways;Outcome;Pathologic;Pathway interactions;Persons;Pharmaceutical Preparations;Phenotype;Predisposition;Probability;Proxy;Publishing;Regenerative capacity;Research;Risk Factors;Risk Reduction;Site;Smell Perception;Stress;Supporting Cell;Symptoms;Testing;Tissues;Work;age effect;age related;age-related disease;apolipoprotein E-3;apolipoprotein E-4;cell type;disease model;experimental study;gene therapy;genetic manipulation;genetic variant;glucose uptake;improved;in vivo;in vivo Model;lipidome;middle age;mouse model;mutant;neural;neuroinflammation;neuron apoptosis;neuronal survival;neuroprotection;novel;olfactory sensory neurons;prevent;protective effect;response;single-cell RNA sequencing;slow axonal transport;success;sustentacular cell;synergism;therapy design;transcriptome;young adult

public_health_relevance:
Project Narrative:Deficits in olfaction are long-established symptoms of Alzheimers Disease whose potential to revealmechanisms leading to this disease has yet to be realized. Recent evidence that the olfactory epithelium andits olfactory sensory neurons are vulnerable to genetic variants linked to Alzheimers Disease openopportunities to investigate early effects leading to neurodegeneration in a neural tissue that is easilyaccessible including via biopsy in humans. This project investigates the effects of human apoliproprotein Ealleles on the olfactory epithelium and its neurons in mouse models including whether switching expressionfrom a neurodegenerative allele to a neuroprotective allele prevents and reverses effects linked to AlzheimersDisease.


