# projects

application_id: 11082967
project_number: 5F31EY034730-02
project_title: Optimizing c-Met signaling to enhance corneal epithelial homeostasis
administering_ic: NEI
award_notice_date: 2025-03-20
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: EY
serial_number: 034730
program_official: AGARWAL, NEERAJ
project_start_date: 2024-04-04
project_end_date: 2025-08-08
study_section: Special Emphasis Panel[ZRG1-F05-Q(20)L]
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
arra_indicator: N
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;Health Care;Homeostasis;Human;Human body;In Vitro;Incidence;Infection;Infectious Agent;Inflammation;Inflammation Mediators;Inflammatory;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;Pharmacotherapy;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;quality of life improvement;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: 11082845
project_number: 3G08LM014412-01S1
administering_ic: NLM
award_notice_date: 2024-09-18
opportunity_number: PA-20-272
application_type: 3
activity_code: G08
ic: LM
serial_number: 014412
suffix: S1
program_official: YOON, SUNG SUG
project_start_date: 2024-01-01
project_end_date: 2026-12-31
contact_pi_person_id: 11808630
contact_pi: WHITE, BRANDI MICHELLE
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-01-01
project_title:
Administrative Supplement to Modify Culturally-Relevant Recipes for Low-Income African American Women

project_abstract:
Hypertension affects 122.4 million Americans and African American (AA) women have significantly higherhypertension estimates (58.4%) compared to White (42.6%) Asian (37.6%) and Hispanic (35.3%) womenresulting in a disproportionate burden of cardiovascular disease (CVD). In the parent G08 study for thisadministrative supplement DASH-ing to Heart Health: Supporting low-income African American women withan interactive Meals that Heal resource book we proposed creating a useful and usable resource Meals thatHeal that increases awareness/knowledge of hypertension and improves ease of following a DASH diet byproviding culturally-relevant and low-cost DASH recipes that low-income African American women can utilizewhen making heart-healthy food choices. DASH recipes in the parent award were compiled from existing peer-reviewed publications and government academic and professional organizations. Although the DASH (DietaryApproaches to Stop Hypertension) diet has been shown to significantly reduce the risk of hypertension andother cardiovascular disease risk factors we found that low-income AA women such as those who live inpublic housing and who may be at the highest risk for hypertension because of poor social determinants ofhealth lack sufficient health information on how to feasibly follow this DASH diet. To preserve the project'soverall impact of reaching the full spectrum of AA populations we propose new research aims in thissupplement to develop new culturally relevant low-cost DASH recipes. In addition the parent award recruitedstudy participants from a public housing community in central Kentucky limiting the generalizability (externalvalidity) of the Meals that Heal resource. In this supplement we will increase our findings' generalizability byrecruiting study participants from additional public housing in a large Midwestern city with similarsociodemographic characteristics. The aims of this supplemental request are to: (1) identify preferred culturally-relevant recipes of low-income AA women by conducting qualitative interviews; (2) modify the culturally relevantrecipes to follow DASH guidelines and fit within a financially constrained food budget; and (3) evaluate theeffectiveness of Meals that Heal with the modified culturally relevant low-cost DASH recipes at increasingDASH knowledge and the likelihood of using DASH recipes among low-income AA women. This supplementalproject is significant because the findings will increase the availability of culturally relevant and low-cost DASHrecipes for a health disparity population and increase the generalizability of Meals that Heal. This knowledgecan improve adherence to the DASH diet and the effectiveness of existing interventions which is critical toreducing hypertension disparities. Specifically the results of this supplemental project will allow future studiesto identify evidence-based strategies to reduce blood pressure and hypertension risk.

project_terms:
Accounting;Adherence;Administrative Supplement;Adopted;Affect;African American;African American Women;African American population;American;Asian;Awareness;Behavioral;Books;Budgets;Cardiac health;Cardiovascular Diseases;Characteristics;Chicago;Cities;Communities;Complex;DASH diet;Data;Diet;Diet Modification;Disparity;Economics;Educational workshop;Effectiveness;Financial Hardship;Food;Future;Goals;Government;Guidelines;Health;Health Care Costs;Health Food;Healthy Eating;Heart;Hispanic;Hypertension;Information Resources;Intervention;Interview;Kentucky;Knowledge;Low income;Marketing;Methods;Outcome;Outcome Study;Parents;Participant;Pathway interactions;Peer Review;Persons;Professional Organizations;Psychosocial Stress;Public Housing;Publications;Recipe;Research;Resources;Risk;Risk Factors;Risk Reduction;Social Environment;Subgroup;United States National Library of Medicine;Woman;Work;adherence rate;blood pressure reduction;built environment;cardiovascular disorder risk;community engaged approach;community organizations;cooking;cost;effectiveness evaluation;evidence base;food insecurity;healing;health disparity populations;high risk;improved;lifestyle intervention;meetings;modifiable risk;parent project;preservation;prevent;racial discrimination;recruit;social health determinants;sociodemographics;usability

public_health_relevance:
This supplemental project will increase the availability of culturally relevant and low-cost DASH (DietaryApproaches to Stop Hypertension) for low-income African American (AA) women and increase thegeneralizability of a targeted useful and usable interactive health information resource. Community-engagedapproaches will be used to identify culturally preferred recipes and modify them into low-cost DASH recipeswith AA women living in two low-income AA communities. Modified DASH recipes will be included in the healthinformation resource and marketed to a broader audience through existing community-based partnerships andnetworks.


application_id: 11082418
project_number: 5T35DK072923-20
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2025-06-05
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;student research;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: 11081793
project_number: 5F30NS124136-04
administering_ic: NINDS
award_notice_date: 2025-04-25
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: 2025-05-09
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: 2025-05-08
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;insight;molecular phenotype;multidisciplinary;multiple omics;neuroimaging;neuropathology;new therapeutic target;old age;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: 11081782
project_number: 5R01AG072728-03
project_title: Emerging Role of Tau Citrullination During Alzheimers disease and Tauopathies
administering_ic: NIA
award_notice_date: 2025-04-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 072728
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2021-05-01
project_end_date: 2027-04-30
study_section: Special Emphasis Panel[ZRG1-MDCN-R(03)M]
contact_pi_person_id: 9300523
contact_pi: LEE, DANIEL CARL
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:
Emerging Role of Tau Citrullination During Alzheimers disease and TauopathiesHuman tauopathies are a group of neurological disorders including Alzheimers disease (AD) for which nodisease modifying therapies exist. Tau proteinopathic phenotypes show a spectrum of pathological hallmarksand clinical syndromes. There is increasing recognition that post-translational modifications (PTMs) promotestrain or conformational assemblies that contribute to tauopathies signifying a need to understand how novelPTMs contribute to tauopathy risk. Protein citrullination (citR) induced by peptidyl arginine deiminases (PADs)leads to an irreversible PTM that alters protein structure/ function by neutralizing positively charged arginineresidues within proteins. We discovered that aberrant tau activates PAD4 in neurons (protein PAD4 genePADi4); tau is client of PAD4 and is citrullinated at 14 arginine residues and those changes are associated withreduced tau fibrillization; citR prevents tau phosphorylation of key epitopes and impacts tau clearance; and taucitR is elevated in AD and in animal models of tauopathy. Our central hypothesis argues that increased PAD4-induced tau citR prevents higher-order fibrillization which decreases tangle formation alters tau metabolismimpacts structure/ function and reduces seeding activity. Assumptions of this model will be tested in vivo and invitro by neuronal PADi4 overexpression and conditional knockout mice multiple biochemical techniqueselectrophysiologic and behavioral approaches. We will establish how neuronal PADi4 expression impacts tauneuropathologic changes. Aim 1 will advance our understanding for PADi4 gain/ loss of function to establish thefoundation for citR tau biology and the impact on behavior in different models of tauopathy. We will establishhow citR regulates tau biochemistry and biology in cellular models. Aim 2 will mechanistically determine howPAD4-induced citR tau alters tau clearance aggregation seeding and microtubule binding. We will establish thespatio-temporal signature of citR tau in common human tauopathies. Aim 3 will provide the qualitative frameworkand seeding activity of citR tau in common human tauopathies. The proposed work provides the necessaryfoundation in not only better characterizing the role of citR in tauopathies but also further establishing the firstmechanistic cause for loss and gain of function of PAD4 during tau pathogenesis. Overall our applicationdescribes a new tau PTM and provide a therapeutic strategy for a new pathway in tau biology and in AD.

project_terms:
Affect;Age;Alzheimer's Disease;Amino Acid Substitution;Animal Model;Animals;Area;Arginine;Arginine deiminase;Behavior;Behavioral;Binding;Biochemical;Biochemistry;Biology;Biosensor;Cell model;Cells;Charge;Client;Clinical;Cognition;Disease;Electrophysiology (science);Epitopes;Fostering;Foundations;Genes;Goals;Human;Impaired cognition;In Vitro;Knock-out;Knockout Mice;Knowledge;Long-Term Potentiation;Metabolism;Microdialysis;Microtubule Polymerization;Microtubules;Modeling;Molecular Conformation;Molecular Target;Mus;Nerve Degeneration;Nervous System Disorder;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurons;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phenotype;Phosphorylation;Play;Polymers;Post-Translational Protein Processing;Proteins;Research;Risk;Role;Site;Structure;Syndrome;Tauopathies;Techniques;Testing;Therapeutic;Tissues;Tubulin;Work;age related;aging related;cell type;conditional knockout;conformer;dimer;extracellular;gain of function;improved;in vivo;in vivo evaluation;loss of function;monomer;neurofibrillary tangle formation;neuropathology;novel;overexpression;polymerization;prevent;protein structure;spatiotemporal;tau Proteins;tau aggregation;tau function;tau interaction;tau-1

public_health_relevance:
Tauopathies consist of a group of neurodegenerative diseases including Alzheimers disease(AD) and currently no therapeutic treatments exist for tauopathies. Post-translationalmodifications (PTMs) of tau are thought to play important mechanistic roles and could serve as atarget strategy. This study will test how the citrullination pathway of tau impacts tau biology andneuropathology in vitro and in vivo which may provide a new foundation for citrullination duringtauopathies and AD.


application_id: 11081053
project_number: 5P20GM103436-25
project_title: Data Science Core
administering_ic: NIGMS
award_notice_date: 2025-06-02
opportunity_number: PAR-23-100
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2029-04-30
study_section: ZGM1-RCB-9
subproject_number: 9167
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC 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:
Data Science Core Summary The Data Science Core for Biomedical Research (DSC) based at the University of Louisville HealthScience Campus and the University of Kentucky consists of several components designed to strengthen theresearch capacity of researchers and build upon data science training for faculty staff and students at primaryundergraduate institutions (PUIs) within the larger KY INBRE network. Components of the DSC include theBioinformatics Training and Education Center (BTEC) Genomics Training and Education Center (GTEC) ImageTraining and Education Center (ITEC) and the Predictive Analytics and Data Science (PADS) Hub that worktogether with the University of Louisville Bioinformatics Core (BC) and Sequencing Technology Center (STC).In order to fulfill the mission of the DSC within the KY INBRE network seven specific aims have been establishedthat will (1) support the generation and analysis of genomic datasets from Illumina Pacific Biosciences andOxford Nanopore sequencing technologies; (2) provide hands-on training in imaging genomics andbioinformatic technologies; (3) provide expertise on experimental design and usage of appropriate statisticalmethodologies; (4) aid in the integration of publicly available data from resources such as dbGAP GTExGenome Data Commons The Cancer Genome Atlas and ENCODE; (5) provide workshops for undergraduatesgraduates staff and faculty; (6) support data science initiatives at PUIs; and (7) provide PUI access to scientificcores in IDeA states across the southeast region.

project_terms:
Address;Applications Grants;Area;Artificial Intelligence;Bioinformatics;Bioinformatics core;Biological Sciences;Biomedical Research;Centers of Research Excellence;Cloud Computing;Computer software;Core Facility;Data Commons;Data Science;Data Science Core;Data Scientist;Development;Educational workshop;Equipment;Experimental Designs;Faculty;Funding;Funding Mechanisms;Generations;Genome;Genomics;Genotype-Tissue Expression Project;Health Sciences;Hybrids;Image;Image Analysis;Institution;Kentucky;Machine Learning;Manuscripts;Methodology;Mission;Participant;Postdoctoral Fellow;Predictive Analytics;Preparation;Research;Research Personnel;Research Support;Research Training;Resources;Sampling;Schedule;Students;System;Teacher Professional Development;Technology;The Cancer Genome Atlas;Training;Training and Education;Universities;Work;biomedical data science;data resource;database of Genotypes and Phenotypes;design;genomic data;graduate student;insight;interest;long-read sequencing;nanopore;nanopore sequencing;novel sequencing technology;primarily undergraduate institution;sequencing platform;single cell sequencing;sound;student research;summer research;symposium;undergraduate student;voucher


application_id: 11081049
project_number: 5P20GM103436-25
project_title: Developmental Research Project Program (DRPP)
administering_ic: NIGMS
award_notice_date: 2025-06-02
opportunity_number: PAR-23-100
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2029-04-30
study_section: ZGM1-RCB-9
subproject_number: 9166
contact_pi_person_id: 9258139
contact_pi: MATTINGLY, BRUCE 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:
Developmental Research Project Program SummaryThe overarching goals of the Developmental Research Project Program (DRPP) are: 1) to continue to increasebiomedical research capacity in Kentucky by assisting faculty at the primarily undergraduate institutions (PUIs)become competitive for independent NIH research funding and 2) to provide the highest quality research trainingto undergraduate students. To achieve these goals the DRPP provides training mentoring and researchfunding to PUI investigators to be successful in competing for new and competing renewal NIH R15 and/or R16awards. These two award mechanisms serve our dual purposes of supporting high quality faculty research whileproviding outstanding hands-on research experiences for undergraduate students. Modeled after NIH R15/R16application guidelines and review procedures the DRPP supports and manages two research fundingmechanisms (Pilot Project (PP) and Research Projects (RP)) from solicitation of proposals through scientificreview and approval. The DRPP also provides grant writing workshops one-on-one mentoring site-visits andother consulting services. While primarily aimed at early stage investigators the PP and RP grant mechanismsprovides support to productive investigators at all stages of career development. Complemented by otherresearch support and training programs provided by the Administrative and Data Science Cores the DRPP aimsto build a sustainable statewide biomedical research network.

project_terms:
Applications Grants;Award;Biomedical Research;Career Mobility;Core Facility;Data;Data Science;Data Science Core;Development;Discipline;Educational workshop;Eligibility Determination;Faculty;Funding;Funding Mechanisms;Goals;Grant;Guidelines;Infrastructure;Institution;K-Series Research Career Programs;Kentucky;Mentors;Modeling;Pilot Projects;Preparation;Procedures;Process;Productivity;Program Research Project Grants;Research;Research Personnel;Research Project Grants;Research Support;Research Training;Services;Site Visit;Students;Training;Training Programs;Underrepresented Populations;United States National Institutes of Health;Universities;Work;Workforce Development;Writing;career;career development;college;experience;faculty research;hands on research;primarily undergraduate institution;programs;research and development;research faculty;student research;success;training opportunity;undergraduate research experience;undergraduate student;undergraduate summer research


application_id: 11081042
project_number: 5P20GM103436-25
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2025-06-02
opportunity_number: PAR-23-100
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2029-04-30
study_section: ZGM1-RCB-9
subproject_number: 9165
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Administrative Core Summary The Administrative Core will provide leadership and direction to enable the KY INBRE network to growin a purposeful and managed way. The Administrative Core will provide oversight of the DevelopmentalResearch Project Program and Data Science Core and coordinate the activities of the governance committeesand overall network. In addition to this global management of the network the specific duties of theAdministrative Core will include management of programs to engage students in research recruit faculty withbiomedical research experience provide promising early career scientists with mentored research experiencesdevelop curricula that includes research and provide infrastructure support to the network. Specific duties ofthe Administrative Core also include management of the budget development of predictive financial plans andtracking and reporting outcomes. In the next funding cycle the Administrative Core will work with the other KYINBRE components to continue to build research capacity and develop a strong biomedical research workforcein KY. We propose to accomplish these goals via the following specific aims: (1) provide research experiencesfor students; (2) promote curriculum development in KY institutions; (3) recruit faculty with biomedical researchtraining and mentor early career scientists; (4) provide sound management of KY INBRE funds and ensurefinancial support of PUIs; and (5) evaluate the KY INBRE program and report outcomes.

project_terms:
Advisory Committees;Applications Grants;Biomedical Research;Budgets;Collaborations;Data Science Core;Development;Education;Educational Curriculum;Educational workshop;Ensure;Faculty;Faculty Recruitment;Financial Support;Funding;Geographic Distribution;Goals;Home;Infrastructure;Institution;Joints;Kentucky;Laboratory Research;Leadership;Manuscripts;Mentors;Outcome;Peer Review;Peer Review Grants;Population;Postdoctoral Fellow;Program Research Project Grants;Publications;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Research Training;Resource Sharing;Science;Scientist;Students;Teacher Professional Development;Training;Universities;Work;career;career development;curriculum development;equipment acquisition;experience;high school;meetings;primarily undergraduate institution;programs;recruit;research faculty;sound;student participation;symposium;undergraduate student


application_id: 11081041
project_number: 5P20GM103436-25
project_title: IDeA Networks of Biomedical Research Excellence in Kentucky
administering_ic: NIGMS
award_notice_date: 2025-06-02
opportunity_number: PAR-23-100
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
program_official: ZHOU, YANG
project_start_date: 2001-09-30
project_end_date: 2029-04-30
study_section: ZGM1-RCB-9(IN)
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
KY INBRE Overall Summary The Kentucky Institutional Development Award (IDeA) Network of Biomedical Research Excellence (KYINBRE) is a collaborative network of educational institutions working to build capacity for health-related andbiomedical research in the Commonwealth of Kentucky. The KY INBRE network is currently composed of 25institutions that are geographically distributed across the state of Kentucky. The partner institutions include 2research intensive universities and 7 primarily undergraduate institutions (PUIs). Another 16 PUIs participate inKY INBRE activities. The KY INBRE program is managed by 4 interactive components. The Administrative Coreoversees student research faculty recruitment curriculum development the budget and financial plan as wellas internal evaluation and reporting. The governance committees provide oversight evaluation and guidance toensure adherence of the KY INBRE to its mission in building research capacity across the state. TheDevelopmental Research Project Program provides research funding mentoring oversight and training toenable KY INBRE faculty to successfully compete for independent NIH funding. The Data Science Core provideseducation training and equipment access to assist investigators and trainees collect efficiently analyze andshare research data. In the next funding cycle these 4 components will work together to continue to buildbiomedical research capacity strengthen research culture develop faculty research careers and providestudents with research opportunities to help develop a strong biomedical research workforce in Kentucky. Wepropose to accomplish these goals with the following overall specific aims: 1) provide engaging researchexperiences to recruit KY undergraduate students into biomedical science majors/careers; 2) promote researchinfrastructure and curriculum development in KY institutions; 3) develop research skills of faculty and trainees tobuild research capabilities in KY; and 4) recruit faculty with biomedical research training and provide mentoredcareer development to build research capacity in KY institutions.

project_terms:
Adherence;Award;Biomedical Research;Budgets;Core Facility;Data;Data Analyses;Data Science;Data Science Core;Development;Diagnosis;Education;Ensure;Equipment;Evaluation;Faculty;Faculty Recruitment;Funding;Geography;Goals;Growth;Health;Health Care;Institution;Kentucky;Laboratory Research;Mentors;Mission;Oranges;Privatization;Program Research Project Grants;Recruitment Activity;Reporting;Research;Research Infrastructure;Research Personnel;Research Training;Science;Students;Technology;Training;Training and Education;United States National Institutes of Health;Universities;Work;career;career development;college;course development;curriculum development;data sharing;experience;faculty research;human disease;improved;infrastructure development;member;primarily undergraduate institution;programs;recruit;skills;student research;undergraduate research;undergraduate student

public_health_relevance:
Project NarrativeThe goals of the KY INBRE are to build capacity for biomedical research and provide training todevelop the research and healthcare workforce in the Commonwealth of Kentucky. These goalswill lead to the improved diagnosis and treatment of human diseases.


application_id: 11080815
project_number: 3R43HL169087-01A1S1
project_title: A breakthrough mobile phone technology that aids in early detection of COPD - TABA fund supplement
administering_ic: NHLBI
award_notice_date: 2024-05-15
opportunity_number: PA-20-272
application_type: 3
activity_code: R43
ic: HL
serial_number: 169087
suffix: A1S1
program_official: SHENOY, SIDDHARTH KAUP
project_start_date: 2024-06-01
project_end_date: 2024-09-14
contact_pi_person_id: 78826114
contact_pi: WOLFSON, DAVID
other_pis: Not Applicable
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: 2024-06-01
budget_end_date: 2024-09-14
project_abstract:
Project Summary / Abstract: This application is for TABA funds as a supplement to thefollowing phase I project.COPD is the fourth leading global killer in part because of the failure of frontline medicine todetect the disease. Poor early detection leads to unfavorable outcomes and high healthcarecosts. Tele-stethoscope* or TS is novel technology that allows acoustic data captured fromordinary mobile phones to perform robust analysis of hemodynamics and pneumodynamics.TS is intended to be used in primary care particularly in Tele-health and before scheduledphysical examination. Its purpose is to alert primary care physicians to the need for physicalexamination and possibly referral. In these situations there are no other comparable testingoptions.TS has three important innovations. First is a clinical use innovation which brings remoteimpromptu patient evaluation to anyone with a smartphone. Customer discovery has validatedboth a workflow and reimbursement strategy consistent with commercial success. FurtherFDA guidance suggests viability of agency clearance. Second is TSs novel approach tomaking AI algorithms. TS uses acoustic data captured by OEM phone microphones intorigorous physics-based features that describe organ hemodynamics and pneumodynamics.The features or independent variables are then used to create binary classification modelswith logistic regression. By relying on physics TS never has to use neural networks oroverfitting strategies that have raised concerns about data intensity model stability regulatorytransparency and unknown reliability. The third innovation is that by relying on passiveacoustic data TS classifies organ function by observing organ dynamics directly rather thanfrom forced air capacity. TS uses many ideas from physics that were not available until fairlyrecently. By relying on dynamics TS offers a novel approach to forced air that may eventuallybe additive to our understanding of respiratory conditions even in PFT labs.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 soon tobe published study on the ability of TS to reproduce echocardiogram estimates of ejectionfraction. Analysis of stethoscope recordings suggests that the COPD diagnostic will rely ona combination of right heart side hemodynamics and low frequency lung pneumodynamics. Asignificant body of research is presented which validates the use of mobile phones as anauscultation device with the ability to detect and diagnosis COPD.The Aim of this study is to develop evaluate and test an algorithm that allows ordinary mobilephones to detect COPD. Our hypothesis is that TS technology can detect COPD by matchingphone acoustic recordings to diagnosis. Diagnosis will be determined by a physician afterconsidering gold standard testing. Performance of the models will be evaluated by usingcommon statistical approaches such as area under the receiver operating curve AUCsensitivity specificity accuracy. The research will have 3 milestones based on recruitment of30 60 and 100 patients respectively.Our approach is based on recruitment from patients assigned to a hospital PFT lab so thatrecordings and gold standard testing are done concurrently. Our team consists of a broadrange of talent including the inventor of TS pulmonology expertise the research director ofemergency medicine for the hospital running the tests statistical expertise and projectmanagement.* Tele-stethoscope or "TS" is patent pending technology developed by Fleming Scientific.

project_terms:
Acoustics;Air;Algorithms;Area;Auscultation;COVID-19 detection;Cardiopulmonary;Cellular Phone;Chronic Obstructive Pulmonary Disease;Classification;Clinical;Data;Devices;Diagnosis;Diagnostic;Disease;EFRAC;Early Diagnosis;Echocardiography;Emergency Medicine;Evaluation;Failure;Frequencies;Funding;Health Care Costs;Heart;Hospitals;Image;Legal patent;Logistic Regressions;Lung;Lung Capacity;Medicine;Modeling;Organ;Outcome;Patient Recruitments;Patients;Performance;Phase;Physical Examination;Physicians;Physics;Primary Care;Primary Care Physician;Publishing;Pulmonology;Research;Research Support;Running;Schedule;Side;Specificity;Stethoscopes;Talents;Technology;Telephone;Testing;artificial intelligence algorithm;hemodynamics;human study;improved;improved outcome;innovation;microphone;neural network;new technology;novel;novel strategies;recruit;respiratory;success;technology development;telehealth

public_health_relevance:
The research supports development of technology that allows ordinary mobile phones to be usedto detect COPD in patients remotely. The intent is to improve early detection of the disease infrontline medicine thereby improving outcomes and lowering healthcare costs. The technology isscientifically important in that it relies on dynamics modeling rather than lung capacity evaluationor imaging and employs a novel rigorous approach to AI.


application_id: 11080747
project_number: 6U54OH007547-20M004
administering_ic: NIOSH
award_notice_date: 2024-04-25
opportunity_number: PAR-15-353
application_type: 6
activity_code: U54
ic: OH
serial_number: 007547
suffix: M004
program_official: DEARWENT, STEVE
project_start_date: 2016-09-30
project_end_date: 2022-09-29
study_section: ZOH1-EHG(01)
contact_pi_person_id: 8433958
contact_pi: SANDERSON, WAYNE T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Southeast Center for Agricultural Health and Injury Prevention: Enteric bacteria antibiotic resistance and farm worker health on livestock farms


application_id: 11078954
project_number: 2U01AA026980-06
project_title: Integrated therapies for alcohol use and ALD (ITAALD) Network -UofL Clinical Center
administering_ic: NIAAA
award_notice_date: 2024-09-18
opportunity_number: RFA-AA-24-004
application_type: 2
activity_code: U01
ic: AA
serial_number: 026980
program_official: GAO, PETER
project_start_date: 2018-08-01
project_end_date: 2029-06-30
study_section: Special Emphasis Panel[ZAA1 DD (05)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: SINGAL, ASHWANI K;STEWART, CHRISTOPHER M
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:
Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality/morbidity and there is noFDA-approved therapy for any stage of ALD. Advanced ALD conditions including severe alcohol-associatedhepatitis (sAH) and decompensated alcohol-associated cirrhosis (deAC) have especially poor outcomes.Indeed the 90-day mortality for sAH is ~30%. Return to drinking impacts quality of life and mortality in thesepatients. There are limited drug therapies or well-studied behavior therapies in this patient population. An optimalapproach would be the integration of AUD and ASLD care givers and therapies but there are no guidelines forthis approach. Our proposed AUD/ALD team approach seeks to overcome the perceived stigma of alcoholmisuse which can adversely affect treatment seeking quality of care and patient outcomes. The AlcHepNet studywas stopped at the interim analysis because of the unexpected 90% 90-day survival in sAH patients treated withprednisone using the Lille stopping rule. These dramatic results need to be confirmed and novel therapies suchas IL-22 need to be studied in sAH. Treatment with Lactobacillus rhamnosus GG (LGG) improved MELD scoreat 30 days and reduced drinking at 6 months in patients with moderate AH (e.g. novel AUD/ALD therapy).Acamprosate appears to be the safest FDA-approved therapy for AUD in patients with ALD but safety andefficacy in severe ALD need to be evaluated. Take Control is a novel computer-based behavioral platform derivedfrom the NIAAAs Rethinking Drinking. Based on preliminary data and identified gaps in knowledge our overallhypothesis is that an integrated management of ALD and AUD will improve clinical outcomes in patientswith sAH and decompensated ALD. This proposal will utilize the following AIMS:Aim 1. Perform a double-blind randomized controlled trial of treatment for steroid-eligible patients withsevere AH. A masked study comparing daily prednisone for 28 days (with the 7-day Lille score-based stop rule)vs. IL-22 fusion protein (F-652). Early intervention for AUD will include behavioral therapy platform (Take Control)in all subjects and either acamprosate or placebo before discharge from the hospital. The primary endpoint ofthe trial will be a composite measure of mortality liver and alcohol use related outcomes.Aim 2. Evaluate Lactobacillus rhamnosus GG (LGG) in patients with decompensated ALD cirrhosis. Inpatients with decompensated cirrhosis due to ALD in whom corticosteroids are not effective a randomizedplacebo-controlled trial of LGG in combination with Take Control and locally accepted SOC for 6 months will beperformed. A composite measure (as in AIM 1) at 6 months will be the primary end point for this AIM also.AIM 3. Build a platform for biosamples data repositories and patient registries to support site-specificand network-wide ancillary studies.In summary these proposed studies will leverage the existing resources of the AlcHepNet to evaluate the clinicalimpact of integrated ALD/AUD treatment in a diverse cohort of typically underserved patients.

project_terms:
Address;Adrenal Cortex Hormones;Affect;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Ancillary Study;Antimicrobial Effect;Antioxidants;Apoptotic;Behavior Therapy;Behavioral;Biological Specimen Banks;Caregivers;Chimeric Proteins;Cirrhosis;Clinical;Clinical Data;Clinical Treatment;Clinical Trials;Collaborations;Collection;Combined Modality Therapy;Compensation;Computers;Data;Databases;Diagnosis;Double-Blind Method;Early Intervention;Eligibility Determination;Evaluation;FDA approved;Funding;Glucocorticoids;Guidelines;Health Personnel;Heavy Drinking;Hospitals;Individual;Informatics;Interleukin-1 Receptors;Knowledge;Lactobacillus casei rhamnosus;Link;Liver;Liver diseases;Masks;Measures;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Observational Study;Outcome;Patient Preferences;Patient-Focused Outcomes;Patients;Pattern;Pharmacotherapy;Phase;Phosphatidylethanolamine;Physicians;Placebos;Prednisone;Quality of Care;Quality of life;Randomized;Randomized Controlled Trials;Regression Analysis;Reporting;Research Design;Research Personnel;Resource Allocation;Resources;Safety;Site;Steroids;Systems Biology;Testing;Thinking;Translational Research;Transplantation;Zinc;acamprosate;alcohol abstinence;alcohol abuse therapy;alcohol misuse;alcohol use disorder;anakinra;antagonist;behavioral study;care outcomes;catalyst;clinical center;cohort;data repository;drinking;evidence base;group counseling;healthy volunteer;improved;interleukin-22;longitudinal database;meetings;mortality;new therapeutic target;novel;novel therapeutics;open label;optimal treatments;patient population;patient registry;placebo controlled trial;primary endpoint;prospective;randomized placebo controlled trial;social stigma;standard of care;translational study;treatment strategy

public_health_relevance:
Project Narrative: Alcohol-associated liver disease (ALD) is a leading cause of mortality/morbidity; yet there isno FDA-approved therapy for any stage of ALD and patients with ALD rarely have their underlying alcohol usedisorder (AUD) concomitantly addressed. This consortium links health care providers with expertise in AUD andALD in a unified treatment strategy to evaluate novel combined treatments for AUD/ALD in patients withadvanced ALD. The existing resources of the NIAAA-funded AlcHepNet are used for patient studiesbiospecimen collection and site-specific translational studies.


application_id: 11078849
project_number: 5R01AG079525-04
project_title: The impact of insulin sensitivity on the potential of metformin to delay age-related inflammation
administering_ic: NIA
award_notice_date: 2025-03-26
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: 2027-04-30
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 delay;aging related;arm;clinical practice;cytokine;glycemic control;healthspan;improved;inflammatory marker;insight;insulin sensitivity;life span;predictive modeling;primary endpoint;promote healthspan;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: 11078696
project_number: 5R01HL163977-04
project_title: Data-driven optimization of therapy for heart failure
administering_ic: NHLBI
award_notice_date: 2025-04-04
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: 2027-04-30
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;Arteries;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: 11078393
project_number: 3K23AG075262-03S1
administering_ic: NIA
award_notice_date: 2024-08-14
opportunity_number: PA-20-272
application_type: 3
activity_code: K23
ic: AG
serial_number: 075262
suffix: S1
program_official: RIDDLE, MELISSA
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: Career Development for Clinicians/Health Professionals Study Section [AGCD-3]
contact_pi_person_id: 16198324
contact_pi: RHODUS, ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Improving Person-Environment Fit of Community-Residing Older Adults with Dementia Through Assessment and Individualized Intervention

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

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

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


application_id: 11078346
project_number: 5R01HL168294-03
administering_ic: NHLBI
award_notice_date: 2025-04-25
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: 2025-04-01
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;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;pulmonary;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: 11078238
project_number: 5R01DK135603-02
project_title: AHR-NLRP6 interactions in gut barrier dysfunction and colitis
administering_ic: NIDDK
award_notice_date: 2025-08-28
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 135603
program_official: SHEA-DONOHUE, TEREZ
project_start_date: 2024-05-01
project_end_date: 2028-04-30
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_abstract:
Abstract:Inflammatory Bowel Diseases (IBD) which consist of ulcerative colitis and Crohns disease affect as many as1.4 million people in the USA. Intestinal barrier dysfunction is one of the hallmarks associated with IBD. Currentlythere are no treatments available to target gut barrier dysfunction in IBD pathogenesis. The aryl hydrocarbonreceptor (AHR) is a transcription factor expressed in several cell types and is activated by a variety of exogenousand endogenous ligands including microbial metabolites. Activation of AHR regulates many pathophysiologicalfunctions including inflammation and gut barrier integrity. Recently we identified that the microbial metaboliteUrolithin A (UroA) is an AHR ligand that enhances gut barrier function. Treatment with UroA mitigated colitis inpre-clinical models. This proposal originated from the novel observation that selective activation of AhR by UroAin intestinal epithelial cells (IEC) is critical for the regulation of gut barrier function. This process requiresactivation of the NLRP6-IL-18 pathway in IEC to induce IL-22 from type 3 innate lymphoid cells (ILC3).Furthermore we identified that UroA-induced genes are responsible for goblet cell differentiation leading toincreased mucins and enhanced gut barrier function. In this proposal we will test the hypothesis that UroAselectively activates the AHR-NLRP6-dependent secretion of homeostatic levels of IL-18 in IEC leading to highlydifferentiated goblet cells that enhance gut barrier function reduce unwarranted inflammation and mitigate IBD.We propose three specific aims to test this hypothesis. Aim 1 will determine the role of each component of theAHR-NLRP6-IL-18/IL-22 axis in UroA-mediated protective activities against IBD pathogenesis using pre-clinicalmodels of colitis. We will establish the novel cross-talk mechanisms of IEC selective activation of AHR-NLRP6pathways that regulate IL-18 and IL-18 dependent IL-22 production from ILC3. In Aim 2 we will examine themechanisms of UroA-mediated goblet cell differentiation and production of different types of mucus that enhancegut barrier function. Aim 3 will establish the translational relevance of selective activation of IEC AHR-IL-18pathway by UroA in human IBD patient samples. Upon completion of this study the mechanisms and beneficialeffects of selective activation of the AHR-NLRP6-IL-18 axis to enhance gut barrier function and the therapeuticimplications in IBD will be established.

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

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

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


application_id: 11078233
project_number: 5R01DA058933-03
project_title: Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal
administering_ic: NIDA
award_notice_date: 2025-04-17
opportunity_number: RFA-DA-23-015
application_type: 5
activity_code: R01
ic: DA
serial_number: 058933
program_official: VEMURI, KIRAN R V
project_start_date: 2023-06-15
project_end_date: 2028-04-30
study_section: ZDA1-SKM-N(M2)R
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: HINDS, TERRY D
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTPrescription and illicit opioid use have risen to a public health crisis with the landscape shifting to fentanyl use.Given that fentanyl is 100-fold more potent than morphine its use is associated with a higher risk of fataloverdose. Naloxone (Narcan) reverses opioid overdose and precipitates withdrawal. However recent reportsindicate that xylazine an anesthetic that is increasingly detected in accidental fentanyl overdose deaths hasbecome a highly sought-after adulterant that can prolong both the fentanyl high and the onset of fentanylwithdrawal as well as precipitate resistance to naloxone in the reversal of overdose. Despite this no systematicstudies to date have evaluated the neurobehavioral mechanistic contributors to these effects. While opioidpharmacological mechanisms of action have been studied it is not clear how the addition of xylazine to fentanylinhibits the actions of naloxone as either alone does not have this action. Excitingly we have possibly discoveredthe mechanisms of how xylazine combined with fentanyl causes resistance to naloxone using our State-of-the-Art PamGene PamStation technology that measures hundreds of kinase activities in a single sample. We showpreliminary data for the signaling pathways in the nucleus accumbens core (NAcore) that are hyper- or hypo-active which gives us numerous potential targets for reversing naloxone resistance and xylazines effects onfentanyl self-administration (SA). We hypothesize that the xylazine-fentanyl combination activates non-canonical pathways that reduce consumption and prolong the onset of fentanyl withdrawal signs. Our objectivehere is to uncover these unknown mechanisms using our PamGene technology and determine how these impactneurocircuitry and behavior. Therefore we will test these in our following Aims: 1) Determine how xylazineimpacts the effects of fentanyl 2) Determine viable therapeutic targets to resensitize fentanyl withdrawalfollowing the escalation of xylazine-fentanyl SA and 3) Determine neural circuits altering the NAcore and ventraltegmental area (VTA) kinomes following the escalation of xylazine-fentanyl SA and if these underlie naloxoneresistance. We will map the active kinome of the NAcore and VTA following xylazine-fentanyl co-use and willtest novel treatment targets that we find are changed via our extensive analysis. We will further test if theseneural circuits contribute to co-use-induced alterations in targets that we have identified from our PamGeneanalysis and thus we will determine if suppressing these circuits may enhance the actions of naloxone andrestore neural targets altered by xylazine-fentanyl co-use (measured via kinome analysis). Together thesehypothesis-driven studies will markedly enhance our understanding of the neurobehavioral mechanismsunderlying xylazine-fentanyl polysubstance use and withdrawal and will likely reveal novel treatment strategiesfor reversing the xylazine-fentanyl-induced naloxone inefficacy.

project_terms:
Accidents;Adrenergic Agents;Affect;Agonist;Anesthetics;Behavior;Biological Assay;Brain;CSF1R gene;Clinical;Consumption;Data;Disinhibition;Dopamine;Dose;Drug Combinations;Drug usage;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Event;FDA approved;Fentanyl;Future;Heroin;Hyperactivity;Impact evaluation;Individual;Maps;Measures;Morphine;Naloxone;Neurobiology;Nucleus Accumbens;Opioid;Opioid Receptor;Overdose reversal;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Precipitation;Public Health;Rattus;Reporting;Research;Resistance;Rewards;Sampling;Self Administration;Signal Pathway;Signal Transduction;Technology;Testing;Therapeutic;Urine;Ventral Tegmental Area;Western Blotting;Withdrawal;Xylazine;behavioral phenotyping;fentanyl overdose;fentanyl self-administration;fentanyl use;genetic manipulation;high risk;high risk population;illicit opioid;improved;lofexidine;manufacture;neural;neural circuit;neurobehavioral;neuromechanism;novel;opioid overdose;opioid use;opioid withdrawal;overdose death;pharmacologic;polysubstance use;prescription opioid;prevent;receptor;response;therapeutic target;treatment strategy

public_health_relevance:
PROJECT NARRATIVE Prescription and illicit opioid use have been recognized as a public health crisis and heroin is beingrapidly replaced with illicitly-manufactured fentanyl. Xylazine a veterinary anesthetic is being used as anadulterant in fentanyl use and this pattern of polysubstance use renders naloxone ineffective at precipitatingwithdrawal and thus reversing overdose. The proposed research has the potential to not only uncover novelneurobehavioral mechanisms by which xylazine and fentanyl polysubstance use uniquely alter the rewardpathway behavior and render naloxone unable to precipitate withdrawal but will also identify and targetmechanisms to reverse these effects.


application_id: 11077863
project_number: 5P20GM148326-03
administering_ic: NIGMS
award_notice_date: 2025-05-07
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: 2025-03-01
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;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 pathology;neurovascular unit;novel;oxidative damage;primary outcome;protective efficacy;repaired;response;restoration;small molecule;therapeutic development;therapeutic target


application_id: 11077861
project_number: 5P20GM148326-03
project_title: Identifying Metabolomic Markers in Conversion to Cognitive Impairment in Parkinson's Disease
administering_ic: NIGMS
award_notice_date: 2025-05-07
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;Health Care Costs;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: 11077856
project_number: 5P20GM148326-03
project_title: CNS-Met Metabolomics Core
administering_ic: NIGMS
award_notice_date: 2025-05-07
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: 8908
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
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:
Neurological disorders and central nervous system (CNS) injuries show clear metabolic defects which inturn disrupts bioenergetics balances redox status and neurotransmitter biosynthesis that are required formaintaining synaptic activity neuronal homeostasis and neuroinflammation. For these reasons CNSmetabolism research has generated interest from those studying Alzheimers disease traumatic brain injuryepilepsy spinal cord injury Parkinsons disease and others. Modern metabolomics allows for the profiles ofhundreds of metabolites from a single sample. It is both informative and transformative supports bothhypothesis-generating and hypothesis-driven research. Current applications of metabolomics includemolecular basis of metabolic diseases biomarker discovery disease prediction drug responses andpersonalized medicine. The overarching goal of the CNS-Met Metabolomics Core is to make cutting-edge metabolomics andmitochondrial energetics techniques and analyses available to CNS-Met Research Project Leaders (RPL) andpilot project PIs. The available expertise and instrumentation are well-aligned with the RPL proposals. The coredirectors have worked with each RPL to generate exciting preliminary data. The core will engage with assist inexperimental design run samples train personnel and analyze brain metabolism data. The CNS-MetMetabolomics Core will support the talented RPLs in the area of CNS metabolism and enhance their successin competing for NIH R-level grants. To achieve these goals the core will Aim 1: Provide experimental design consultation and project-specificstudy planning. The core has worked closely with the RPLs and will continue to do so on experimental designdata processing and biostatistical analyses. Proper experimental design and sample preparation will lay thefoundation for a successful metabolomics experiment. Aim 2: Provide metabolomics expertise and training.The core will house an Agilent 5977B GCMS 2) Agilent 6545 quadrupole time of flight LC/CE-QTOF and 3) aSeahorse Biosciences XF24e and XFe96 Flux Analyzers as well as Oroboros O2KFluorometer. The core willrun samples assist train and/or supervise data analysis from basic data reduction incorporating proceduralcontrol normalization pathway ontology matching data interpretation and offer possible next steps. Aim 3:Perform sample processing technical analyses and data reduction-interpretation-presentation. The core willassist users by performing sample preparation instrument operation mass spectrometry peak matching tometabolites with a known compound library sample normalization and statistical analyses. The core will utilize integrated processes established by core leadership from experimental design thoughrapid and consistent sample acquisition sample fixation sample extraction data reduction statistical analysisdata analysis and biological interpretation to ensure the success of the CNS-Met RPLs and pilot project PIs.

project_terms:
Address;Alzheimer's Disease;Area;Behavior;Biochemical;Biochemical Pathway;Bioenergetics;Biological;Biological Sciences;Biomass;Biometry;Brain;Cells;Centers of Research Excellence;Central Nervous System;Cerebrum;Cognition;Communication;Consult;Consultations;Data;Data Analyses;Defect;Diagnosis;Disease;Ensure;Epilepsy;Experimental Designs;Fostering;Foundations;Freezing;Future;Generations;Genus Hippocampus;Glucose;Goals;Grant;Homeostasis;Human Resources;Individual;Infrastructure;Kentucky;Leadership;Libraries;Mass Fragmentography;Mass Spectrum Analysis;Measures;Memory;Mentorship;Metabolic;Metabolic Diseases;Metabolism;Methods;Mitochondria;Modernization;Molecular;Nervous System Disorder;Neurons;Ontology;Output;Oxidation-Reduction;Parkinson Disease;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Pilot Projects;Preparation;Process;Research;Research Personnel;Research Project Grants;Running;Sampling;Scientist;Spinal cord injury;Statistical Data Interpretation;Sustainable Development;Synapses;Talents;Techniques;Technology;Testing;Time;Tissue Microarray;Tissue Sample;Tissues;Training;Training and Education;Traumatic Brain Injury;Treatment outcome;United States National Institutes of Health;Universities;Work;biomarker discovery;brain metabolism;career development;central nervous system injury;clinical translation;cohort;computerized data processing;data acquisition;data reduction;defined contribution;design;disease prognosis;experimental study;glucose metabolism;improved;instrument;instrumentation;interest;mass analyzer;member;metabolome;metabolomics;mitochondrial metabolism;monomer;multidisciplinary;neuroinflammation;neurotransmitter biosynthesis;operation;personalized medicine;prospective;response;sample fixation;skills;skills training;success


application_id: 11077852
project_number: 5P20GM148326-03
project_title: CNS-Met Administrative Core
administering_ic: NIGMS
award_notice_date: 2025-05-07
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: 8907
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  ADMINISTRATIVE CORE  Research in CNS metabolism has garnered interest from many fields including Alzheimers Disease brain injury (including traumatic injury stroke etc) epilepsy and Parkinsons Disease and likely involves all areas of CNS-related research. The University of Kentucky College of Medicine has made significant investments over the last few years in both metabolomics instrumentation and investigators with metabolomics expertise that enhanced existing UK strengths in neuroscience cancer cardiovascular and diabetes & obesity research. The objective of this application is to create an NIH Center of Biomedical Research Excellence (COBRE) in CNS Metabolism (CNS-Met). This proposal builds on existing strengths at UK as well as strengths of both the senior and junior investigators in brain physiology neuropathology and CNS metabolism. The CNS-Met Administrative Core (Admin Core) will coordinate communication and access among the CNS-Met groups the above-mentioned metabolism-centric research programs and other existing UK strengths as well as core facilities established by other UK COBREs to support a multidisciplinary team-based program that trains the next generation of faculty focused on brain metabolism. The CNS-Met Administrative Core is directed by Dr. Matthew Gentry and co-directed by Dr. Patrick Sullivan senior scientists with complementary expertise in CNS metabolism and demonstrated leadership skills. The Core will ensure and provide effective coordination and oversight of research projects research cores usage and service general infrastructure administrative and fiscal matters. It will provide robust and timely financial management and will facilitate internal communication between CNS-Met constituents. It will be responsible for coordinating the recruitment of future research project leaders and mentors and for managing and implementing pilot program funding. The Admin Core will do all of these activities while ensuring that CNS-Met activities are in compliance with federal regulations. The overarching goal of the CNS-Met Administrative Core is to deliver administrative fiscal and scientific leadership and center-wide coordination to COBRE Research Project Leaders their mentors research core and other COBRE-supported investigators. To achieve these goals the core will: 1) Coordinate operational and fiscal management infrastructure and program planning and communication processes across all COBRE components.; and 2) Facilitate and coordinate research training mentoring and career development activities for early-stage investigators in brain metabolism research; 3) Implement a pilot studies program to seed new research across neuroscience research thrusts; and 4) Provide effective formative and summative assessment of COBRE projects and activities of the CNS-Met group.

project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Area;Biology;Biomedical Research;Brain;Brain Injuries;Cardiovascular Diseases;Cardiovascular system;Centers of Research Excellence;Central Nervous System;Collaborations;Committee Members;Communication;Core Facility;Data Science;Dedications;Diabetes Mellitus;Disease;Ensure;Epilepsy;Evaluation;Faculty;Fostering;Funding;Glucose;Goals;Homeostasis;Human Resources;Infrastructure;Interdisciplinary Study;Investments;Kentucky;Laboratories;Leadership;Life;Malignant Neoplasms;Medicine;Mentors;Metabolism;National Institute of General Medical Sciences;Nervous System Disorder;Neurons;Neurosciences;Neurosciences Research;Obesity;Occupational activity of managing finances;Parkinson Disease;Physiology;Pilot Projects;Process;Regulation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Resources;Role;Schedule;Scientist;Senior Scientist;Services;Specific qualifier value;Stroke;Structure;Synapses;System;Techniques;Training Programs;Traumatic brain injury related dementia;Traumatic injury;United States National Institutes of Health;Universities;brain metabolism;career;career development;collaborative environment;college;defined contribution;experience;faculty mentor;infrastructure development;innovation;instrumentation;interest;knowledge translation;meetings;metabolomics;metabolomics resource;mitochondrial metabolism;multidisciplinary;neural;neuroinflammation;neuropathology;neurotransmission;next generation;novel;operation;programs;recruit;senior faculty;skills;spinal cord and brain injury;stable isotope;synergism;tumor metabolism


application_id: 11077851
project_number: 5P20GM148326-03
project_title: Center of Biomedical Research Excellence in CNS Metabolism
administering_ic: NIGMS
award_notice_date: 2025-05-07
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;TDP43 proteinopathy;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;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: 11077812
project_number: 5R34DA060087-02
administering_ic: NIDA
award_notice_date: 2025-04-22
opportunity_number: PA-21-205
application_type: 5
activity_code: R34
ic: DA
serial_number: 060087
program_official: JENKINS, RICHARD A
project_start_date: 2024-05-01
project_end_date: 2027-04-30
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-05-01
project_title:
Optimizing Low Threshold TelePrEP Care in Syringe Service Programs for People who Inject Drugs in Appalachia

project_abstract:
ABSTRACTKentucky (KY) is a high priority Ending the HIV Epidemic (EHE) jurisdiction due to heavy rural HIV burden andexceptionally high rates of new HIV diagnoses driven by injection drug use (IDU). Despite ongoing need forrobust HIV prevention and the strong evidence for Pre-Exposure Prophylaxis (PrEP) uptake remains severelylimited among people who inject drugs (PWID). PWID are notably impacted by structural challenges thatimpede entry and retention in PrEP care including poverty and unstable housing violence social isolationand stigma; in rural and remote areas including Appalachia limited healthcare access and a dearth of PrEPproviders further constrain access to PrEP along geographic boundaries. An interim assessment of EHEprogress notes that PrEP coverage remains well below threshold to reach established EHE targets and setsout broad policy recommendations to enhance PrEP access by engaging people where they are. ForPWID in particular there is broad scientific consensus that PrEP efforts be intensified and intentional insupporting low threshold PrEP access. The proposed R34 will leverage KYs robust harm reductioninfrastructure to develop integrate and test a low threshold peer-facilitated TelePrEP intervention forAppalachian PWID in syringe service programs (SSPs) that operate within PrEP deserts filling a critical needto implement innovative approaches that mitigate geographic disparities in PrEP access. The PIs ongoingresearch and existing partnerships with local health department SSPs in Appalachian KY have demonstratedthat PWID have low PrEP awareness and social determinant barriers to PrEP uptake yet interest in PrEP ishigh at 73%. Building on this existing work we will conduct a pilot randomized trial to examine efficacy onPrEP initiation (measured by dispensed PrEP prescription) and retention in PrEP care 3- and 6- months post-baseline (measured by self-report and biomarker confirmation) as well as implementation outcomes guided bythe Implementation Outcomes Framework. The Specific Aims are to: 1) Collaborate with the Clark CountyHD (CCHD) and Kentucky River District HD (KRDHD) harm reduction communities to develop the optimalcontent delivery structure and implementation strategies for the peer-facilitated TelePrEP intervention inSSPs and rapidly manualize the novel low threshold protocol; 2) Conduct a pilot randomized trial to evaluatethe preliminary efficacy of: a) peer-facilitated integrated TelePrEP; compared with b) peer-delivered PrEPeducation and referral on PrEP initiation and persistence among Appalachian PWID; and 3) Examinefeasibility acceptability appropriateness and fidelity implementation outcomes of the two interventioncomparators among PWID participants and partner harm reduction staff using a mixed methods approach.The proposed study will establish preliminary evidence and proof-of-concept for an integrated low-thresholdTelePrEP intervention for Appalachian PWID which is designed to increase PrEP initiation and persistence.

project_terms:
AIDS prevention;Appalachian Region;Area;Awareness;Biological Markers;Caring;Collaborations;Communities;Consensus;County;Data;Disease Outbreaks;Drug user;Education;Epidemic;Frequencies;Geography;HIV;HIV Infections;HIV diagnosis;Harm Reduction;Health;Health Personnel;Indiana;Infrastructure;Injecting drug user;International AIDS;Intervention;Kentucky;Manuals;Measures;Methods;Needle-Exchange Programs;North Carolina;Participant;Patient Self-Report;Persons;Population;Poverty;Prevention;Protocols documentation;Provider;Recommendation;Reporting;Research;Rural;Site;Social isolation;Societies;Stigmatization;Structure;Testing;Time;Violence;West Virginia;Work;access disparities;care systems;design;efficacy evaluation;experience;geographic disparity;health care availability;housing instability;implementation fidelity;implementation outcomes;implementation strategy;improved;injection drug use;innovation;interest;medical specialties;men;novel;novel strategies;peer;peer support;point of care;point of care testing;policy recommendation;pre-exposure prophylaxis;randomized trial;rural area;scale up;social determinants;social stigma;telehealth;traditional care;transmission process;uptake;women's diagnosis

public_health_relevance:
PROJECT NARRATIVEKentucky (KY) is a high priority Ending the HIV Epidemic (EHE) jurisdiction due to heavy rural HIV burden andexceptionally high rates of new HIV diagnoses driven by injection drug use. A central pillar of EHE is theprevention of new HIV infections through scale up of PrEP in key populations including people who inject drugs(PWID) who are notably impacted by structural challenges to PrEP uptake. This R34 application proposes todevelop integrate and test a low threshold peer-facilitated telehealth (TelePrEP) intervention for AppalachianKY PWID in syringe service programs (SSPs) filling a critical need to implement innovative approaches tomitigate geographic disparities in PrEP access and improve the care cascade among PWID.


application_id: 11076959
project_number: 1R01AI181567-01A1
administering_ic: NIAID
award_notice_date: 2025-08-29
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 181567
suffix: A1
program_official: PESCE, JOHN T
project_start_date: 2025-08-29
project_end_date: 2029-07-31
study_section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Microglial IFN-y production is a key defense system to coordinate both innate and T cell-mediated protective immunity in the brain for preventing reactivation of cerebral Toxoplasma infection

project_abstract:
Toxoplasmic encephalitis (TE) caused by reactivation of chronic infection with Toxoplasma gondii is a life-threatening opportunistic infectious disease in AIDS patients. To improve prevention and treatment of TE it iscritical to define the mechanisms by which the immune system prevents cerebral T. gondii growth and TE. Werecently discovered that IFN- production by brain-resident cells is crucial not only for activating the innateimmunity to limit the parasite growth during the early stage of reactivation of the infection but also for facilitatingT cell-mediated immunity in the brain to prevent TE. We also identified that microglia (one of brain-resident cellpopulations) produce IFN- in response to cerebral T. gondii growth. These evidences led us to hypothesizethat IFN- production by microglia is a key first-line defense system of the brain to coordinate both the innateand T cell-mediated immunity to prevent TE. Aim 1 will employ the mice deficient in IFN- only in microgliaamong brain-resident cells and identify an importance of microglial IFN- for recruiting monocytes NK cellsand ILC1 cells and activating their IFN- production to suppress the pathogen growth. Although the innateimmunity is important for limiting cerebral tachyzoite growth during the early stage of reactivation of theinfection IFN- production by CD8+ T cells is ultimately required to prevent TE. CD8+ T cells recognize theirtarget antigens presented by MHC class I molecules. Thus Aim 2 is to reveal crucial coordinating roles ofmicroglial IFN- in recruiting CD8+ T cells to areas of cerebral tachyzoite growth and augmenting the MHCclass I antigen presentation in those areas for activating those T cells to prevent TE. For understanding themechanisms of the protective immunity to prevent TE it is also crucial to identify the T. gondii antigens thatactivate the protective CD8+ T cells. There are three most common MHC class I molecules HLA-A2 -A11 and-B7 in humans. Thus Aim 3 is to identify the T. gondii antigens that effectively activate IFN--producing CD8+T cells capable of preventing TE specifically for each of HLA-A2 -A11 and -B7 using transgenic miceexpressing these human HLA molecules. The proposed studies all together will shed light on the crucial first-line defense roles of microglial IFN- production to coordinate both innate and CD8+ T cell-mediated immunityin the brain and markedly improve our understanding on the mechanisms of the protective immunity to preventTE. Notably we identified that once the protective CD8+ T cells are efficiently primed with their target antigensin the presence of CD4+ T cells those primed CD8+ T cells can prevent TE without further depending on CD4+T cells. Thus priming the protective CD8+ T cells by a vaccination with the T. gondii antigens identified in Aim3 in individuals co-infected with HIV and T. gondii specifically for the HLA molecules expressed in theseindividuals before their CD4+ T cell counts decrease could prevent their development of TE even when theirCD4 counts become low at later time points. Thus the proposed studies also have a potential to compose thevital basis for an immunological intervention for preventing TE in individuals co-infected with HIV and T. gondii.

project_terms:
Acquired Immunodeficiency Syndrome;Antigen Presentation;Antigen Targeting;Antigens;Area;Brain;CCL8 gene;CD4 Lymphocyte Count;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CXCL10 gene;CXCL11 gene;CXCL9 gene;Cell Count;Cells;Cellular Immunity;Cerebrum;Collaborations;Communicable Diseases;Defense Mechanisms;Development;Disease;Foundations;Goals;Growth;HIV;HLA-A2 Antigen;Hematopoietic;Histocompatibility Antigens Class I;Host Defense;Human;IL18 gene;ITGAM gene;Immune;Immune system;Immunity;Immunocompetent;Individual;Infection;Infection prevention;Interferon Type II;Interferons;Interleukin-12;Interleukin-15;Knockout Mice;Life;LoxP-flanked allele;Macrophage;Mediating;Microglia;Molecular;Mus;Natural Immunity;Natural Killer Cells;Parasites;Partner in relationship;Patients;Population;Prevention;Production;Proliferating;Resistance;Role;Sentinel;System;T-Cell Activation;T-Lymphocyte;Time;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Transgenic Mice;Transgenic Organisms;Vaccination;brain parenchyma;chemokine;chronic infection;conditional knockout;cytokine;immunological intervention;improved;microbial;monocyte;novel;pathogen;prevent;recruit;response;toxoplasmic encephalitis;vaccine development

public_health_relevance:
Reactivation of chronic infection with Toxoplasma gondii causes life-threatening toxoplasmicencephalitis (TE) in AIDS patients. The proposed studies aim to define the molecularmechanisms by which IFN- production by microglia (one of the brain-resident cell populations)coordinate recruitment of multiple key cell populations in the immunity system into the brain andfacilitate their activation to prevent TE and shed light on a novel key host defense system in thebrain against a microbial infection in general. The proposed studies will also identify the T.gondii molecules that most efficiently activate the protective T cells and provide the vitalfoundation for developing a vaccine to prevent TE in individuals co-infected with HIV and T.gondii.


application_id: 11076626
project_number: 5U01DK135111-03
project_title: Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of Kentucky
administering_ic: NIDDK
award_notice_date: 2025-04-10
opportunity_number: RFA-DK-21-020
application_type: 5
activity_code: U01
ic: DK
serial_number: 135111
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2022-09-25
project_end_date: 2027-12-31
study_section: ZDK1-GRB-9(O1)
contact_pi_person_id: 7926891
contact_pi: FISHER, SIMON J
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:
Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of KentuckyAbstractFor insulin-treated people with Type 1 Diabetes (T1D) hypoglycemia is the rate limiting step in their goals toappropriately control their blood sugar and avoid long-term diabetes complications. Unfortunately repeatedepisodes of hypoglycemia have been shown to induce a pathological process leading to impaired awarenessof hypoglycemia (IAH) and an impaired counterregulatory response hypoglycemia that increases the risk forlife-threatening hypoglycemia. This grant application (in response to RFA-DK-21-020) seeks to establish a 10-site clinical consortium to determine the factors that contribute to the heterogeneity in the restoration of IAHand improved counterregulatory responses in adult individuals with T1D. It is proposed to test the hypothesisthat a combination of 1) advanced diabetes care technology comprised of a hybrid closed loop insulin pumpwith continuous glucose monitor (CGM) coupled with 2) intensive hypoglycemia avoidance education will leadto a decrease in the frequency/severity of hypoglycemia and thereby improve the awareness of hypoglycemiaand improve the counterregulatory response. The specific aims of this proposal as outlined in the RFA are; 1)determine if diabetes care with use of the most up-to-date management strategies (i.e. a hybrid closed loopsystem and hypoglycemia avoidance education) which optimizes HbA1c while minimizing hypoglycemia canrestore awareness of hypoglycemia in individuals with T1D and IAH 2) determine the physiological factors thatare associated with restoration of hypoglycemia awareness and counterregulatory response including but notlimited to age duration of diabetes and metrics of glycemia (eg time in range time spent in hypoglycemia orother CGM metrics) and 3) determine the association of the current self-report questionnaires (or develop newmetrics) for identification of IAH with measurement of CRR using "state of the art" metabolic assessments i.e.hypoglycemic hyperinsulinemic clamps. The University of Kentucky is well-poised to contribute to this valuableconsortium effort because 1) the University has the requisite institutional infrastructure to support all aspects ofthis research 2) this proposal outlines several novel approaches to measure and analyze hypoglycemiaawareness 3) the PI has assembled an experienced leadership team has the requisite expertise in T1Dsubject recruitment and conducting hypoglycemia awareness studies and importantly 4) this site will providethe NIDDK with access to unique pool of US-based often understudied rural study subjects with T1D.

project_terms:
Adult;Age;Applications Grants;Awareness;Blood Glucose;Caring;Clinical Research;Closure by clamp;Complications of Diabetes Mellitus;Continuous Glucose Monitor;Coupled;Development;Diabetes Mellitus;Education;Event;Failure;Frequencies;Glucose;Glucose Clamp;Glycosylated hemoglobin A;Goals;Heterogeneity;Hormones;Hybrids;Hypoglycemia;Impairment;Individual;Infrastructure;Institution;Insulin;Insulin Infusion Systems;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Leadership;Life;Measurement;Measures;Metabolic;Methodology;National Institute of Diabetes and Digestive and Kidney Diseases;Pathologic Processes;Patient Self-Report;Patients;Persons;Physiological;Play;Questionnaires;Recurrence;Research;Research Project Grants;Risk;Role;Rural;Severities;Site;Study Subject;Symptoms;System;Technology;Testing;Time;U-Series Cooperative Agreements;Universities;burden of illness;clinical research site;counterregulation;experience;follow-up;improved;novel;novel strategies;recruit;response;restoration

public_health_relevance:
Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of KentuckyNarrativeFor people with Type 1 Diabetes (T1D) who must use insulin daily to stay alive hypoglycemia (low blood sugar)is the rate limiting step in their goals to appropriately control their blood sugar and avoid long-term diabetescomplications. People with T1D often develop an inability to sense when their blood sugar is low (known asimpaired awareness of hypoglycemia) that increases their risk for life-threatening episodes of severehypoglycemia. This grant application seeks to establish a 10-site clinical consortium to determine if advanceddiabetes care technology coupled with intensive hypoglycemia avoidance education will improve their awarenessof hypoglycemia and thus decrease their risk for life-threatening low blood sugar events.


application_id: 11075836
project_number: 5R35GM141478-05
project_title: Relative adrenal insufficiency as a risk factor and an endotype for sepsis
administering_ic: NIGMS
award_notice_date: 2025-04-28
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: 2027-04-30
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;sepsis mortality;sepsis treatment;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: 11075788
project_number: 5R01NS119165-03
project_title: Translational Approaches to Mitigate Enhanced Alzheimers Disease Risk Following a Mild TBI
administering_ic: NINDS
award_notice_date: 2025-03-12
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 119165
program_official: AWWAD, HIBAH OMAR
project_start_date: 2021-04-01
project_end_date: 2027-02-28
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
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:
ABSTRACTA traumatic brain injury (TBI) is a well-known risk factor for Alzheimer's disease. There is not a one-to-onerelationship where a TBI will lead to the development of Alzheimer's disease. The lack of a direct connectionsuggests a selective vulnerability. Problematically when a person has a mild TBI it is not possible to know ifthey will recover without an impact on their brain health or if they have now increased their vulnerability todeveloping Alzheimer's disease. What can be done? One approach is a broad administration of therapy shortlyafter the injury. Since this approach requires treating some people who would recover from the TBI withoutintervention the benefit-to-risk ratio must be very high. That is you do not want to cause harm by giving anunneeded drug. Our long-term goal is to identify safe treatments to be used after a mild TBI in an older adultpopulation to lessen the chance of developing Alzheimer's disease. There are currently no FDA approveddrugs to be used after a mild TBI to reduce secondary injury mechanisms. We believe that not treating after amild TBI is a missed opportunity but the treatment needs to be safe. Our preliminary evidence shows that aTBI causes deficits in energy metabolism and increased neuroinflammation both of which are exacerbated bypreexisting proteinopathies such as amyloid-beta. To target these mechanisms we have identified Beta-hydroxybutyrate (BHB; 3-hydroxybutyric acid) as a safe multimodal intervention. BHB is a ketone body whichis continuously produced by the liver at low levels but can rise above 1mM during periods of fasting calorierestriction prolonged exercise or by the ketogenic diet. Clinically BHB is safe to be administered orally BHBrapidly crosses the blood-brain-barrier and in cases of starvation ketones can provide as much as 70% of thebrain's energy. BHB is an alternative biofuel that can bypass blockages in the electron transport systemcaused by amyloid-beta and TBI which decrease mitochondrial bioenergetics. BHB has also been shown tosuppress inflammation via an inflammasome-dependent mechanism and by binding to a recently deorphanizedGPCR called HCA2. We will test the central hypothesis that BHB will be effective at reducing functionaldeficits seen in APP/PS1 KI mice following a mild TBI through both energetic and neuroinflammatorydependent mechanisms in three specific aims (SA). SA1: Dose-dependent effects of BHB on mitochondrialfunction and neuroinflammation after TBI. SA2: Define the immunomodulatory properties of the HCA2receptor via dose-dependent effects of niacin a high-affinity HCA2 agonist. SA3: Define theimmunomodulatory properties BHB through the HCA2 receptor through loss of function experiment. Our workseeks to address the mechanisms associated with the increased fragility of the older brain which keeps it fromrecovering from a mild TBI. We also will define the therapeutic potential of the BHB/HCA2 axis as a post-TBIneuroprotective strategy for use in a population at risk for Alzheimer's disease.

project_terms:
APP-PS1;Acceleration;Acids;Address;Adult;Affinity;Age;Agonist;Agreement;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Assisted Living Facilities;Binding;Bioenergetics;Brain;Bypass;Caloric Restriction;Chronic;Clinical;Closed head injuries;Cognitive;Cognitive deficits;Complex;Data;Dementia;Development;Disease;Dose;Electron Transport;Energy Metabolism;Environmental Risk Factor;Epidemiology;Exercise;Experimental Designs;Exposure to;FDA approved;Family member;Fasting;G-Protein-Coupled Receptors;Goals;Head;Implant;Incidence;Independent Living;Individual;Inflammasome;Inflammation;Injury;Interleukin-1 beta;Intervention;Ketone Bodies;Ketones;Knock-in Mouse;Knockout Mice;Liver;Measures;Microglia;Mitochondria;Mus;Neurodegenerative Disorders;Neurologic;Nicotinic Acids;Odds Ratio;Older Population;Oral Administration;Osmosis;Pathologic;Persons;Pharmaceutical Preparations;Population;Populations at Risk;Positron-Emission Tomography;Predisposition;Property;Pump;Radiology Specialty;Receptor Activation;Recovery;Reporting;Risk;Risk Factors;Risk Reduction;Societies;Starvation;System;TBI treatment;Testing;Therapeutic;Time;Traumatic Brain Injury;Work;beta amyloid pathology;beta-Hydroxybutyrate;blood-brain barrier crossing;brain health;demented;design;efficacious intervention;experience;experimental study;falls;human old age (65+);immunoregulation;ketogenic diet;later life;loss of function;loved ones;medical attention;member;mild traumatic brain injury;mitochondrial dysfunction;modifiable risk;mouse model;multi-component intervention;neurodegenerative dementia;neuroinflammation;neuroprotection;older adult;pre-clinical;prevent;receptor;subcutaneous;translational approach;young adult;-amyloid burden

public_health_relevance:
A significant way to reduce the overall burden of Alzheimers disease is to identify modifiable risk factors whichcould be avoided or treated that would slow or prevent the onset of Alzheimers disease. Traumatic braininjury is a well-established environmental risk factor for the development of Alzheimers disease. Completion ofthese studies will uncover the largely unexplored therapeutic approach of Beta hydroxybutyrate for individualsexposed to a traumatic brain injury to reduce the risk of developing a neurodegenerative disease.


application_id: 11075500
project_number: 2UG1OD024954-08
project_title: The Kentucky ECHO Pediatric IDeA Research Center (KE-PIRC)
administering_ic: OD
award_notice_date: 2025-08-18
opportunity_number: RFA-OD-24-008
application_type: 2
activity_code: UG1
ic: OD
serial_number: 024954
program_official: RAJU, TONSE N
project_start_date: 2016-09-23
project_end_date: 2030-05-31
study_section: Special Emphasis Panel[ZRG1 EMS-E (51)]
contact_pi_person_id: 14437890
contact_pi: WATSON, SARA E
other_pis: DEVLIN-PHINNEY, LORI ANN
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Kentucky is a largely rural state holding one of the nations highest poverty rates and lowest rankings in educational achievement. It leads the nation in many pediatric and adult acute and chronic environmentally related diseases. These adverse factors combine to result in Kentuckys children experiencing a high prevalence of congenital anomalies cancer respiratory disease autism neonatal opioid withdrawal syndrome secondhand smoke exposure and adolescent smoking diabetes sedentary lifestyle etc. Many of these outcomes are related to poor nutrition obesity parental smoking and substance abuse and environmental exposures. Kentucky also leads the nation in the percentage of pediatric populations with special health care needs. Prior work has shown that most adult diseases begin in childhood with some beginning during the prenatal period making childhood the ideal time for intervention to improve health outcomes for all Kentuckians. Improving health outcomes and wellness in children is contingent upon expanding and sustaining high quality clinical research. Pediatricians at the University of Louisville with its healthcare and key academic medical center partners serve children throughout Kentucky. To bring healthcare innovation and to better serve these children we are building upon our successes in mentorship pediatric clinical trials and community support as we collaborate with other ECHO IDeA Pediatric Clinical Trials Network and ECHO Cohort sites to advance healthcare for all children. Education and training of local and regional faculty and staff is critical to sustain this initiative. The Kentucky ECHO-Pediatric IDeA Research Center (KE-PIRC) as part of the ECHO IDeA States Pediatric Clinical Trials Network will 1) enhance opportunities for children in rural and urban populations to participate in multi-center clinical trials that address research gaps in health priorities for their local communities; 2) further cultivate our ability to develop the capacity and skills for early-stage investigators to expand a sustainable workforce in pediatric clinical trials research; 3) continue to develop sustainable clinical trial research infrastructure by building upon a network of existing partnerships and 4) strengthen our community partnerships locally and across the Commonwealth of Kentucky through a multi-disciplinary and structured approach. The five ECHO focus areas are 1) pre- peri- and postnatal outcomes; 2) obesity; 3) upper and lower airways; 4) neurodevelopment; and 5) positive health. These primary focus areas address healthcare challenges that are highly prevalent in Kentucky. Therefore the efforts of KE-PIRC in collaboration with our community partners will improve the health outcomes of Kentucky children and their families. Building on ongoing relationships we will develop mature and sustain collaborations with regional and national pediatric clinical trial investigators to maximize efficient use of limited clinical research resources and communicate research findings.

project_terms:
Academic Medical Centers;Active Learning;Acute;Address;Adolescent;Adult;Airway Disease;Area;Child;Child Health;Childhood;Chronic;Clinic;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Clinical Trials Network;Collaborations;Communication;Communities;Development;Development Plans;Diabetes Mellitus;Disease;Education;Educational Status;Environment;Environmental Exposure;Etiology;Faculty;Family;Fostering;Funding;Generations;Health;Health Benefit;Health Care;Health Priorities;Health Professional;Health Promotion;High Prevalence;Intervention;Kentucky;Knowledge;Malignant Neoplasms;Manuscripts;Measures;Mentors;Mentorship;Multi-Institutional Clinical Trial;Neonatal Abstinence Syndrome;Nonprofit Organizations;Nutrition;Obesity;Outcome;Participant;Patients;Perinatal;Phase I Clinical Trials;Physicians;Population;Poverty;Preventive;Primary Care;Process;Professional Organizations;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Respiratory Disease;Rural;Rural Population;Site;Smoking;Structure;Substance abuse problem;Talents;Time;Training;Training and Education;United States National Institutes of Health;Universities;Urban Population;Work;adolescent smoking;autism spectrum disorder;clinical research site;clinical trial protocol;cohort;community advisory board;community center;community partners;community partnership;congenital anomaly;environmental tobacco smoke exposure;experience;high risk;high risk infant;improved;innovation;interest;member;multidisciplinary;neurodevelopment;next generation;novel strategies;outreach program;pediatrician;pediatrician scientist;postnatal;prenatal;programs;rural area;sedentary lifestyle;senior faculty;skill acquisition;skills;success;urban area

public_health_relevance:
The Kentucky ECHO-Pediatric IDeA Research Center (KE-PIRC) as part of the ECHO IDeA States Pediatric Clinical Trials Network will continue to make it possible: 1) for rural and high risk infants children and adolescents to participate in clinical trials research; 2) to build pediatric clinical trials research capacity through the training of early stage investigators in clinical trials research and community partnerships and 3) to create a regional network of partners to sustain this clinical research initiative. The five primary focus areas are 1) pre- peri- and postnatal outcomes; 2) neurodevelopment; 3) upper and lower airways; 4) obesity; and 5) positive health. These primary focus areas align with health priorities in Kentucky; therefore the efforts of KE-PIRC in collaboration with our community partners will improve the health outcomes of children in Kentucky.


application_id: 11075271
project_number: 5R35HL150818-06
project_title: Platelet Exocytosis and Endocytosis in Thrombosis and Immunity
administering_ic: NHLBI
award_notice_date: 2025-03-27
opportunity_number: RFA-HL-20-011
application_type: 5
activity_code: R35
ic: HL
serial_number: 150818
program_official: KINDZELSKI, ANDREI L
project_start_date: 2020-04-01
project_end_date: 2027-03-31
study_section: ZHL1-CSR-R(O1)
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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:
AbstractSurprisingly platelets are capable of bidirectional interactions with their microenvironmentthrough basic cellular processes that are largely unexplored. In this R35 proposal we expand onour active research themes: one unraveling the mechanistic role of exocytosis in hemostasis andthe other investigating endocytosis as an entry pathway to define the role of platelets in innateimmunity. By linking these two areas we can gain deeper insights into how platelet interact withtheir microenvironments. Despite advances in understanding signaling from vascular damagedetection our view of how activated platelets execute the steps needed for clot formation islimited. We have probed the mechanisms of platelet secretion and how it affects hemostasisusing genetically altered models and determined that modulating secretion controls thrombusgrowth without compromising hemostasis. To build on that advance a better understanding ofplatelet exocytosis is clearly needed so logical therapeutic strategies can be developed. Our workon platelet endocytosis endo-lysosomal trafficking and processing of endocytosed cargo led tothe discovery that platelets take up pathogens e.g. viruses and are activated. Increasinglyplatelets are being associated with immune responses yet the mechanisms underlying thesenon-hemostatic functions are largely unknown. Very little is known about platelet endocytosisand next to nothing is known about how platelets traffic and process endocytosed material. OurR35 research program seeks to fill these gaps in knowledge by taking a holistic approach to thestudy of platelet cell biology. Building on our innovative past work (>50 publications) we willfurther define platelet membrane trafficking (endocytosis exocytosis cargo sorting/processingetc.). We hypothesize that bidirectional trafficking processes endo- and exocytosis are essentialfor platelet-specific functions specifically thrombosis and innate immune responses. To addressthis hypothesis we will examine platelet exocytosis and endocytosis at mechanistic andphysiological levels using an extensive suite of reagents transgenic mouse strains andtechnologies. Going forward we will use these powerful tools and approaches to define howplatelet membrane trafficking (both exo- and endocytosis) affects hemostasis/thrombosis andimmune responses at molecular and organismal levels. The data generated are directlyapplicable to the understanding and treatment of human disease especially thrombotic diseaseswhich accounts for 1 in 4 deaths world-wide and chronic viremia e.g. AIDS/HIV1 whichincreases CVD risk.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;Area;Blood Platelets;Blood Vessels;Cell Physiology;Cellular biology;Cessation of life;Chronic;Coagulation Process;Cytoplasmic Granules;Data;Detection;Endocytosis;Exocytosis;Growth;HIV-1;Hemostatic function;Immune response;Immune system;Immunity;Innate Immune Response;Knowledge;Link;Membrane;Modeling;Molecular;Mouse Strains;Natural Immunity;Pathogen detection;Pathway interactions;Physiological;Process;Publications;Reagent;Research;Risk;Role;Signal Transduction;Sorting;Technology;Therapeutic;Thrombosis;Thrombus;Transgenic Mice;Viremia;Virus;Work;holistic approach;human disease;innovation;insight;pathogen;programs;tool;trafficking

public_health_relevance:
Platelets detect vessel damage and secrete granule cargo to form clots. They also detectpathogens via endocytosis and process them to alert the immune system. Understanding howplatelets do these things will lead to a better understanding of thrombotic disease.


application_id: 11074231
project_number: 1R13AI188931-01
project_title: Mid-Atlantic Microbial Pathogenesis Meeting
administering_ic: NIAID
award_notice_date: 2025-01-23
opportunity_number: PA-24-141
application_type: 1
activity_code: R13
ic: AI
serial_number: 188931
program_official: STRICKLER-DINGLASAN, PATRICIA M
project_start_date: 2025-01-23
project_end_date: 2025-12-31
study_section: Special Emphasis Panel[ZAI1 RD-D (S2)]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT The Mid-Atlantic Microbial Pathogenesis Meeting (MAMPM) was founded in 2003 and is a biennialmeeting that will be held in early February 2025 at Wintergreen Resort and Conference Center nearCharlottesville Virginia. The purpose of MAMPM is to foster communication and collaboration among scientistsengaged in microbial pathogenesis research in the Mid-Atlantic Region (North Carolina Virginia MarylandThe District of Columbia West Virginia and Delaware). Numerous NIH/NIAID-funded investigators studyingthe virulence mechanisms of pathogens of importance to human health are in this geographic region and haveparticipated in multiple MAMPMs. However MAMPM attracts scientists both from within and outside the Mid-Atlantic region  on average for the last 5 meetings 80% of the 190 attendees were from the Mid-Atlanticregion while 20% traveled from at least 8 states outside the region per meeting. MAMPMs primary goal is to provide students postdoctoral fellows and junior faculty with the opportunity topresent their work in a collegial yet scientifically rigorous environment. As such MAMPM is a formativeexperience for young scientists professional development which remains one of the most appealing andpositively evaluated aspects of this conference. MAMPM will consist of four scientific sessions over three days.Each session will feature an invited keynote speaker and talks by graduate students postdoctoral fellows anda limited number of junior principal investigators (selected from the submitted abstracts by the ScientificProgram Committee). Two highly interactive poster sessions will also be held to provide the opportunity for allparticipants to present and discuss their work face-to-face. For MAMPM 2025 Drs. Sean Crosson (MichiganState Univ.) Michael Jonhson (Univ. Arizona) Carol Kumamoto (Tufts Univ.) and Christina Stallings(Washington Univ. St. Louis) have agreed to be Keynote Speakers. The conference will be publicizedthrough advertisements in professional publications and local American Society for Microbiology branchessocial media posts and direct electronic mailings to relevant departments at academic institutions andgovernment and private laboratories within the region. MAMPM remains committed to ensuring a balanced representation of women underrepresented minoritiesand persons of disability in the leadership conference participation and as speakers including the keynotespeakers. The conference will also feature a diversity-focused session each year. For MAMPM 2025 wewill hold a mentoring workshop lead by Keynote Speaker Dr. Johnna Frierson (Duke Univ.) which willhighlight mentoring strategies in increase inclusivity in STEM. In addition MAMPM specifically includesDine with a Keynote opportunities for trainees to discuss professional development issues and promotescientific networking.

project_terms:
Advertisements;Agreement;American;Arizona;Collaborations;Communication;Dedications;Delaware;Development;Din Nation;Discipline;Disease;District of Columbia;Educational workshop;Electronic Mail;Ensure;Environment;Evaluation;Faculty;Fostering;Funding;Geographic Locations;Goals;Government;Health;Home;Human;Institution;Laboratories;Laboratory Technicians;Lead;Leadership;Location;Maryland;Mentors;Michigan;Microbe;Microbiology;Mid-Atlantic Region;National Institute of Allergy and Infectious Disease;North Carolina;Participant;Pathogenesis;Persons;Postdoctoral Fellow;Principal Investigator;Privatization;Publications;Relaxation;Research;Research Personnel;Resort;Scientist;Societies;Students;Training;Travel;Underrepresented Minority;United States National Institutes of Health;Virginia;Virulence;Washington;West Virginia;Woman;Work;disability;diversity and inclusion;equity diversity and inclusion;experience;graduate student;meetings;microbial;pathogen;posters;programs;social media;symposium;undergraduate student

public_health_relevance:
PROJECT NARRATIVEThe purpose of the Mid-Atlantic Microbial Pathogenesis Meeting (MAMPM) is to foster communication andcollaboration between scientists engaged in research focused on disease-causing microbes in this geographicregion. The goal of the organizers is to assemble a high-quality scientific program to attract outstandingprincipal investigators along with their undergraduates laboratory technicians graduate students post-doctoralfellows and junior faculty. This meeting will provide an opportunity for junior scientists to present their work toa knowledgeable audience in a supportive and collegial environment.


application_id: 11074217
project_number: 2R13AI129382-07
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2024-11-13
opportunity_number: PA-24-141
application_type: 2
activity_code: R13
ic: AI
serial_number: 129382
program_official: BARTELS, ADELINA EWURA-ABENA
project_start_date: 2016-11-01
project_end_date: 2026-10-31
study_section: Special Emphasis Panel[ZAI1 RD-D (S2)]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal requests 2 years of support for the Autumn Immunology Conference (AIC) an annual gatheringof immunologists at the Marriott Downtown Magnificent Mile hotel in Chicago IL. Year 1 will support the 52ndannual AIC on November 22-25 2024 and Year 2 will support the 53rd annual meeting to be held November 21-24 2025. The purpose of AIC is to foster communication and collaboration among immunologists particularlythose located in the middle of the US. Chicago is an exciting destination and within driving distance for manymidwestern academic institutions that are home to numerous NIAID-funded investigators. Since its inception in1972 AIC continues to be very highly regarded and has a fiercely loyal group of regular attendees from acrossthe US. The Specific Aims of AIC are to: 1) disseminate new immunological research findings from leadingscientists in the field 2) provide a forum for trainees to improve their presentation skills and 3) increaseinteractions between a diverse group of scientists interested in immunology research. The meeting starts witha Meet the Speakers event for trainees a Keynote speaker and a welcome reception on Friday. Saturday &Sunday have similar schedules: morning symposia then smaller themed breakout sessions followed by posters.The meeting ends on Monday with just a morning plenary session. Each year three different topic areas arechosen for the morning symposia. For 2024 6 female & 6 male invited speakers will present talks on InnateImmunity Immune Regulation at Barriers & Mucosal Vaccines; the 2025 topics will be chosen by the AIC Chairin consultation with the Executive Council (EC) at the spring planning meeting. All accepted abstracts (typically~270) are invited to give a 10 min. talk during the afternoon workshops followed by a 1 h poster presentation.AIC is run by a dedicated all-volunteer group of faculty that serve multi-year terms including the Leadershiptrack that consists of a 4 year commitment to serve as the Workshop Coordinator the Secretary the Chair andthen the Past Chair/Councilor. Since 1992 the EC has strived to maintain a gender balance amongst itsmembers; we typically rotate males and females to enter the leadership track. Another unique feature of AIC isthe Undergraduate Workshop with a Careers in Immunology panel discussion and a table fair of PhD programsin Immunology. AIC is truly a formative experience for trainees and this remains one of the most positivelyevaluated aspects of the meeting. New for this renewal is a partnership with Black in Immuno that will involvea breakfast panel discussion focused on trainees who are underrepresented minorities (URM) in science. Thiswill further enhance the trainee experience and AIC and we anticipate that this will increase the number of URMattendees at the meeting. This year we will also expand our Wallace Diversity Fellows program which has beenproviding travel awards and networking opportunities to URM since 1972. The volunteer EC works hard to solicitexternal funding to support this meeting so we can keep the registration fee low allowing as many trainees aspossible to attend. In fact the registration fee is waived for any undergrad who submits an abstract.

project_terms:
Address;Allergy;Anniversary;Area;Autoimmune Diseases;Autoimmunity;Automobile Driving;Award;Beer;Black race;Budgets;Cheese;Chicago;Coffee;Collaborations;Communicable Diseases;Communication;Consultations;Data;Dedications;Destinations;Development;Doctor of Philosophy;Education;Educational workshop;Equilibrium;Event;Faculty;Fees;Female;Fostering;Funding;Gender;Goals;Home;Immunologics;Immunologist;Immunology;Institution;International;Laboratories;Leadership;Learning;Malignant Neoplasms;Mission;National Institute of Allergy and Infectious Disease;Natural Immunity;Oral;Persons;Postdoctoral Fellow;Principal Investigator;Productivity;Public Health;Regimen;Request for Applications;Request for Proposals;Research;Research Personnel;Rotation;Running;Schedule;Science;Scientist;Therapeutic;Transplantation;Travel;Underrepresented Minority;United States National Institutes of Health;Vaccines;Visit;Volunteer Group;Wine;Work;cancer immunotherapy;career;career development;design;equity diversity and inclusion;experience;graduate student;immunoregulation;improved;interest;male;meetings;member;mucosal vaccine;new technology;posters;prevent;programs;recruit;skills;symposium;undergraduate student;volunteer

public_health_relevance:
This application requests funding to support the Autumn Immunology Conference an annual gathering ofscientists (primarily from the midwestern US) that is designed to facilitate the dissemination of new researchresults to establish or strengthen collaborations between laboratories and to serve as a platform for thedevelopment of young trainees in the field of immunology. Research in immunology is important for the publichealth mission of NIH and greatly impacts our ability to understand autoimmunity and allergy to design effectivevaccines to prevent infectious diseases and to improve cancer immunotherapy regimens.


application_id: 11074049
project_number: 5F31HL170558-02
project_title: The myosin super-relaxed state and human dilated cardiomyopathy
administering_ic: NHLBI
award_notice_date: 2025-04-09
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: HL
serial_number: 170558
program_official: CHEON, YEWON
project_start_date: 2024-04-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-F10A-K(20)L]
contact_pi_person_id: 78299799
contact_pi: WELLETTE-HUNSUCKER, AUSTIN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Dilated cardiomyopathies are a frequent cause of heart failure worldwide characterized by reducedsystolic function and left ventricular dilation. Dilated cardiomyopathy has been linked to various causes includingviral infections drug abuse endocrine dysfunction and genetic mutations. Reduced effective myocardialcontractility presents as a symptom early in disease progression of dilated cardiomyopathy. Studying themolecular basis of decreased contractility by investigating the myosin motors that power contractions can provideimportant insight and allow testing of potential therapeutic modulation. Current therapeutics for dilatedcardiomyopathy (e.g. ACE inhibitors -blockers etc.) target symptoms but do not attenuate the underlyingsource of contractile dysfunction. At the molecular level force generation in cardiac muscle is determined by thenumber of myosin motors that bind to the actin thin-filament during the systolic rise of calcium. Once myosinmotors bind myosins hydrolyze ATP and undergo conformational steps to generate force. Recent attention hasfocused on the myosin biochemical super-relaxed state an energy-conserving auto-inhibited state of cardiacmyosin that determines the proportion of myosin motors available. Thus the amount of myosin motors in thesuper-relaxed state modulates the magnitude of myosin motors available to generate sarcomere power uponactivation. The stability of the super-relaxed state can be modulated by phosphorylation of regulatory light chainand myosin binding protein C. Additionally as force increases stress on the thick filament rises resulting in therelease of myosin heads allowing greater force production. A decrease in available myosin motors as a resultof a shift towards the super-relaxed state is a potential mechanism of systolic dysfunction in human dilatedcardiomyopathy and has yet to be fully investigated. Therefore our central hypothesis is that depressedcontractile force in dilated cardiomyopathy results from increased myosins in the super-relaxed state (Aim 1)mediated by depressed regulatory protein phosphorylation (Aim 2) which may be able to be reversed with theuse of myosin activators (Aim 3). To test our hypothesis we will utilize the fluorescent ATP pulse-chasetechnique to quantify the proportion of myosins in the super-relaxed state and test the effects of myosin activatorsat short and long sarcomere lengths. Also using Phos-TagTM western blotting we will measure thephosphorylation status of regulatory proteins. This proposal will provide novel insight into the effects of myosinactivators on the super-relaxed state demonstrate fundamental aspects of myosin biochemical states and theirrole in the molecular basis of human dilated cardiomyopathy.

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

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


application_id: 11073609
project_number: 1R01DA060632-01A1
project_title: Advancing Troriluzole as a Treatment for Methamphetamine Use Disorder: A Human Laboratory Study
administering_ic: NIDA
award_notice_date: 2025-04-09
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: DA
serial_number: 060632
suffix: A1
program_official: FOSTER, KATRINA L
project_start_date: 2025-04-15
project_end_date: 2029-02-28
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTMethamphetamine use disorder (MUD) presents a serious public health problem in the United States ofAmerica. Overdose death rates from methamphetamine have also risen considerably which has been causedby both methamphetamine use alone AND co-use of methamphetamine and opioids. Similarly althoughproblems posed by MUD are attributable largely to use of methamphetamine MUD is often co-morbid withopioid use disorder (OUD) making MUD even more difficult to treat. Novel pharmacotherapeutic strategiesneed to be evaluated and advanced to better treat MUD alone as well as co-morbid MUD and OUD.Glutamate systems play an essential role in the direct reinforcing effects of methamphetamine andmethamphetamine-induced reinstatement of drug seeking. Previous research has also demonstratedmethamphetamine produces persistent disruptions in brain glutamate systems (i.e. disrupted glutamatehomeostasis). A growing body of literature largely preclinical indicates targeting disrupted glutamatehomeostasis is a promising strategy for reducing methamphetamine intake and mitigating other abuse-relatedeffects of methamphetamine. Troriluzole a third-generation prodrug of riluzole reduced methamphetamineintake and seeking behaviors in self-administration assays inhibited development expression andmaintenance of methamphetamine conditioned place preference and ameliorated methamphetamine-inducedchanges in glutamate neurochemistry. The overarching goal of this study is to translate preclinical findings withtroriluzole into the human laboratory to advance troriluzole as an MUD pharmacotherapy. We seek to extendthat work by evaluating troriluzole in people with MUD alone and co-morbid MUD and OUD given theepidemiological findings described above and the key role of glutamate in opioid addiction. To this end 40non-treatment seeking human subjects meeting diagnostic criteria for MUD (20 with MUD alone and 20 withco-morbid MUD and OUD; 50% men and 50% women in each group) will be enrolled in a placebo-controlleddouble-blind randomized human laboratory experiment in which we will assess the reinforcing effects ofintravenous methamphetamine (0 15 and 30 mg) following treatment with troriluzole (0 140 and 280 mg/day).Validated and widely used subjective drug-effect physiological and side effects measures will also be used.The research proposed here will directly translate findings from preclinical research and provide the initialclinical evidence that troriluzole reduces the reinforcing and other abuse-related effects of methamphetamine.This study will also provide basic science information about the glutamatergic mechanisms underlying thepharmacodynamic effects of methamphetamine in humans. As such the outcomes will advance ourunderstanding of the clinical neurobiology of MUD alone and co-morbid MUD and OUD.

project_terms:
Address;Admission activity;American;Asian;Astrocytes;Attenuated;Basic Science;Behavior;Behavior Therapy;Biological Assay;Black Populations;Brain;Clinical;Clinical Research;Clinical Trials;Data;Death Rate;Development;Dextroamphetamine;Dose;Double-Blind Method;Drug Kinetics;Enrollment;Epidemiology;Formulation;Generations;Glutamates;Goals;Hispanic;Homeostasis;Human;Hydromorphone;Individual;Inpatients;Intake;Intravenous;Laboratories;Laboratory Study;Literature;Maintenance;Measures;Methamphetamine;Methamphetamine use disorder;Motivation;Native Hawaiian or Other Pacific Islander;Neurobiology;Neurons;Opiate Addiction;Opioid;Oral;Outcome;Persons;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacotherapy;Physiological Effects of Drugs;Placebo Control;Placebos;Play;Population;Preclinical data;Prevalence;Process;Prodrugs;Public Health;Randomized;Research;Research Personnel;Riluzole;Role;Sampling;Self Administration;System;Testing;Time;Translating;United States;Woman;Work;comorbidity;conditioned place preference;contingency management;design;diagnostic criteria;experience;experimental study;human subject;laboratory experiment;meetings;men;methamphetamine effect;methamphetamine exposure;methamphetamine use;neurochemistry;neuropsychiatric disorder;novel;novel therapeutics;opioid use disorder;overdose death;pre-clinical;pre-clinical research;reinforcer;restoration;side effect;uptake

public_health_relevance:
PROJECT NARRATIVEMethamphetamine produces profound changes in the glutamate system which may present a target for novelMethamphetamine Use Disorder (MUD) pharmacotherapies. No clinical research has evaluated whetherameliorating disrupted glutamate function in MUD reduces abuse-related effects of methamphetamine. Wepropose a rigorous human laboratory study to determine whether troriluzole a drug that restores glutamatefunction after methamphetamine exposure reduces methamphetamine intake and other abuse-related effects.


application_id: 11073142
project_number: 1R01AR084282-01A1
project_title: Using the gut microbiome to treat skeletal muscle atrophy
administering_ic: NIAMS
award_notice_date: 2025-01-27
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AR
serial_number: 084282
suffix: A1
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2025-02-01
project_end_date: 2030-01-31
study_section: Special Emphasis Panel[ZRG1 MSOS-U (05)]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
SUMMARYWhen skeletal muscle is not used on a regular basis it becomes smaller as a result of myofiber atrophy; notsurprisingly this muscle atrophy is accompanied by a loss of strength. Disuse atrophy is most often caused bydisease surgery injury or aging. Although there is a good understanding of the molecular mechanismsunderlying atrophy and how they can differ given the cause the development of an effective treatmentremains an ongoing challenge. Resistance exercise is currently the most effective treatment to help reduce thelevel of atrophy and regain strength; however many individuals are unable to perform exercise at a sufficientintensity to promote muscle growth. Thus there is a critical need to develop a new therapeutic approach towork as an adjunct to resistance exercise or as a stand-alone treatment. Research over the last couple ofdecades has provided a deeper understanding of how the gut microbiome impacts human health and diseasethroughs its pervasive interactions with cells of the body via microbial-derived metabolites. Studiesinvestigating hibernating squirrels and germ-free mice have established a gut microbiome-skeletal muscle axisinvolved in regulating skeletal muscle mass and function. We reported the disruption of the mouse gutmicrobiome by antibiotic treatment blunted skeletal muscle hypertrophy in response to exercise training. Wehave now acquired preliminary data showing cecal microbial transplant from exercised-trained mice to miceundergoing unilateral hind limb immobilization significantly reduced the magnitude of muscle atrophy.Metagenomic and metabolomic analyses have identified promising candidate bacterial species and microbial-derived metabolites respectively that we hypothesize mediate the observed reduction in muscle atrophy. Totest this hypothesis we will first determine if cecal microbial transplant from exercise-trained mice alsoattenuates muscle atrophy in male mice and fast-twitch muscles. We will also determine if mTORC1 activationis the mechanism underlying the reduced muscle atrophy. We will next investigate if the administration of aprobiotic composed of candidate bacterial species identified by metagenomics is able to mimic the effect ofcecal microbial transplant by reducing muscle atrophy. A final aim will test if the administration of a post-biotic(a microbial-derived metabolite identified by metabolomics) is capable of attenuating disuse atrophy. Regularexercise is known to change the composition and function of the gut microbiome. Our preliminary dataprovides compelling evidence that the gut microbiome of exercise-trained mice is able to significantly reducethe magnitude of muscle atrophy following disuse. The proposed studies will determine if a probiotic and/orpost-biotic are capable of ameliorating muscle atrophy and preserving muscle function thereby providing anovel therapeutic strategy to treat muscle atrophy.

project_terms:
Adult women;Affect;Aging;Animals;Antibiotic Therapy;Area;Atrophic;Attenuated;Bacteria;Cancer Cachexia;Cell Culture Techniques;Cells;Computer Simulation;Contralateral;Data;Development;Disease;Disuse Atrophy;Effectiveness;Environment;Epithelium;Eukaryotic Cell;Evolution;Exercise;Female;Fiber;Flexor;Food;Formulation;Future;Gel;Genome;Germ-Free;Goals;Growth;Health;Human;Immobilization;Immunohistochemistry;Individual;Injury;Leg;Life;Limb structure;Mammals;Measures;Mediating;Metabolic;Metagenomics;Methods;Molecular;Mus;Muscle;Muscle function;Muscular Atrophy;Operative Surgical Procedures;Persons;Pipecolic Acids;Planet Earth;Probiotics;Production;Protein Biosynthesis;Regulation;Reporting;Research;Skeletal Muscle;Soleus Muscle;Source;Squirrel;Succinates;Testing;Training;Transplantation;Western Blotting;Work;bone disuse atrophy;commensal microbes;effective therapy;exercise training;experimental study;gut bacteria;gut colonization;gut microbiome;in vivo;male;metabolomics;microbial;microbiome composition;muscle form;muscle hypertrophy;muscle strength;novel therapeutic intervention;preservation;probiotic supplementation;protein biomarkers;protein degradation;resistance exercise;response;sedentary;skeletal muscle wasting;transcriptome sequencing

public_health_relevance:
NARRATIVEWhen skeletal muscle is not used on a regular basis because of disease surgery or injury it becomes smaller(atrophy) and weaker. While resistance exercise is the most effective treatment for muscle atrophy it is oftennot practical or possible for some people to do. Thus the goal of this project is to determine if a probiotic orpost-biotic (substance made by gut bacteria) can be used to treat muscle atrophy.


application_id: 11071376
project_number: 1R21HD117520-01
administering_ic: NICHD
award_notice_date: 2024-11-05
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: HD
serial_number: 117520
program_official: SURPRIS, MARIPIERRE PAYEN
project_start_date: 2024-11-06
project_end_date: 2026-10-31
study_section: Special Emphasis Panel[ZRG1 MGG-K (02)]
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
budget_start_date: 2024-11-06
project_title:
Evaluating causes for failure to thrive in a Noonan-like syndrome with loose anagen hair (NSLH) patients using NSLH vertebrate model

project_abstract:
SummaryEven though the genetic basis of RASopathies has been acknowledged for more than adecade the development of therapies that radically improve clinical outcomes for RASopathypatients has not rapidly progressed. Failure to thrive gain weight and grow are commonsymptoms of RASopathies but the underlying causes of these symptoms are not known. Ourlab is studying a RASopathy called Noonan syndrome with loose anagen hair (NSLAH) wherepatients suffer from delayed development of the gastrointestinal system and perturbations inmetabolic pathways. In these studies we will use zebrafish as a vertebrate model to investigatehow mutations in the shoc2 gene found in patients with NSLAH affect the early stages ofgastrointestinal development and metabolism. Zebrafish offer distinct advantages fordevelopment studies including their transparency and rapid external development. Thusdetermining how metabolic perturbations affect this clinically relevant model's growth anddevelopmental patterns will lead to better treatment for patients with NSLAH. These insightscould identify oral supplements for patients similar to what recently was found for congenitaldisorders of glycosylation and neonatal hypoxia-ischemia patients. While this work focuses on aspecific RASopathy our findings will impact other RASopathies where patients present withsimilar difficulties to thrive. The proposed work will also establish a foundation for successfulfuture studies focused on developing specific strategies for therapeutic approaches inRASopathies.

project_terms:
Affect;Anabolism;Attention;Biological Process;CRISPR/Cas technology;Carbon;Child;Clinical;Cognitive;Complex;Congenital disorders of glycosylation;Cysteine;Development;Diagnosis;Diet;Disease;Disease Progression;Eating;Energy Intake;Energy Metabolism;Enteral;Enteric Nervous System;Enzymes;Etiology;Face;Failure;Failure to Thrive;Fluorescence Microscopy;Foundations;Future;Gastrointestinal tract structure;Genes;Genetic;Glycine;Glycolysis;Growth;Growth and Development function;Guidelines;Hair;Heart Abnormalities;Hereditary Disease;Homeostasis;Knock-in;Knock-out;Knowledge;MAPK3 gene;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mutation;Nervous System control;Neural Crest Cell;Neurons;Non-Essential Amino Acid;Noonan Syndrome;Outcome;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Pattern;Persons;Phenotype;Point Mutation;Population;Pre-Clinical Model;Rare Diseases;Research;Scaffolding Protein;Serine;Signal Transduction;Specific qualifier value;Structural defect;Symptoms;Syndrome;Testing;Therapeutic;United States;Variant;Weight Gain;Work;Zebrafish;autosome;clinically relevant;common symptom;developmental disease;experience;experimental study;feeding;follow-up;gastrointestinal;gastrointestinal symptom;gastrointestinal system;improved;in vivo;insight;metabolomics;myoelectric control;neonatal hypoxic-ischemic brain injury;nervous system development;neurodevelopment;novel;oral supplementation;pre-clinical;public health relevance;therapeutic target;therapy development;transcription factor;transcriptome sequencing;zebrafish genome

public_health_relevance:
Public Health Relevance StatementRare diseases collectively affect approximately 25-30 million people in the United States anddisproportionally affect children. The proposed work will result in a novel vertebrate model and insightsinto the pathogenesis of the rare developmental disorder Noonan syndrome with loose anagen hair.Ultimately this work will provide a model for the future development of guidelines for the diagnosis andtreatment of this rare disease and will lead to a better understanding of the etiology of a rare disease.


application_id: 11069759
project_number: 1F31HL175979-01A1
project_title: PPARgamma Coregulators in Rosiglitazone-Induced Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2024-12-05
opportunity_number: PA-23-271
application_type: 1
activity_code: F31
ic: HL
serial_number: 175979
suffix: A1
program_official: HUANG, LI-SHIN
project_start_date: 2025-01-01
project_end_date: 2027-12-31
study_section: Special Emphasis Panel[ZRG1 F06-J (20)]
contact_pi_person_id: 78972495
contact_pi: BATES, EVELYN A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
SummaryRosiglitazone (Rosi) treats type 2 diabetes (T2D) and effectively lowers blood glucose via the nuclear receptorPPAR activation. Rosi has been reduced in use due to it inducing congestive heart failure (CHF). PPAR is aligand-activated transcription factor that is highly expressed in adipose tissues and to a lesser extent in cardiactissue. It is regulated through various mechanisms like coregulators that physically interact with PPAR toactivate or repress its transcriptional activity. Hence the PPAR-interactome regulates functions that drive ittoward genes that control specific pathways. My goal for this project is to determine the global genome view ofthe heart and adipose tissue during Rosi activation of PPAR that leads to the deleterious effects associatedwith the drug. We will investigate if the PPAR interactome changes based on diet (high-fat versus chow diets)and whether this guides the transcription factor to specific PPAR-response elements (PPREs) in gene promotersinducing specific pathways. These concepts have led to the central hypothesis that chronic high-fat feeding inthe obese causes a change in the PPAR interactome and pathways controlled by the transcription factor thatleads to cardiac dysfunction. We will measure these in the following aims: Aim 1: We hypothesize that high-fat(HFD) feeding alters PPAR-directed pathways in the heart causing a switch in gene regulatory actions andcardiac steatosis. Aim 2: We hypothesize that PPAR activation in adipose tissue of chronically obese miceactivates inflammatory hormones that cause cardiac dysfunction. To measure these we will use our state-of-the-art PamGene PamStation to measure the PPAR coregulator interactome RNA-sequencing and PPARchromatin immunoprecipitation (ChIP)-seq in adipose and heart tissues in the mice described above. We expectto find that chronic high-fat feeding changes the PPAR coregulator interactome driving it to pathways that leadto deleterious outcomes such as our finding that Serpine1 mRNA (plasminogen activator inhibitor 1 PAI-1protein) levels were increased in the HFD Rosi but not in normal chow mice with Rosi treatments. PAI-1 isinvolved in cardiovascular disease but nothing is known about its role in PPAR-induced CHF. Our studies herewill improve the understanding of PPAR in cardiac function and possibly provide methods of treating personswho experience CHF.

project_terms:
Adipocytes;Adipose tissue;Automobile Driving;Binding Proteins;Bioinformatics;Biological Process;Blood Glucose;Blood Plasma Volume;Calories;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Categories;ChIP-seq;Chronic;Code;Complex;Computer software;Congestive Heart Failure;Data;Data Analyses;Development;Diet;Disease;Edema;FABP4 gene;FDA approved;Fat-Restricted Diet;Fatty Acids;Fatty acid glycerol esters;Fellowship;Female;Foundations;Future;Gene Expression Regulation;Gene Targeting;Genes;Genetic Transcription;Genome;Goals;Heart;Heart failure;Heterocyclic Compounds;Hormones;Image;Inflammation;Inflammatory;Insulin;Insulin Resistance;Knock-out;Lead;Ligand Binding;Ligands;Link;Measures;Messenger RNA;Metabolic Diseases;Methods;Mus;Myocardial dysfunction;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Receptors;Obese Mice;Obesity;Outcome;PPAR gamma;Pathogenesis;Pathway interactions;Peripheral;Peroxisome Proliferator-Activated Receptors;Persons;Pharmaceutical Preparations;Phosphotransferases;Pioglitazone;Plasminogen Activator Inhibitor 1;Populations at Risk;Prevention;Proteins;Regulation;Repression;Research;Research Personnel;Response Elements;Role;Scientist;Set protein;Signal Transduction;Stimulus;Swelling;Technology;Therapeutic;Thiazolidinediones;Thinking;Thinness;Time;Tissues;Training;Work;Writing;blood pressure reduction;career;career development;experience;falls;feeding;genetic corepressor;heart function;high risk;improved;intercalation;male;patient subsets;promoter;receptor binding;rosiglitazone;therapeutic target;transcription factor;transcriptome sequencing;uptake

public_health_relevance:
Project Narrative:The work proposed in this fellowship has the potential to uncover a possible link between obesity coregulatorprotein interactomes and rosiglitazone-induced congestive heart failure. This research could lead to thediscovery of therapeutic targets for the prevention of rosiglitazone-induced heart failure and the development ofspecialized therapeutics for the at-risk population.


application_id: 11069358
project_number: 2R44OD032088-02
project_title: A novel rat sperm cryopreservation and artificial insemination system
administering_ic: OD
award_notice_date: 2025-08-14
opportunity_number: PAR-21-225
application_type: 2
activity_code: R44
ic: OD
serial_number: 032088
program_official: CONTRERAS, MIGUEL A
project_start_date: 2022-09-15
project_end_date: 2027-08-31
study_section: Special Emphasis Panel[ZRG1 EMS-S (10)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryParaTechs Corporation aims to provide researchers with advanced technology and methods to simplifyprocedures for laboratory animal models. This proposal is a direct response to PAR-21-225; Novel Tools andDevices for Animal Research Facilities and to Support the Care of Animal Models. The goal is to improvevivarium management through cryopreservation strategic breeding and organizational approaches currentlyunavailable for rats. The rat artificial insemination system (RAIS) is a complete rat sperm cryorecovery system.This system will revolutionize cryopreservation practices and vivarium management for rat models. First spermis cryopreserved in a Cryodropper device which will quickly and easily freeze rat sperm. Second sperm isrecovered in a novel motility enhancing device (MED) which selects for motile sperm removes cryoprotectantsand concentrates the sperm sample. The third part of the system is a novel device which is used to transferconcentrated motile sperm to the uterine horn of recipient female rats. This non-surgical insemination device(NSID) provides a non-surgical alternative to traditional surgical artificial insemination and requires no anesthesiaor analgesia. Each innovative part of the system provides a critical function for rat cryorecovery and togetherprovide a cohesive system for rapid inexpensive and efficient vivarium management. The system will providesubstantial cost savings versus contracted cryopreservation services and increase the simplicity and reliabilityof rat sperm cryopreservation procedures. RAIS will directly benefit the welfare of laboratory animals by reducingthe number of animals kept in idle colonies improving vivarium management options and protecting rat modelsfrom catastrophic loss due to natural disasters genetic drift disease and breeding problems. RAIS is designedto provide both a reduction in animal numbers and a refinement to minimize animal suffering and improvewelfare meeting the requirements of the 3Rs of animal research.

project_terms:
Absence of pain sensation;Anesthesia procedures;Animal Experimentation;Animal Model;Animal Welfare;Animals;Archives;Artificial Insemination;Assisted Reproductive Technology;Behavior;Biomedical Research;Biotechnology;Breeding;Collaborations;Contracts;Core Facility;Cost Savings;Cryopreservation;Dedications;Development;Device or Instrument Development;Devices;Disease;Embryo Transfer;Female;Fertilization in Vitro;Freezing;Funding Opportunities;Gene Modified;Generations;Genetic Drift;Goals;Health;Horns;Human;Insemination;Laboratory Animal Models;Laboratory Animal Production and Facilities;Laboratory Animals;Laboratory Procedures;Maintenance;Marketing;Methods;Missouri;Modeling;Motility;Mouse Strains;Mus;Natural Disasters;Operative Surgical Procedures;Physiology;Procedures;Process;Protocols documentation;Qualifying;Rat Strains;Rattus;Recovery;Replacement Reduction and Refinement;Research;Research Personnel;Resources;Rodent;Sampling;Services;Shipping;Sperm Motility;System;Techniques;Technology;Toxicology;United States National Institutes of Health;Universities;Uterus;animal care;assisted reproduction;assistive reproductive technique;cost;design;drug development;embryo culture;experience;experimental study;improved;innovation;manufacture;manufacturing test;meetings;novel;preservation;protocol development;response;sperm cell;sperm cryopreservation;success;tool;welfare

public_health_relevance:
NarrativeRodents are the most prevalent animals used for biomedical research and rat models are superior for use intoxicology behavior and physiology. This proposal is in direct response to the NIH funding opportunityannouncement PAR-21-225 to develop novel tools and devices for animal research facilities and to support thecare of animal models. ParaTechs proposes to develop and manufacture a rat artificial insemination system(RAIS) a complete rat sperm cryorecovery system which will reduce the number of animals kept in idle coloniesimprove vivarium management options and protect animal models from catastrophic loss due to naturaldisasters genetic drift disease and breeding problems.


application_id: 11068995
project_number: 2R44AG078020-02
project_title: Wicked Smart Pad: Washable Sensorized Bedding for the Prevention and Detection of Moisture Events
administering_ic: NIA
award_notice_date: 2025-09-19
opportunity_number: PAS-22-196
application_type: 2
activity_code: R44
ic: AG
serial_number: 078020
program_official: BAKOS, ALEXIS DIANE
project_start_date: 2023-02-01
project_end_date: 2027-05-31
study_section: Special Emphasis Panel[ZRG1 CCHI-E (10)]
contact_pi_person_id: 78348749
contact_pi: TRUTTMANN, ALLISON
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 017805579
primary_uei: XG5NUX82V251
duns_number: 017805579
uei: XG5NUX82V251
fips: US
organization_id: 10065690
organization_name: WICKED SHEETS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402183064
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYDue to decreased mobility deterioration in activities of daily living and neurological decline that contributes toloss of bladder control incontinence is a leading comorbidity for those individuals suffering from Alzheimersdisease and related dementias (ADRD). Individuals with incontinence are susceptible to the development ofpressure ulcers (PUs) and other iatrogenic skin injuries that are often regarded as an inevitable part of aging.Incontinence and related dermatological conditions are a significant comorbidity in senior residents with PUsoccurring in nearly 40% of advanced dementia patients. As such maintaining skin integrity in ADRD patients isan ever-present challenge for healthcare providers and caregivers as well as a significant financial burden. Earlydetection of moisture events mitigates the complications associated with incontinence improving the quality-of-care patients receive. To address this need Wicked Sheets a Kentucky-based woman-owned business hasdeveloped the Wicked Smart Pad (WSP) -- a washable and reusable sensorized bedding pad system. It alertscaregivers when a moisture event occurs via wireless communication collecting vital information to support thecare team. In Phase I the PI and the collaborating site Atria Park of Great Neck New York evaluated thefeasibility and usability of our WSP system its acceptability by care staff and residents alike and identified keyareas for improvement in their initial design. Our team tested 200 WSPs at three locations involving 36 memorycare residents for 8-12 weeks each. Use of the WSP real-time alerts allowed staff to establish the IncontinenceResponse Rate (IRR) as a metric for care delivery; reduced average spillovers to a single event in six weeks;reduced 35-minute bedding changes to a five-minute exchange of the WSP; and coincided with zero observedbedsores in participating residents. We also constructed the Wicked Smart dashboard  an interface for memorycare staff enabling them to view moisture event data over several months for any resident  to improveoperational intelligence and curation of data-driven staffing and resident care plans. In this Phase II proposalwe aim to address challenges identified during our pilot study namely the need for improved hardware designand expanded compatibility of the accompanying software by revising our hardware and software systems forimproved integration with care staff needs and to meet industry and regulatory standards. Subsequently we aimto validate our improved designs and assess the efficacy of the WSP system in reducing incontinence events byinforming resident care schedules through a multi-site single-arm clinical study in partnership with Atria SeniorLiving. Completion of Phase II will result in a commercially viable WSP platform ready for deployment in memorycare facilities that can reduce the burden of incontinence care reduce the incidence of PUs and otherincontinence related skin conditions and improve resident quality of life.

project_terms:
Activities of Daily Living;Address;Adult;Adverse event;Aging;Alzheimer's disease patient;Alzheimer's disease related dementia;Area;Beds;Bladder Control;Businesses;COVID-19 pandemic;Caregivers;Caring;Clinical Research;Clinical Trials;Collaborations;Collection;Communication;Community Health Care;Computer software;Data;Dementia caregivers;Dermatologic;Detection;Deterioration;Development;Devices;Early Diagnosis;Event;Feedback;Financial Hardship;Floor;Head;Health Care Facility;Health Insurance Portability and Accountability Act;Health Personnel;Home;Iatrogenesis;Incidence;Incontinence;Individual;Industry;Intelligence;Kentucky;Location;Long-Term Care;Mobility decline;Monitor;Neck;Neurologic;New York;Notification;Nursing Homes;Pain;Patients;Phase;Pilot Projects;Population;Predisposition;Prevention;Protocols documentation;Quality of Care;Quality of life;Reporting;Risk;Risk Factors;Sampling;Schedule;Security;Site;Skin;Skin injury;System;Testing;Time;Training;Urinary tract infection;Woman;Work;advanced dementia;arm;atrium;care costs;care delivery;caregiver stress;comorbidity;cost effective;dashboard;data curation;data exchange;data preservation;data privacy;decubitus ulcer;design;digital repositories;efficacy evaluation;encryption;implementation protocol;improved;incontinence care;innovation;manufacture;meetings;member;memory care;mortality;predictive test;response;routine care;sensor;sensor technology;software systems;usability;wireless communication

public_health_relevance:
PROJECT NARRATIVEPatients suffering from Alzheimers disease and related dementias (ADRD) are at an elevated risk of developingpressure ulcers (PUs) and skin breakdowns as a result of incontinence; together incontinence and skin-relatedcomorbidities contribute to lower quality of life for ADRD patients while incurring significant care costs andcaregiver distress. To address this need Wicked Sheets has developed the Wicked Smart Pad: a washable andreusable sensorized system that provides ADRD caregivers with early detection of moisture events. Our WickedSmart Pad is the first adult incontinence solution that combines active moisture notification and passive moisturemanagement into a durable and reusable cost-effective platform for improving care delivery and increasingADRD patient quality of life.


application_id: 11067764
project_number: 5R03DE033707-02
project_title: Cobalamin in Porphyromonas gingivalis Pathogenicity
administering_ic: NIDCR
award_notice_date: 2025-03-05
opportunity_number: PAR-21-084
application_type: 5
activity_code: R03
ic: DE
serial_number: 033707
program_official: MCNEALY, TAMARA L
project_start_date: 2024-04-06
project_end_date: 2027-03-31
study_section: ZDE1-YM(09)
contact_pi_person_id: 79184346
contact_pi: GHODS, SHIRIN
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPeriodontitis is a polymicrobial-driven and prevalent inflammatory disease of the tissues supporting the teethin adults with adverse effects on overall human health. Studies have revealed that cobalamin (vitamin B12)transporters are highly active in the periodontal microbiome associated with the periodontal pockets ofindividuals with periodontitis. Yet the functional correlation between cobalamin utilization and the pathogenicpotential of periodontal pathogens remains largely unknown. Our studies have elucidated an interconnectionbetween cobalamin utilization stress responses and the virulence potential of Porphyromonas gingivalis(Pg) a key periodontal pathogen in periodontitis disease. As a potent redox sensor cobalamin promotes cellularhomeostasis under redox-changing stresses caused by nutritional limitation and reactive oxygen species (ROS).These stressors represent intrinsic attributes of the inflammatory mechanisms to eliminate infections. Based onour findings and that cobalamin plays a significant role in maintaining cellular homeostasis under redox-changing stresses we hypothesize that cobalamin acts as a key redox-active mediator orchestratinggenomic and metabolic adaptations thereby enabling the pathogen to overcome diverse stressesand foster pathogenicity. To investigate this hypothesis we propose two specific aims. Specific Aim 1. Theimpact of cobalamin on the genomic-metabolic adaptations in Pg strain 381 under stress conditions. This aimwill investigate; i) the impact of cobalamin on the gene expression profile of Pg under two separate biologicallyrelevant stresses including iron limitation and ROS availability. To this end we will perform RNA sequencingfollowed by RT-qPCR-based validation; and ii) the impact of cobalamin on the metabolic profile of Pg cellsgrown under the stress conditions by performing untargeted and targeted metabolomic analyses. Overall thisaim will greatly inform about the intricate connections between cobalamin utilization and the genomic-metabolicadaptations in Pg under biologically relevant stress conditions. Specific Aim 2. To understand cobalamin-regulated virulence potential and survival of Pg strain 381 in the presence of host defense mechanisms. We willdetermine: i) the effect of cobalamin on the virulence potential of Pg cells mediated by proteases known asgingipains; and ii) the impact of cobalamin on the survival of Pg and its immunostimulatory potential usingwhole blood killing and neutrophil assays. This aim will enable us to determine the impact of cobalamin on Pg'sability to survive within the host and modulate its pathogenic potential. Upon completion of the proposedstudies for the first time we will uncover the biological significance of cobalamin utilization in Pg's survivaland pathogenesis during infection. Understanding the role of cobalamin in the pathogenesis of periodontalpathogens has the potential to open new avenues for therapeutic interventions in periodontal disease.

project_terms:
Adult;Adverse effects;Anaerobic Bacteria;Applications Grants;Bacteria;Biological;Biological Assay;Cells;Cobalamin;Cobalt;Data;Disease;Disease Progression;Ensure;Etiology;Exhibits;Fostering;Foundations;Gene Expression Profile;Gene Expression Regulation;Genes;Genomics;Growth;Health;Homeostasis;Host Defense Mechanism;Human;Immune response;Individual;Infection;Inflammatory;Iron;Laboratories;Mediating;Mediator;Metabolic;Modification;Molecular;Mouth Diseases;Nutritional;Outcome Study;Oxidation-Reduction;Pathogenesis;Pathogenicity;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Periodontal Pocket;Periodontitis;Play;Porphyromonas gingivalis;Proliferating;Reactive Oxygen Species;Research;Role;Stress;Therapeutic Intervention;Time;Tissues;Tooth structure;Upregulation;Validation;Virulence;Virulence Factors;Vitamin B 12;Whole Blood;biological adaptation to stress;differential expression;environmental stressor;gingipain;insight;metabolic profile;metabolomics;microbial;microbiome;neutrophil;oxidation;pathogen;periodontopathogen;sensor;stressor;transcriptome sequencing;virulence gene

public_health_relevance:
PROJECT NARRATIVEPeriodontitis is a prevalent oral disease in adults. This study seeks to elucidate the biological significance ofcobalamin (Vitamin B12) utilization in the survival and pathogenesis of Porphyromonas gingivalis amajor contributing pathogen to periodontitis.


application_id: 11066459
project_number: 5R01CA258751-04
project_title: Combating melanoma resistance by targeting ABL1/2
administering_ic: NCI
award_notice_date: 2025-04-03
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;Immunosuppression;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: 11065838
project_number: 1R43DK142274-01
project_title: Novel Over-the-Scope Platform for Control of Variceal Bleeding
administering_ic: NIDDK
award_notice_date: 2025-07-15
opportunity_number: PA-23-230
application_type: 1
activity_code: R43
ic: DK
serial_number: 142274
program_official: LUNSFORD, DWAYNE
project_start_date: 2025-07-15
project_end_date: 2026-06-30
study_section: Special Emphasis Panel[ZRG1 KUDS-R (10)]
contact_pi_person_id: 11871743
contact_pi: APPLING, ANTHONY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 104266816
primary_uei: PK4YP8GE9EL5
duns_number: 104266816
uei: PK4YP8GE9EL5
fips: US
organization_id: 10059617
organization_name: ENDONAVIS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402224650
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractUpper gastrointestinal (UGI) bleeding from variceal hemorrhage marks a major turning point in the life of a patientwith cirrhosis. Up to 20% of these patients will die from the event. A major shortcoming in the treatment of UGIvariceal hemorrhage stems from the lack of a safe and effective method for controlling refractory bleedingepisodes and maintaining that control until a long-term definitive therapy can be deployed. Definitive therapy isgenerally only available at specialized/tertiary centers. Even at these locations assembly of the therapeutic teammay take hours before the patient receives the required procedure to stop the bleeding. Massive resuscitationefforts may be required to maintain the patients life prior to definitive therapy. Stop gap measures do exist todayin the form of blindly placed hemostatic balloons. Many shortcomings have been attributed to the use of thesedevices including esophageal perforation and death. Their ability to stop bleeding varies by location of thebleeding site with control rates as low as 0-50% for gastric varices and 50-80% for esophageal varices. Fewclinicians properly deploy these devices which contributes to the low rates of utilization despite an urgent need.EndoNavis is a rising medical device company focusing on the focused application of single-use disposablelow profile endoscopes for novel clinical applications in the GI space. Our pioneering Over-the-Scope technologyprovides new approaches to common clinical disorders. In the setting of variceal hemorrhage our approach ofendoscopic visualization during placement ensures proper alignment of the balloon with the bleeding site.Furthermore direct visualization allows for active monitoring of bleeding cessation. The scope of this project willfocus on mating existing single-use endoscope technology developed by EndoNavis with a novel balloon design.The project has been tailored to assess essential characteristics of this technology in benchtop anatomic andbleeding models to verify function and efficacy. Specific Aim 1 will focus on designing a therapeuticballoon/catheter capable of passage through the UGI anatomy with appropriate optical qualities to ensureexcellent endoscopic visualization. Specific Aim 2 will establish the optimal balloon design to control bleedingfrom both esophageal and gastric variceal sources. Specific Aim 3 will assess feasibility of the bleeding controlplatform in conducting post-treatment monitoring. The overall deliverable from this project will consist of afunctional bleeding control system ready for next stage verification and validation testing. EndoNavis will seekapproval via the 510(k) pathway. EndoNavis has substantial experience navigating the regulatory hurdlesrequired for single-use endoscopes. This Phase I grant will support the steps required to establish design freezefor this technology platform. Additional funds from either a Phase II grant or A round of investor funding will allowEndoNavis to take the final steps to commercialization. EndoNavis will likely utilize current OEM partners to fullytake this platform to market. An effective user-friendly and safe alternative to current technology will be awelcome addition providing a sure path for entry into the $850B hemostasis segment of the GI market.

project_terms:
Accident and Emergency department;Accounting;Adoption;Affect;Aftercare;Anatomy;Attention;Balloon Dilatation;Blood;Capital;Caring;Catheters;Cessation of life;Characteristics;Cirrhosis;Clinical;Coupled;Dangerousness;Development;Devices;Disease;Elasticity;Endoscopes;Engineering;Ensure;Equilibrium;Esophageal Varix;Esophagus;Etiology;Event;Face;Failure;Freezing;Funding;Fundus;Gastric Balloon;Gastric Varices;Gastrointestinal Hemorrhage;Glues;Grant;Helmet;Hemorrhage;Hemostatic Agents;Hemostatic function;Hospitals;Hour;Individual;Injections;Intervention;Interventional radiology;Life;Location;Manufactured football;Marketing;Masks;Measures;Medical Device;Methods;Modeling;Monitor;Nasopharynx;Optics;Partner in relationship;Pathway interactions;Patients;Perforation;Pharmaceutical Preparations;Phase;Procedures;Provider;Recurrence;Refractory;Resuscitation;Sclerosing Agents;Site;Source;Specific qualifier value;Stomach;Surgical Portosystemic Shunt;Symptoms;System;Technology;Testing;Therapeutic;Tube;Upper digestive tract structure;Validation;Visualization;Work;aspirate;blind;care costs;clinical application;commercialization;cost;design;esophageal stents;experience;gastrointestinal;hospital care;improved;interest;new technology;novel;novel strategies;pre-clinical;safe patient;stem;stomach cardia;success;technology platform;user-friendly;verification and validation

public_health_relevance:
NarrativeGastrointestinal bleeding occurs in over half of the 650000 US citizens affected by cirrhosis from any etiology.Up to 20% will die from uncontrolled bleeding or its complications. Hospital care costs for bleeding eventsapproach $71000 accounting for a cost of $2.5 trillion dollars per year. EndoNavis is developing a novelapproach to refractory variceal bleeding that will effectively control and monitor bleeding until delivery of definitivetherapy.


application_id: 11063575
project_number: 5P20GM130456-05
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: FRINCU, CRINA
project_start_date: 2024-02-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9(C1)
subproject_number: 6060
contact_pi_person_id: 11987895
contact_pi: CZUBA, LINDSAY CHRISTINE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Mechanistic insight into the regulation of the apical bile acid transporter (ASBT) using chemical biology approaches

project_abstract:
The proposed research is relevant to public health due to the essential role of bile acids in the regulation of lipid and glucose metabolism. Identification of mechanisms that modulate the stability of the human apical bile acid transporter may facilitate the development of innovative therapeutic strategies to restore bile acid flux and signaling in humans.

project_terms:
Apical;Bile Acids;Biology;Centers of Research Excellence;Chemicals;Development;Human;Pharmacologic Substance;Public Health;Regulation;Research;Role;Signal Transduction;Therapeutic;bile acid transporter;glucose metabolism;innovation;insight;lipid metabolism


application_id: 11062866
project_number: 3RF1AG084134-01S1
project_title: Diversity Supplement for Jenny Lutshumba
administering_ic: NIA
award_notice_date: 2024-05-28
opportunity_number: PA-23-189
application_type: 3
activity_code: RF1
ic: AG
serial_number: 084134
suffix: S1
program_official: ROVESCALLI, ALESSANDRA C
project_start_date: 2023-09-01
project_end_date: 2026-08-31
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: GERMAN, DWIGHT C.;ZHANG, RONG ;ZHU, DAVID C
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThere is a sex-based difference in the etiology of Alzheimers disease (AD) and Vascularcontribution to cognitive impairment and dementia (VCID) the two most common forms ofdementia. Females have a higher incidence of Alzheimers disease and related dementias(ADRD) as well as sex-based differences in cardiovascular risk factors for dementia. In asubgroup of participants from the risk reduction for Alzheimers disease (rrAD; NCT02913664)clinical trial at baseline we found a sex difference in plasma AD biomarkers. Females hadhigher levels of total tau and total tau/Ab42 while pTau181 was higher in males with nodifference found in the Ab42/40 ratio. VCID biomarkers also show no sex-based differences.There was however a sex-based difference in the association between AD and VCIDbiomarkers. In females VEGF-D associated with total Tau while in males VEGF-D associatedwith pTau181 and pTau181/Ab42 and bFGF associated with Tau/Ab42. These preliminaryfindings support a sex-based difference of biomarkers in the pathogenesis of VCID and AD incognitively healthy older adults. However there is still a reluctance in human studies to stratifycohorts by sex. Moreover there is great appreciation for the importance of the crosstalkbetween the systemic immune system and the brain pathologies in ADRDs. However the role ofsystemic inflammation in the pathogenesis of ADRDs remains under-explored. The purpose ofthe proposed supplement is to investigate the sex effects of independent and combined effectsof Intensive pharmacological Reduction of Vascular Risk factors (IRVR) i.e. hypertension anddyslipidemia and aerobic Exercise (Ex) on inflammation and cognitive function. Here we willtest the hypothesis that females in IRVR+Ex will ameliorate AD/VCID-associated biomarkersand pro-inflammatory cytokines and associate with better cognitive function by testing thefollowing aims: Aim1: To determine whether there is a sex difference in inflammatory cytokinesand injury markers in the plasma between IRVR+Ex and IRVR or Ex and their association withAD/VCID biomarkers. Aim2: To determine whether there is a sex-mediated amelioration inalteration in peripheral immune cells in IRVR+Ex compared to IRVR or Ex.The long-term goal of this project is to identify inflammatory biomarkers that will be predictive ofADRD in males and females.

project_terms:
Adult;Aerobic Exercise;Age;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimer's disease risk;Alzheimers disease biomarker;Anti-Inflammatory Agents;Biological Markers;Biometry;Blood Pressure;Brain Pathology;Cardiovascular Diseases;Cells;Clinical Trials;Cognitive;Data Analyses;Data Collection;Dementia;Development;Development Plans;Diagnosis;Doctor of Medicine;Doctor of Philosophy;Dyslipidemias;Ensure;Etiology;Experimental Designs;FGF2 gene;Female;Fibrinogen;Foundations;Funding;Future;Goals;Grant;Health;Human;Hypertension;Immune;Immune system;Immunophenotyping;Incidence;Inflammation;Inflammatory;Injury;Intervention;Learning;Lipids;Liquid substance;Manuscripts;Mediating;Mentors;Mentorship;Outcome;Participant;Pathogenesis;Peripheral;Peripheral Blood Mononuclear Cell;Plasma;Risk Reduction;Role;Sex Differences;Subgroup;Testing;Training;Vascular Endothelial Growth Factor D;Women's prevalence;Writing;aged;cardiovascular risk factor;career;career development;cognitive function;cohort;cytokine;dementia risk;drug development;effective intervention;high risk;improved;lifestyle intervention;male;older adult;pharmacologic;sex;specific biomarkers;systemic inflammatory response;tau Proteins;vascular cognitive impairment and dementia;vascular risk factor

public_health_relevance:
Diversity Supplement on Funded Grant RF1 AG084134 Biomarkers to Track Effective Interventions ThatDelay Dementia Onset In Participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" TrialProject Narrative: This proposed supplement aims to identify sex differences in immune dysregulation andinflammatory cytokines in subjects with cardiovascular risk factors (i.e hypertension and dyslipidemia) and atrisk for Alzheimers disease and related dementias (ADRD) and determine if an effective lifestyle interventionwill delay the development of dementia. Additionally this project will help refine the fluid biomarkers anddistinguish between males and females with high risk for ADRD consequently improving diagnosis and drugdevelopment for Alzheimers disease and related dementias.


application_id: 11062237
project_number: 3R01CA251478-04S1
project_title: Local Flavor Policies to Enhance Equity in Tobacco - A Diversity Supplement
administering_ic: NCI
award_notice_date: 2024-09-05
opportunity_number: PA-23-189
application_type: 3
activity_code: R01
ic: CA
serial_number: 251478
suffix: S1
program_official: RODITIS, MARIA LEIA
project_start_date: 2024-09-01
project_end_date: 2026-03-31
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTPolicies restricting the sale of flavored tobacco products (FTP) are being enacted in localities around the US.We seek to expand the evidence base about the extent to which these policies decrease access to FTPs andexposure to flavored tobacco marketing and would likely reduce use of tobacco among youth and youngadults. Additionally few studies examine the potential of these policies to reduce tobacco-related healthdisparities among youth/young adult populations of color and those of lower socioeconomic status (SES).These vulnerable populations use flavored products at higher rates and FTPs are heavily marketed incommunities where these vulnerable groups live. Determining the impact of FTP policies overall and onpopulations of color and lower SES youth/young adults in these communities can make sure that policies arestructured to ensure equitable reach and reduce tobacco use disparities. The purpose of this study is todetermine the impact of flavor policies on reducing exposure to and use of FTPs among vulnerableyouth/young adults. Using the Policy Implementation Framework and the Elaboration Likelihood Model as ourtheoretical guides we combine national local and individual data to examine the equity impact of flavorpolicies around the US. To accomplish the study purpose we will conduct several aims. (1) We will use alongitudinal national dataset of youth and young adults (n=13892) followed for nine waves twice a year from2014 to examine changes in tobacco marketing exposure and FTP and non-FTP use in those exposed to anFTP policy with no FTP policy exposure over time focusing on differences by race/ethnicity and SES. (2) Wewill compare marketing exposure to and appeal of FTP/non-FTPs between emerging adults in communitiescovered by flavor policy variants through ecological momentary assessment (EMA) evaluating differences inoutcomes by SES and race/ethnicity at the individual and neighborhood level. (3) Finally among EMAparticipants we will assess the predictive validity of exposure to FTP/non-FTP marketing exposure on use ofFTP and non-FTPs at 6-month follow-up and evaluate whether these outcomes are associated with SES andrace/ethnicity. For all of these activities we will partner with national and local FTP policy experts who willdisseminate lessons learned to communities who have or are considering an FTP policy. Achieving the aims ofthis R01 will expand the evidence base of the impacts of FTP policies on reducing tobacco use and potentialequity impact of these policies to reduce tobacco and ultimately cancer disparities.

project_terms:
Acceleration;Affect;Age;Area;Cessation of life;Cigarette;Cohort Studies;Communities;Complement;Data;Data Collection;Data Set;Disparity;Disparity population;Ecological momentary assessment;Electronic cigarette;Ensure;Equation;Equity;Ethnic Origin;Exposure to;Goals;Health;High School Student;Individual;Inequity;Longitudinal cohort;Longitudinal cohort study;Longitudinal trends;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Mediating;Mediation;Methods;Modeling;Morbidity - disease rate;Neighborhoods;Outcome;Participant;Persons;Play;Policies;Population;Populations at Risk;Prevalence;Protocols documentation;Race;Research;Research Personnel;Role;Sales;Socioeconomic Status;Structure;Surveys;Testing;Time;Tobacco;Tobacco Industry;Tobacco use;Training;United States;Variant;Visit;Vulnerable Populations;Youth;cancer health disparity;career;cigarette smoking;cohort;electronic cigarette use;emerging adult;ethnic minority;evidence base;follow-up;health disparity;health equity promotion;implementation framework;innovation;insight;low socioeconomic status;marginalization;mortality;parent grant;people of color;public policy on tobacco;racial difference;racial minority;reduce tobacco use;tobacco advertising;tobacco exposure;tobacco flavor;tobacco products;tobacco regulatory science;uptake;vulnerable community;young adult

public_health_relevance:
PROJECT NARRATIVEThis project seeks to examine whether innovative local tobacco control policies restricting sales of flavoredtobacco products can reduce tobacco use and disparities in tobacco and ultimately cancer. The study willexamine trajectories of flavored tobacco use in a large longitudinal national cohort of youth and young adultsamong those exposed and not exposed to policy. It will also examine youth and young adult non-tobacco userexposure to tobacco marketing and subsequent tobacco use outcomes in real-time in eight communities withdifferent flavor policy variants and will have a particular focus on assessing differences in policy impact acrossvulnerable group status.


application_id: 11061926
project_number: 5R01NS121193-05
project_title: Functional Diversity of Reactive Astrocytes in Spinal Cord Repair
administering_ic: NINDS
award_notice_date: 2025-04-02
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 121193
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-04-01
project_end_date: 2027-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9380335
contact_pi: CHEN, MEIFAN
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 / ABSTRACTAs key modifiers of injury outcome following CNS insults reactive astrocytes represent a rational cellular targetfor neural repair. CNS injury results in scar-forming astrogliosis at the primary lesion and diffuse astrogliosis inareas of distal axon degeneration the latter of which is poorly characterized. Without a complete understandingof how reactive astrocyte subtypes impact the CNS injury response harnessing the full therapeutic potentials ofreactive astrocytes will remain unlikely. The long-term goal is to translate knowledge of the diverse functions ofreactive astrocytes to treat CNS trauma. Towards this goal the objective of this proposal is to identify themolecular and cellular mechanisms that determine location-specific functions of scar-forming and diffuseastrogliosis in the injured spinal cord. The hypothesis is that scar-forming astrogliosis supports pathologicalmacrophage retention within the chronic scar at the lesion whereas diffuse astrogliosis induces axon growthdistal to the lesion after spinal cord injury (SCI). The rationale for this proposal is that defining the cell-intrinsicand environmental contributions to the diverse functions of reactive astrocytes will inform on how to targetreactive astrocytes efficaciously for CNS repair. Based on strong supporting data this hypothesis will be testedby pursuing three specific aims: 1) determine the role of scar-forming astrocytes in macrophage maintenance atthe chronic SCI scar; 2) examine the role of diffuse astrogliosis in promoting axon growth distal to the lesion; and3) assess the effects of locally modifying either scar-forming or diffuse astrogliosis by an AAV-mediated approachon SCI recovery. These studies will significantly advance understanding of reactive astrocytes and the ability todevelop novel astrocyte-targeted therapeutic approaches to attenuate chronic scarring and promote axon growthafter SCI.

project_terms:
Abbreviations;Area;Astrocytes;Attenuated;Axon;Cells;Chest;Chronic;Cicatrix;Corticospinal Tracts;Data;Diffuse;Distal;Functional disorder;Genetic;Glial Fibrillary Acidic Protein;Goals;Hindlimb;Human;Injury;Knock-out;Knowledge;Lateral;Lesion;Leucine Zippers;Location;Macrophage;Macrophage Colony-Stimulating Factor;Maintenance;Mediating;Microglia;Microinjections;Modeling;Molecular;Motor;Mus;Outcome;Paralysed;Pathologic;Pathology;Pathway interactions;Phenotype;Phosphotransferases;Primary Lesion;Proliferating;Reaction;Recovery;Regulation;Repression;Research;Role;Sensory;Site;Spinal;Spinal Cord;Spinal cord injury;Tamoxifen;Testing;Therapeutic;Tissues;Translating;Traumatic CNS injury;United States;Work;astrogliosis;axon growth;axonal degeneration;axonal sprouting;cellular targeting;central nervous system injury;disability;genetic manipulation;in vivo;injury and repair;injury recovery;insight;monocyte;neural;neural repair;novel;overexpression;promoter;repair strategy;repaired;response to injury;restoration;spinal cord repair;targeted treatment;tool;translational approach

public_health_relevance:
PROJECT NARRATIVESpinal cord injury is a leading cause of paralysis in the United States with limited treatment options. Astrocytesinfluence injury outcome after spinal cord injury and therefore present an attractive cellular target for repairstrategies. This proposed research will determine location specific functions of reactive astrocytes in the injuredspinal cord to provide the basis for an astrocyte-targeted approach to promote neural recovery and reducehuman disability.


application_id: 11061878
project_number: 5R01NS079507-11
administering_ic: NINDS
award_notice_date: 2025-04-02
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 079507
program_official: LEENDERS, MIRIAM
project_start_date: 2012-09-30
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-04-01
project_title:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy

project_abstract:
Blood-brain barrier dysfunction is recognized as both a cause and consequence of seizures in epilepsy. Two keycharacteristics of barrier dysfunction in epilepsy include 1) neurovascular inflammation and 2) barrier leakageboth of which have been linked to seizures. In spite of increasing evidence supporting that glutamate causesblood-brain barrier dysfunction knowledge of the associated underlying mechanisms remain to be fully defined.Moreover therapeutic options for restoring barrier function are currently not available. Thus there is an unmetcritical need to determine how glutamate promotes blood-brain barrier inflammation and leakage and to developtargeted strategies to restore barrier function. The consequence of this unmet need is that development of noveltreatments to improve seizure control in epilepsy will likely remain a clinical challenge. The long-term goal of theinvestigator is to contribute toward the development of mechanism-based strategies to repair blood-brain barrierdysfunction in brain diseases. The overall objective in this application is to establish the efficacy of a mechanism-based intervention to treat blood-brain barrier dysfunction in epilepsy thereby vertically extending what has beenlearned under current funding. Based on preliminary data the central hypothesis of this project is that glutamatesignaling mediates blood-brain barrier dysfunction and that therapeutic intervention targeting this mechanismwill resolve seizure-induced neurovascular inflammation repair barrier leakage and reduce seizure burden. Therationale for the proposed research is that its successful completion will provide a robust framework for thecontinued development and clinical translation of a novel evidence-based therapeutic intervention to help treatseizures in patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identifysignaling steps responsible for seizure-induced inflammation of the blood-brain barrier. 2) Determine themechanism responsible for capillary leakage at the human blood-brain barrier and 3) Develop a therapeuticintervention to reduce seizure burden in a chronic epilepsy model. Under Aim 1 signaling steps that lead toseizure-mediated neuroinflammation will be determined in capillaries isolated from knockout mouse models andverified in vivo. Under Aim 2 key signaling steps that trigger barrier leakage will be determined in human braincapillaries from seizure-free control individuals and from patients with epilepsy. Under Aim 3 an interventiontherapy designed to repair barrier dysfunction will be developed and the therapeutic benefit of this strategy onreducing seizure burden will be evaluated in a rat chronic epilepsy model. The proposed research is innovativebecause it represents a substantive departure from the status quo by shifting the focus to molecular targets atthe blood-brain barrier to resolve neurovascular inflammation restore barrier function and improve epilepsysymptoms. The proposed research is significant because it holds the promise of a novel therapeutic approachto repair barrier dysfunction that has translational potential for clinical use to advance treatment of patients withepilepsy and other seizure disorders with underlying barrier dysfunction.

project_terms:
Agonist;Arachidonate 5-Lipoxygenase;Attenuated;Automobile Driving;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Blood capillaries;Brain Diseases;Cell Adhesion Molecules;Characteristics;Chronic;Clinical;Combined Modality Therapy;Data;Data Reporting;Development;Disease;Endothelium;Epilepsy;Extracellular Matrix Proteins;Extravasation;FPR2 gene;Feedback;Functional disorder;Funding;Glutamates;Goals;Human;Individual;Inflammation;Intervention;Knockout Mice;Knowledge;LOX gene;Lead;Learning;Leukocytes;Leukotrienes;Link;Lipoxygenase;Matrix Metalloproteinases;Mediating;Mission;Modeling;Molecular Target;Mus;National Institute of Neurological Disorders and Stroke;Nervous System Disorder;Neurons;PTGS2 gene;Pathway interactions;Prostaglandins;Proteins;Public Health;Publishing;Rattus;Research;Research Personnel;Seizures;Signal Transduction;Symptoms;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;cerebral capillary;clinical translation;cyclooxygenase 2;epilepsy patient;evidence base;expectation;glutamatergic signaling;improved;in vivo;innovation;mouse model;neuroinflammation;neurotransmitter release;neurovascular;new therapeutic target;novel;novel therapeutic intervention;repaired;therapy design;translational potential;vascular inflammation

public_health_relevance:
The proposed research is relevant to public health because it is expected to identify molecular targets that can be exploited to repair the blood-brain barrier after seizure-induced neuroinflammation and dysfunction. Thistherapeutic strategy is expected to improve seizure control in patients with epilepsy. Thus the proposed research is relevant to the part of the NIH/NINDS mission that pertains to developing fundamental knowledge that will help reduce the burden of neurological disease.


application_id: 11061831
project_number: 5K99DA060267-02
administering_ic: NIDA
award_notice_date: 2025-05-15
opportunity_number: PA-20-187
application_type: 5
activity_code: K99
ic: DA
serial_number: 060267
program_official: LAO, GUIFANG
project_start_date: 2024-07-01
project_end_date: 2026-06-30
study_section: ZDA1-MXS-T(J1)M
contact_pi_person_id: 78355881
contact_pi: REGNIER, SEAN
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-07-01
project_title:
Adapting and Testing a Smoking Cessation Intervention in Adults with Intellectual and Developmental Disabilities

project_abstract:
ABSTRACTCigarette smoking is the leading cause of preventable death in the United States. Despite a substantial decreasein cigarette smoking over the past decade cigarette smoking accounts for nearly half a million deaths nationallymore than alcohol and illicit drug use combined. People living with intellectual and developmental disabilities(IDDs) are exceptionally vulnerable to dangers posed by cigarette smoking because it may worsen healthconditions common among people with IDDs including diabetes and asthma. People living with IDDs are at anincreased risk of developing a tobacco use disorder (TUD) have a lower likelihood of entering treatment andhave a higher probability of dropping out of treatment. These issues highlight serious health equity concerns forpeople with IDDs including stigma exclusion underrepresentation and lack of access to high quality care andmay contribute to both the onset of cigarette smoking and serve as barriers to tobacco treatment enrollmentthus making people with IDDs vulnerable to persistent TUD and tobacco-related disease. The goal of thisK99/R00 Pathway to Independence Award is to use a community engaged approach to elucidate treatmentdifficulties in IDD populations and use the information gained from the community to adapt and test an evidence-based smoking cessation intervention. Achieving this goal is a crucial step in a larger process of establishing anessential line of research treating TUDs with people with IDDs. Through this K99 we aim to complete 40 semi-structed interviews with staff and patients actively engaged and not engaged in tobacco treatment to 1) identifybarriers that contribute to low TUD treatment enrollment and high drop-out rates for people with IDDs and 2)select and adapt an existing intervention for use with those with IDDs. Through the R00 we will utilize the resultsof our K99 to evaluate the feasibility acceptability and initial efficacy of a tailored behavioral smoking cessationintervention in this population. The modified intervention based on findings from the K99 will be implementedin a feasibility trial in people with IDDs. Outcomes will include intervention feasibility and acceptability (primaryoutcome) self-reported cigarette smoking (secondary outcome) and cigarette smoking measured by expiredbreath carbon monoxide (secondary outcome). The results of this project will inform the development andimplementation of a larger randomized controlled trial to be conducted as part of a future R01 grant. This projectwill fill a profound research gap by understanding significant smoking treatment barriers and developing andpiloting a tailored smoking cessation intervention for people with IDDs. This award will include substantial trainingand mentorship from a diverse group of K99 mentors who will supplement Dr. Regniers experience in theapplication of evidence-based treatments to IDD populations and provide him with skills in implementationscience clinical trial research community engagement and professional development that will help him obtainhis goal of becoming a leader in addiction research in people with IDDs.

project_terms:
Address;Adult;Alcohols;Asthma;Award;Behavior Therapy;Behavioral;Carbon Monoxide;Cessation of life;Clinical;Clinical Trials;Collaborations;Communities;Consult;Data;Development;Developmental Disabilities;Diabetes Mellitus;Disadvantaged;Disease;Dropout;Drops;Enrollment;Evidence based intervention;Evidence based practice;Evidence based treatment;Exclusion;Feedback;Foundations;Future;General Population;Goals;Grant;Health;Health Care;Human Development;Impairment;Incentives;Intellectual functioning disability;Intervention;Interview;Lived experience;Maps;Measures;Mentors;Mentorship;Modeling;Modernization;Modification;Outcome;Participant;Pathway interactions;Patient Self-Report;Patients;Persons;Pilot Projects;Population;Positioning Attribute;Poverty;Preparation;Probability;Process;Provider;Publishing;Quality of Care;Randomized Controlled Trials;Research;Research Training;Review Literature;Risk;Smoke;Smoking;Smoking Cessation Intervention;Smoking treatment;Suggestion;Testing;Time;Tobacco;Tobacco Use Disorder;Tobacco use;Token Economy;Training;United States;Vocabulary;Vulnerable Populations;Work;acceptability and feasibility;addiction;career development;cigarette smoking;community engaged approach;community engagement;contingency management;design;evidence base;experience;feasibility trial;health equity;illicit drug use;implementation science;improved;individualized medicine;preventable death;primary outcome;secondary outcome;skills;smoking cessation;smoking prevalence;social health determinants;social stigma;substance use;systematic review;treatment research

public_health_relevance:
PROJECT NARRATIVEThis project will increase our understanding of critical cigarette smoking treatment barriers for people living withintellectual and developmental disabilities. This project will also bridge a significant treatment-focused researchgap between people with intellectual disabilities and the general population. The studies proposed in thisK99/R00 will identify and adapt a tailored evidence-based smoking cessation treatment for people withintellectual and developmental disabilities (IDDs) utilizing stakeholder feedback and perspectives.


application_id: 11061254
project_number: 5R01CA249734-05
project_title: Targeting Lipid Metabolism in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2025-03-06
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 249734
program_official: WATSON, JOANNA M
project_start_date: 2021-04-01
project_end_date: 2027-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated and activated in CRC and its activity is associated with poor prognosis higher risk of disease recurrence and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis palmitate is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipid implicated in metastasis. Therefore in Aim 1 we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore our preliminary studies show a correlation between expression of FASN and CD36 a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore in Aim 2 we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3 we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients human primary CRC cells tumor organoids established from genetically modified mice and CRC metastasis models which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches including targeted and stable isotope-resolved metabolomics (SIRM) to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN SphKs and CD36 as therapeutic targets in CRC the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.

project_terms:
Biological;Biological Assay;Biological Sciences;CD36 gene;Cancer Etiology;Cancer Patient;Cause of Death;Cecum;Cell Survival;Cessation of life;Clinical;Clinical Trials;Collaborations;Colorectal Cancer;Compensation;Data;Development;Disease;Drug Evaluation;Drug Targeting;Environment;Enzymes;Fatty Acids;Fatty-acid synthase;Gene Modified;Goals;Growth;Human;In Vitro;Incidence;Injections;Knowledge;Lipids;Literature;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Microarray Analysis;Modeling;Molecular;Morbidity - disease rate;Mus;Neoplasm Metastasis;Oncology;Organ;Organoids;Outcome;Palmitates;Pathway interactions;Patients;Phase;Phase I/II Clinical Trial;Phase II Clinical Trials;Pre-Clinical Model;Prognosis;Public Health;Recurrent disease;Regulation;Research;Role;Sampling;Signal Pathway;Solid;Solid Neoplasm;Specimen;Sphingolipids;Sphingosine;Testing;Therapeutic;Tissue Microarray;Tumor Angiogenesis;United States;Upregulation;Validation;Woman;analog;cancer cell;colorectal cancer metastasis;colorectal cancer progression;fatty acid metabolism;genetic approach;high risk;in vivo;in vivo Model;inhibitor;lipid biosynthesis;lipid metabolism;men;metabolomics;mortality;mouse model;neutralizing antibody;new therapeutic target;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;pharmacologic;preclinical study;prevent;resistance mechanism;response;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;therapeutic target;transcriptome sequencing;translational impact;translocase;tumor;tumor metabolism;uptake

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the 2nd most common cause of cancer death among men and women in the Unites States with a majority of the mortality associated with metastasis that has spread to other organs. We have proposed to investigate the mechanisms of how lipid metabolism promotes CRC metastasis. The completion of this study will help to advance our knowledge of the contribution of lipid metabolism to CRC metastasis and to further guide the development of novel therapeutic strategies to treat CRC and potentially other solid cancers.


application_id: 11061026
project_number: 5R01DE028883-05
project_title: Topical Vitamin D and Periodontal Disease
administering_ic: NIDCR
award_notice_date: 2025-03-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 028883
program_official: CHANDER, PREETHI
project_start_date: 2021-04-02
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-V(02)M]
contact_pi_person_id: 1891127
contact_pi: DIAMOND, GILL
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTPeriodontal disease is associated with an increase in Porphyromonas gingivalis dysbiosis of the commensalmicrobiota in the subgingival crevice and chronic inflammation resulting in bone resorption and ultimately toothloss. Vitamin D is best known as a principal factor that maintains calcium homeostasis and is required for bonedevelopment and homeostasis. However it is becoming clear that vitamin D has profound actions in immunityand inflammation as well. Both the chronic and aggressive forms of periodontal disease have been associatedwith vitamin D deficiency in numerous populations. Our recently published data show that the active form ofvitamin D 125(OH)2D3 promotes anti-bacterial activity against P. gingivalis by gingival epithelial cells (GEC)and inhibits pro-inflammatory cytokine expression. Experimental vitamin D deficiency in mice leads to gingivalinflammation and bone loss. However clinical trials examining the effect of oral vitamin D supplementation onperiodontal disease have led to conflicting results likely due to natural feedback mechanisms. We thereforehypothesized that topical administration of vitamin D to the gingiva could circumvent this problem. Ourpreliminary results indicate that when inactive vitamin D is delivered directly to the surface of the gingivalepithelium both in vitro and in mice we observe a rapid induction of vitamin D-mediated genes as well as aninhibition of pro-inflammatory cytokines without cytotoxicity. We also observed that the epithelial cells convertinactive vitamin D3 to both the inactive intermediate (25OHD3) and to active 125(OH)2D3 through epithelial cell-expressed hydroxylases and that this conversion resulted in increased production of the host defense peptideLL-37. Thus our overarching hypothesis is that that the gingival epithelium maintains its own intrinsic regulationof vitamin D status and that topical delivery of vitamin D to the oral epithelium allows direct introduction of highconcentrations of active vitamin D to the tissue. This delivery can lead to regulation of vitamin D-regulated genesthat can downregulate inflammation and prevent the growth of periopathogenic bacteria and the resulting boneloss. To address this we propose the following specific aims: 1) Quantify the relationship between vitamin Dand periodontal disease in a mouse model. 2) Define the shifts in the oral microbiome regulated byvitamin D. 3) Characterize the mechanism of vitamin D-mediated induction of innate immunity in culturedhuman GEC. Together these aims will support our hypothesis that vitamin D is essential for periodontal healthwill help define the mechanism by which this occurs and will provide a proof of principle that topicaladministration of vitamin D in the oral cavity can maintain this health status. Vitamin Ds actions are complex andmultifaceted but harnessing its beneficial activities has the potential to change periodontal practice replacingexpensive mechanical and surgical procedures with well-reasoned safe and reliable topical treatments with notoxicity.

project_terms:
3-Dimensional;Actinobacillus actinomycetemcomitans;Address;Affect;Anti-Bacterial Agents;Apical;Bacteria;Bioinformatics;Bone Development;Bone Resorption;Calcium;Cells;Cholecalciferol;Chronic;Clinical;Clinical Trials;Complex;Data;Development;Epigenetic Process;Epithelial Cells;Epithelium;Feedback;Genes;Genetic;Gingiva;Growth;Health;Health Status;Homeostasis;Host Defense;Human;Immune;Immunity;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Inflammatory Response Pathway;Kinetics;Link;Mechanics;Mediating;Mixed Function Oxygenases;Molecular;Mus;Natural Immunity;Operative Surgical Procedures;Oral;Oral cavity;Outcome;Pathway interactions;Peptides;Periodontal Diseases;Periodontitis;Population;Porphyromonas gingivalis;Preventive therapy;Production;Publishing;Regulation;Reporting;Role;Signal Pathway;Surface;Tissues;Tooth Loss;Topical application;Toxic effect;Vitamin D;Vitamin D Deficiency;Vitamin D supplementation;Vitamin D3 Receptor;Vitamins;absorption;antimicrobial;bone loss;cathelicidin antimicrobial peptide;commensal microbes;cytokine;cytotoxicity;dysbiosis;mouse model;oral cavity epithelium;oral infection;oral microbial community;oral microbiome;oral supplementation;pathogenic bacteria;periodontopathogen;prevent;response;supervitaminosis;three dimensional cell culture;transcription factor

public_health_relevance:
PROJECT NARRATIVEPublished and preliminary results demonstrate that vitamin D can increase the immune defenses of gingival cellsagainst the bacteria associated with periodontal disease. Here we propose to examine the role of vitamin D inperiodontal disease in a mouse model and to study the mechanism by which this occurs. The results will supportthe development of vitamin D as a therapy for periodontal disease and other oral infections.


application_id: 11060983
project_number: 5R01DE030103-04
project_title: Therapeutic vascularization to support repair of damaged salivary glands
administering_ic: NIDCR
award_notice_date: 2025-03-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 030103
program_official: VERBRIDGE, SCOTT SPENCER
project_start_date: 2022-04-01
project_end_date: 2027-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 11258094
contact_pi: SANDELL, LISA L
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Damage to salivary glands is a devastating condition  identification of therapies topromote regeneration of these important organs is imperative. Great progress is being made inengineering and transplantation of salivary gland epithelium. A major remaining hurdle ingland engineering is the need to establish a functional vasculature which is essential for survivalof any replacement tissue in vivo. In addition to essential support therapeutic angiogenesis alsostimulates healing of non-vascular tissue. This study will characterize methods of promotingvascularization in regenerating salivary gland tissues. Using mice as a pre-clinical model systemwe will evaluate two distinct therapeutic approaches  individually and in combination  topromote vascularization and regeneration of damaged glands. One therapeutic approachinvolves implantation of an exogenous vascular cell milieu as a method to enhance formation offunctional blood vessel networks. The other approach which may be effective when used inconjunction with implanted cells or on its own will involve systemic delivery of a drug withpotential to stimulate angiogenesis. The therapeutic potentials of the of the two approaches willbe evaluated separately and in combination in vivo in mice in a biopsy wound healing model.Cellular and molecular events of vascular assembly associated with each therapy will be definedusing cell culture assays in vitro. For implantation of vascular cells we will use a cell milieu ofstromal vascular fraction derived from adipose (AdSVF). The AdSVF cell milieu has realadvantages as a cell source. It includes many cell types needed to form functional blood vesselnetworks (endothelial pericytes vascular smooth muscle fibroblasts) it reduces inflammationto promote regeneration of parenchymal tissue it is readily available for self-donation andimportantly has proven safe for clinical use. As an adjunct to implanted AdSVF or as astand-alone vascularizing therapeutic we will also test the ability of a systemic pharmacologicagent Tazarotene to stimulate formation of functional vascular networks. Tazarotene is asynthetic retinoid. Its vascular promoting activity is consistent with the action of naturalretinoids including vitamin A and its derivative retinoic acid which are essential for vascularassembly in vivo. This project will identify methods to promote functional vasculature inregenerating salivary glands. Resulting knowledge can be used to enhance success of therapiesaimed at repairing salivary epithelium thereby advancing the field toward developing effectivetherapies for patients suffering from salivary gland damage.

project_terms:
Adipose tissue;Angiogenesis Promoter;Autoimmune Diseases;Biological Models;Biology;Biopsy;Blood Vessels;Blood flow;Cell Culture Techniques;Cells;Clinical;Complex;Endothelial Cells;Endothelium;Engineering;Ensure;Epithelium;Event;FDA approved;Fibroblasts;Gene Expression;Genetic Transcription;Gland;Growth;Implant;In Vitro;Individual;Inflammation;Knowledge;Malignant Neoplasms;Methods;Microbubbles;Molecular;Mus;Natural regeneration;Organ;Pathology;Patients;Perfusion;Pericytes;Persons;Pharmaceutical Preparations;Pilot Projects;Pre-Clinical Model;Proliferating;Radiation therapy;Recovery;Retinoids;Salivary;Salivary Gland Tissue;Salivary Glands;Skin;Smooth Muscle Myocytes;Source;Submandibular gland;Supporting Cell;System;Tazarotene;Testing;Therapeutic;Therapeutic Uses;Tissue Engineering;Tissues;Transplantation;Vascular Smooth Muscle;Vascularization;Vitamin A;Wound models;angiogenesis;blood vessel development;cell type;effective therapy;experience;healing;implantation;in vitro Assay;in vivo;knowledge of results;novel;novel therapeutics;pharmacologic;repaired;replacement tissue;saliva secretion;small molecule;success;therapeutic angiogenesis;wound;wound healing

public_health_relevance:
Project NarrativeLoss of salivary gland function is a devastating condition. Millions of people lose salivary glandfunction from autoimmune disease or cancer radiation treatment and therapies to promotegland repair are needed. Repair of salivary gland tissues requires re-growth of blood vessels thatcan support salivary gland tissue as it heals from damage.


application_id: 11060960
project_number: 5R16GM149498-03
project_title: Brain Development after Early-Life Antipsychotic Treatment
administering_ic: NIGMS
award_notice_date: 2025-04-24
opportunity_number: PAR-21-169
application_type: 5
activity_code: R16
ic: GM
serial_number: 149498
program_official: BASKIR, RUBIN SAM
project_start_date: 2023-06-01
project_end_date: 2027-04-30
study_section: ZGM1-RCB-A(SU)
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. This is an application for a Support of Research Enhancement (SuRE) R16 award. These grants are intended to support small scale research projects at institutions like Northern Kentucky University that do not receive substantial NIH funding with an additional emphasis on providing biomedical research experiences to undergraduate students and enhancing the research environment at the university. Antipsychotic drugs (APDs) are widely used in children mainly as off-label treatments for a multitude of pediatric psychiatric disorders despite the lack of basic research documenting their effects on later brain and behavioral function. One concern is that APD exposure during early brain development alters later sensitivity to drugs of abuse. Our previous NIH-funded research showed that adult rats administered the APD risperidone early in life are hyperactive exhibit enhanced locomotor and rewarding responses to the psychostimulant D-amphetamine and display alterations in forebrain dopamine transporters and receptors. These data were generated by undergraduate students at NKU many of whom served as first- or co- authors on published papers and some of whom went on to pursue graduate study in psychology.  Having ascertained that early-life risperidone modifies responses to psychostimulant drugs that directly target dopamine synapses we now seek to determine if behavioral and neural sensitivity to other classes of drugs such as opioids that indirectly work though dopamine pathways is enhanced by early-life risperidone. The proposed work will ascertain whether behavioral neural and genetic responses to the opioid drug oxycodone are altered in adult rats administered risperidone early in life (daily injections from postnatal day 14-42). This issue is especially germane to NKU students since our geographic area is marked by relatively high rates of opioid use and overdose. Overall the proposed research will address the following questions: 1) Does early-life APD administration enhance the rewarding effects of oxycodone during adulthood? 2) Does early-life APD administration increase neural sensitivity to oxycodone in the forebrain during adulthood? and 3) Does early-life APD administration modify patterns of forebrain gene transcription induced by oxycodone during adulthood? The last aim will be achieved by collaborating with the nearby University of Louisville to quantify mRNA expression in tissue samples using next-generation RNA-Seq technology. A concomitant goal of this work will be to continue engaging NKU undergraduate students in the execution analysis and reporting of research. The proposed work will take advantage of training and pedagogical resources offered by NKU and the KY-INBRE program to enhance these experiences and in turn contribute to the overall research environment at NKU.

project_terms:
Adult;Affect;Amphetamines;Antipsychotic Agents;Attention deficit hyperactivity disorder;Award;Basic Science;Behavioral;Bioinformatics core;Biomedical Research;Brain;Brain region;Child;Childhood;Collaborations;Control Groups;Core Facility;Data;Development;Dextroamphetamine;Disease;Disruptive Behavior Disorder;Dopamine;Dopamine Agonists;Dopamine Receptor;Dose;Drug Exposure;Environment;Exhibits;Extinction;FOS gene;Funding;Genetic;Genetic Transcription;Geographic Locations;Goals;Grant;Hyperactivity;Immediate-Early Genes;Injections;Institution;Kentucky;Label;Laboratory Rat;Life;Long-Term Effects;Mental disorders;Mentors;Messenger RNA;Metabolic;Modification;Neurons;Neurosciences;Neurotransmitter Receptor;Nucleus Accumbens;Opioid;Outcome;Oxycodone;Paper;Pathway interactions;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Policy Maker;Population;Prosencephalon;Psychology;Publishing;Rattus;Recommendation;Reporting;Research;Research Project Grants;Research Support;Resources;Rewards;Risk;Risperidone;Scientist;Series;Short-Term Memory;Students;Substance abuse problem;Synapses;Techniques;Technology;Text;Time;Tissue Sample;Training;Transcript;United States;United States National Institutes of Health;Universities;Work;age related;boys;college;conditioned place preference;conditioning;dopamine transporter;drug of abuse;experience;girls;high risk;later life;mRNA Expression;member;model organism;neural;next generation;opioid overdose;opioid use;postnatal;programs;psychostimulant;response;transcriptome sequencing;undergraduate student

public_health_relevance:
The use of antipsychotic drugs in pediatric populations has increased dramatically over the past 30 years despite a lack of basic research documenting the effects of these drugs on brain and behavioral development. This research will use laboratory rats to ascertain whether early-life antipsychotic drug administration leads to greater behavioral and neural sensitivity to opioid drugs in adulthood. This research will provide scientists policy-makers and practitioners with critical information regarding the impact of prolonged antipsychotic drug treatment during development on the risk of substance abuse in later life as well as offer transformative research experiences in neuroscience to college undergraduates in Kentucky.


application_id: 11060916
project_number: 5R01CA282254-02
project_title: Integrative Targeted Therapy for Melanoma
administering_ic: NCI
award_notice_date: 2025-03-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 282254
program_official: ZAMISCH, MONICA
project_start_date: 2024-04-01
project_end_date: 2030-03-31
study_section: Therapeutic Immune Regulation Study Section[TIR]
contact_pi_person_id: 7598539
contact_pi: YANG, JIN-MING
other_pis: SONG, JIANXUN JIM
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTDespite breaking advances in melanoma treatment such as adoptive cell transfer and immune checkpointblockade the clinical outcomes remain unsatisfactory due to various factors that limit the efficacy of thetherapies. To meet these challenges in immunotherapy for solid tumors this project aims to defineeukaryotic elongation factor-2 kinase (eEF-2K) as a novel and effective immune-modulatory target that canbe exploited to significantly improve effectiveness of the current cancer immunotherapy. eEF-2K belongs tothe family of atypical -kinases and is an evolutionarily conserved regulator of protein synthesis a molecularprocess that affects energy metabolism. This kinase phosphorylates eEF-2 a 100-kDa protein thatpromotes ribosomal translocation from the A to P-site the reaction that induces movement of mRNA alongthe ribosome during translation. Phosphorylated eEF2 is unable to catalyze ribosomal translocation therebyinhibiting peptide elongation. Our preliminary studies strongly suggest that eEF-2K is an as-yet-unappreciated but critical regulator of antitumor immunity and that integrative targeting of this kinase maybeneficially maximize the potency of immunotherapeutic intervention against melanoma one of the mostaggressive and fatal neoplasms responsible for over 80% of skin cancer-related deaths. Building on ourpreliminary observations that eEF-2K is not only highly expressed in melanoma cells and patient specimensand contributes to poor therapeutic outcomes but is also abundantly expressed in immune cells such as Tcells and regulates their functional activity we propose to test the central hypothesis that eEF-2K modulatesantitumor immunity via its regulatory roles in both tumor cells and tumor-reactive immune cells andintegrative targeting of eEF-2K could be exploited as an innovative therapeutic strategy for treatment ofmelanoma. Through comprehensive cellular molecular and pre-clinical studies this multiple PIs project willpursue the following highly related and interactive aims: (1) Determine the role and in-depth mechanism ofeEF-2K in immune evasion; (2) Define the role of eEF-2K as a regulator of tumor-reactive immune cells; (3)Evaluate the antitumor efficacy of the eEF-2K-based and integrative targeted therapy. We have establishedthe humanized mouse (NOD-scid IL2Rgnull) melanoma models as well as murine syngeneic melanomasystems for this research and are well poised to accomplish the above objectives. This research isinnovative and significant because successful completion of this project would not only reveal eEF-2K as anovel and effective immuno-modulatory target for overcoming tumor immune-resistance as well asregulating immune cell functions but also provide new therapeutic opportunities to substantially improveimmunotherapy for advanced treatment-refractory melanoma through the eEF-2K-based integrative-targeted approach.

project_terms:
Adoptive Cell Transfers;Affect;B-Lymphocytes;BRAF gene;Ca(2+)-Calmodulin Dependent Protein Kinase;Cancer Biology;Cell Line;Cell Physiology;Cells;Cessation of life;Clinical;Clinical Research;Cytotoxic T-Lymphocytes;Data;Development;Effectiveness;Elements;Energy Metabolism;Enzymes;Eragrostis;Family;Goals;Human;Immune;Immune Evasion;Immunology;Immunotherapeutic agent;Immunotherapy;In Vitro;Intervention;Knockout Mice;Macrophage;Major Histocompatibility Complex;Malignant Neoplasms;Melanoma;Melanoma Cell;Melanoma patient;Messenger RNA;Modeling;Molecular;Movement;Mus;Mutation;Neoplasms;Organoids;Outcome;Patients;Peptides;Pharmacology;Phosphorylation;Phosphotransferases;Process;Productivity;Protein Biosynthesis;Proteins;Reaction;Refractory;Regulatory T-Lymphocyte;Research;Resistance;Ribosomes;Role;Safety;Site;Skin Cancer;Solid Neoplasm;Specimen;T-Lymphocyte;Testing;Therapeutic;Therapeutic Studies;Translations;Treatment Efficacy;Tumor Antigens;Tumor Cell Line;Tumor Immunity;Tumor-infiltrating immune cells;Woman;calmodulin-dependent protein kinase III;cancer immunotherapy;conditional knockout;cytotoxic CD8 T cells;design;experimental study;humanized mouse;immune checkpoint blockade;immune function;immune resistance;immunoregulation;improved;innovation;insight;melanoma model;men;mutant;neoplastic cell;novel;novel therapeutics;preclinical study;response;systems research;targeted treatment;therapeutic target;therapeutically effective;therapy outcome;treatment response;treatment strategy;tumor;tumor-immune system interactions

public_health_relevance:
Project NarrativeMelanoma one of the most aggressive and fatal neoplasms is the 5th most frequent cancer in men and7th most frequent cancer in women and is responsible for over 80% of the skin cancer-related deaths.By investigating the role and mechanism of elongation factor-2 kinase (eEF-2K) as a novelimmunomodulatory target and by assessing the antitumor efficacy of the eEF-2K-based integrativetargeted therapy we wish to provide innovative and effective immunotherapeutic strategies for patientswith immune poor-responsive melanoma.


application_id: 11059984
project_number: 5R21DA060354-02
project_title: Regulation of cocaine use by astrocyte voltage-gated channels
administering_ic: NIDA
award_notice_date: 2025-03-18
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: DA
serial_number: 060354
program_official: ANANTHAN, SUBRAMANIAM
project_start_date: 2024-04-01
project_end_date: 2027-03-31
study_section: Molecular and Cellular Neuropharmacology Study Section [MCNP]
contact_pi_person_id: 10632329
contact_pi: ORTINSKI, PAVEL IVANOVICH
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/AbstractSignificant effort over the past decades has been devoted to uncovering neuronal mechanisms that regulatesubstance use including the use of cocaine. Notable progress in this effort includes evidence that dysregulationof neuronal signaling after cocaine exposure may rely on plasticity within non-neuronal cells. A particularly largeshare of attention has been paid to astrocytes fueled by early demonstrations that a variety of brain insults fromtrauma to neurodevelopmental disorders profoundly alter astrocyte morphology. Cocaine exposure impactsastrocyte cytoskeleton changing the size and shape of astrocyte cell bodies processes and proximity tosynapses. Additionally cocaine triggers changes in the astrocyte ability to initiate and maintain propagation ofCa2+ waves that have established themselves as a prototypical signature of active astrocyte signaling. Muchless is understood about cocaine effects on astrocyte K+ responses a key feature of neuroglial interface wherebyastrocytes maintain ion homeostasis following neuronal extrusion of K+ ions during action potentials.We provide the first to our knowledge evidence that astrocyte voltage-gated K+ channels are affected by andcontribute to cocaine use in the rat self-administration model. We present preliminary data that the voltage-gatedKCNQ channels in astrocytes of the nucleus accumbens shell (NAc) are rapidly and dose-dependently up-regulated by extracellular dopamine that KCNQ channel activity influences astrocyte Ca2+ responses aftercocaine self-administration and that attenuation of cocaine-seeking by KCNQ inhibition requires functional NAcastrocytes. We propose to use standard pharmacological techniques along with newer molecular approacheselectrophysiology and Ca2+ imaging to further describe astrocyte KCNQ channel contribution to cocaine use.Our hypothesis is that KCNQ channels regulate astrocyte Ca2+ signaling to impact acquired cocaine-seekingbehavior as well as its reinstatement after extinction. Within this hypothesis we define contribution of neuronalactivity relevance of astrocyte Ca2+ compartmentalization to transmembrane and endoplasmic reticulumdomains and cocaine impact on expression of KCNQ subtypes. We predict that astrocyte KCNQ activityindependent of neuronal KCNQ channels influences generation of intracellular Ca2+ signals by membrane-proximal sources and that inhibition of astrocyte KCNQ activity pharmacologically or by virus-mediated knock-down attenuates cocaine seeking and cue-induced reinstatement.Results of this experimentation lay the foundation for investigating contribution of astrocyte K+ channels toneuroglial coupling. For example changes in astrocyte K+ may influence Ca2+ dependent release ofneurotransmitter molecules cytokine production and secretion of extracellular vesicles or other signals toinfluence neuronal output and cocaine-associated behavior. Such studies will promote understanding of dynamicroles of astrocytes in the healthy brain and facilitate novel cell-type specific approaches to mitigate cocaine use.

project_terms:
Abstinence;Action Potentials;Address;Affect;Animals;Astrocytes;Attenuated;Behavior;Binding;Biological;Brain;Cells;Cessation of life;Cocaine;Cocaine Users;Coupling;Cues;Cytoskeleton;Data;Development;Dopamine;Dose;Electrophysiology (science);Endoplasmic Reticulum;Evaluation;Event;Exposure to;Extinction;Foundations;Frequencies;Generations;Homeostasis;Human;Image;Individual;Ions;Link;Literature;Measures;Mediating;Mediator;Membrane;Messenger RNA;Metabolic;Microinjections;Modeling;Molecular;Morphology;Neurodevelopmental Disorder;Neuroglia;Neurons;Nucleus Accumbens;Outcome;Output;Overdose;Permeability;Pharmaceutical Preparations;Potassium Channel;Process;Production;Proteins;Publishing;Rattus;Regulation;Reporting;Research;Role;Self Administration;Shapes;Signal Transduction;Slice;Source;Synapses;Techniques;Toxin;Training;Trauma;United States Substance Abuse and Mental Health Services Administration;Viral;Virus;Voltage-Gated Potassium Channel;aged;antagonist;attenuation;cell type;cocaine cue;cocaine exposure;cocaine relapse;cocaine related behaviors;cocaine seeking;cocaine self-administration;cocaine use;cytokine;defined contribution;extracellular;extracellular vesicles;fluorocitrate;insight;knock-down;neurotransmission;neurotransmitter release;novel;novel therapeutics;pharmacologic;pre-clinical;response;sensor;shared attention;small hairpin RNA;substance use;voltage;voltage gated channel

public_health_relevance:
PROJECT NARRATIVECDC and SAMHSA data indicate that in 2021 there were about 500000 new U.S. cocaine users aged 12 andolder and that cocaine accounted for about 1 in every 4 drug overdose-related deaths. Development of noveltherapies to address the challenge of new and on-going cocaine use depends on insights into the underlyingbiological changes within the brain of affected individuals but prior research has focused overwhelmingly onhow cocaine affects activity of neurons. This proposal explores new evidence that cocaine changes activity ofastrocytes that are predicted to influence on-going cocaine use and relapse to use after abstinence.


application_id: 11059896
project_number: 5R01CA259580-05
project_title: Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2025-03-04
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: 2027-03-31
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;Upregulation;Vertebral column;Xenograft Model;arginine methyltransferase;breast cancer metastasis;breast cancer progression;cancer cell stemness;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;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: 11059248
project_number: 5R00DA056288-04
administering_ic: NIDA
award_notice_date: 2025-03-17
opportunity_number: PA-20-188
application_type: 5
activity_code: R00
ic: DA
serial_number: 056288
program_official: LIN, YU
project_start_date: 2022-04-01
project_end_date: 2027-03-31
study_section: ZDA1-SKM-D(02)S
contact_pi_person_id: 14132436
contact_pi: MCLAURIN, KRISTEN ADDIE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-04-01
project_title:
Neurocognitive Impairments Resulting from Adolescent Prescription Opioid Use Disorder: Longitudinal Impact Neural Mechanisms and Comorbidities

project_abstract:
PROJECT SUMMARY/ABSTRACTThe goals of the proposed K99 career training plan include: 1) gaining expertise and research experience insubstance use disorders (SUD) addictive processes and opioid pharmacology; 2) mastering stereotaxic sur-geries adeno-associated virus gene delivery and in vivo fiber photometry; and 3) mastering and applying ana-lytical skills for the evaluation of third variable effects. The proposed research affords a venue to achieve thegoals of the training plan and address key challenges in the prescription opioid epidemic. Adolescence andyoung adulthood (i.e. 12-25 years of age) are critical developmental periods associated with substance useinitiation and brain circuit maturation with the former having key potential impacts on the latter. To date howeverthe critical role of adolescent prescription opioid use disorder (APOUD) on neurocognitive development andassociated neural mechanisms has yet to be fully elucidated. The role of biological sex and comorbidities (i.e.HIV-1) will be integral to the experimental design. We will causally test the guiding hypothesis that alterationsin the mesocortical dopamine (DA) system mechanistically underlie the differential progression of neurocognitivedevelopment in experimental (oxycodone (OXY) dependent) vs. control animals; and that unique neural mech-anisms will be engaged by comorbid APOUD and HIV-1. The hypothesis will be addressed via two building blockaims (K99 phase) and formally tested in my independent laboratory (R00 phase). Key aspects of human APOUDwill be modeled using a preclinical voluntary oral OXY self-administration experimental paradigm. In SpecificAim #1 (K99 phase) the dose-dependency of OXY self-administration for neurocognitive development (e.g.preattentive processes long-term episodic memory sustained attention) will be established using a longitudinalexperimental design. In Specific Aim #2 (K99 phase) dopaminergic alterations in the mesocortical DA systemfollowing OXY self-administration during assessments of higher-order cognitive processes will be determinedusing novel G protein-coupled receptor based biosensors and in vivo fiber photometry. Specific Aim #3 (R00phase) affords a causal test of the neural mechanism underlying neurocognitive impairments resulting fromAPOUD and/or comorbid HIV-1; the fundamental goal of my independent laboratory. Specifically the mesocor-tical DA system will be stimulated using designer receptors exclusively activated by designer drugs duringassessments of higher-order cognitive processes (e.g. sustained attention). Training (K99 phase) will be con-ducted at the University of South Carolina an outstanding environment under the tutelage of an internationallyrecognized mentoring team including Dr. R.M. Booze (mentor) Dr. E.M. Unterwald (co-mentor) and Dr. A.J.Fairchild (co-mentor). Additionally a Professional Development Advisory Committee including highly-regardedfaculty from multiple institutions (Dr. S. Letendre Dr. T.D. Langford and Dr. S. Fitting) is integral to the careertraining plan. Successful completion of the proposed training career development activities and research willprovide a strong foundation for the candidates transition to an independent scientist.

project_terms:
Address;Adolescence;Adolescent;Adolescent and Young Adult;Adult;Advisory Committees;Age Years;Agonist;Biosensor;Brain;Cells;Chronic;Clinical;Communicable Diseases;Control Animal;Dependence;Dependovirus;Development;Developmental Process;Dopamine;Dose;Environment;Episodic memory;Evaluation;Experimental Designs;Exposure to;Faculty;Female;Fiber;Foundations;Functional disorder;G-Protein-Coupled Receptors;Gene Delivery;Goals;HIV;HIV-1;Hour;Human;Infection;Institution;Intake;International;Laboratories;Mentors;Modeling;Muscarinics;National Institute of Drug Abuse;Neurocognitive;Neurocognitive Deficit;Operative Surgical Procedures;Opioid;Oral;Overdose;Oxycodone;Pharmacology;Phase;Photometry;Prefrontal Cortex;Process;Public Health;Rattus;Research;Role;Saline;Scientist;South Carolina;Strategic Planning;Substance Use Disorder;Synapses;System;Testing;Training;United States Substance Abuse and Mental Health Services Administration;Universities;Ventral Tegmental Area;Viral Proteins;Water;biological sex;biological systems;career;career development;cognitive process;comorbidity;critical developmental period;designer receptors exclusively activated by designer drugs;dopamine system;experience;experimental study;exposure route;high risk population;in vivo;longitudinal design;male;neuromechanism;new therapeutic target;novel;opioid abuse;opioid epidemic;opioid use disorder;oxycodone self-administration;postnatal;pre-clinical;prescription opioid;skills;substance use;sustained attention;therapeutic target;young adult

public_health_relevance:
PROJECT NARRATIVEThe prescription opioid epidemic is a public health crisis with devastating consequences including inadvertentoverdose spread of infectious disease and neurocognitive impairments. Adolescents and young adults areuniquely vulnerable to substance use initiation given ongoing brain maturation. Discovering the neuralmechanisms underlying neurocognitive impairments resulting from adolescent prescription opioid use disorderaffords a critical opportunity to develop novel therapeutic targets; targets which may be unique under conditionsof comorbid opiate abuse and HIV-1.


application_id: 11059133
project_number: 5R01NS136272-02
administering_ic: NINDS
award_notice_date: 2025-02-20
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 136272
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2024-03-20
project_end_date: 2029-02-28
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 14321924
contact_pi: PARK, JONGHYUCK
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-03-01
project_title:
Harnessing engineered drug-free polymeric nanoformulations to reprogram innate immune cells for spinal trauma

project_abstract:
Project Summary/AbstractThe endogenous tissue regeneration after traumatic spinal cord injury (SCI) is limited due to an inhibitoryenvironment by secondary biological events including inflammatory responses. These events result in neural celldeath and demyelination leading to various inflammation-mediated disorders. The long-term goal of this study isto develop effective acute intervention strategies that limit secondary injuries thereby creating a permissiveenvironment that supports regeneration. To achieve this goal polymer based-nanoparticle (NP) formulations willbe employed to reprogram the circulating innate cells in the blood after trauma. The scientific premise of theproposed research is based on preliminary data demonstrating that intravenously administered NPs target thepro-inflammatory sub-set of immune cells prior to extravasation to the injury and reprogram their traffickingpatterns and phenotypes that limit inflammation and additional tissue damage thereby inducing enhancedregeneration. Particularly the immunomodulation is mediated by the physicochemical properties of NPsindicating that NPs functions can be engineered differently to influence immune trafficking and phenotypes. Theproposed engineered-NP formulations differentially reprogram innate cells specifically immunomodulatoryeffects of NPs are sex-dependent and importantly these effects are solely mediated by distinctivephysicochemical properties of NPs without the active biologics that can cause unfavorable off-target effects. Inthis proposal key physicochemical parameters of NP formulations will be identified for effectiveimmunomodulation in males and females respectively since the differences in physiological factors betweensexes play a critical role in inflammation after spinal trauma. Aim 1 will focus on interactions between differentNP formulations and innate cells in circulation to identify more effective NP design factors that limit inflammationin both sexes. Distinct physicochemical properties of NPs will differently affect innate cells trafficking andphenotype which will be sex-dependent and subsequently reprogram an inhibitory environment. NP-induceddifferential cellular internalization phenotype activation pharmacokinetic profiles as well as biodistribution ofNPs will be investigated. Aim 2 will investigate the long-term impacts of NPs on anatomical and functionalregeneration after SCI with a more focused set of NP formulations based on Aim 1. Initially NP-associatedimmune cells will be investigated then the extent of axonal regrowth and remyelination synaptogenesis andfunctional recovery in the chronic phase of SCI will be assessed. Collectively the proposed studies will have thepotential to be a transformational therapy by identifying the relationship between physicochemical parametersand immune modulation for effective NP formulations to support regeneration. Notably NPs are made of FDAapprovedpolymeric biomaterial enabling them to be readily stored for immediate administration non-invasivelyas a means to modulate the innate immune system for functional enhancement.

project_terms:
Acids;Acute;Affect;Anatomy;Anti-Inflammatory Agents;Artificial nanoparticles;Axon;Biocompatible Materials;Biodistribution;Biological;Biological Process;Biological Products;Blood;Cell Death;Cells;Cessation of life;Chronic Phase;Circulation;Data;Demyelinations;Development;Diagnosis;Disease;Drug Kinetics;Engineering;Environment;Event;Extravasation;FDA approved;Female;Formulation;Functional Regeneration;Functional disorder;Gene Expression;Genes;Glucocorticoids;Goals;Growth;Immune;Immune response;Immunotherapeutic agent;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Innate Immune System;Intervention Strategies;Macrophage;Mediating;Methylprednisolone;Natural regeneration;Neurons;Organ;Outcome;Patients;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Physiological;Play;Polymers;Population;Property;Recovery of Function;Research;Role;Secondary to;Sex Differences;Site;Spinal Cord;Spinal cord injury;Spleen;Testing;Therapeutic;Tissues;Trauma;Triage;axon regeneration;clinical application;design;immune cell infiltrate;immunoregulation;intravenous administration;male;minimally invasive;monocyte;nanoformulation;nanoparticle;nanopolymer;nanotherapeutic;neural;neutrophil;novel strategies;novel therapeutics;peripheral blood;permissiveness;programs;remyelination;response;risk/benefit ratio;sex;synaptogenesis;therapeutic effectiveness;tissue injury;tissue regeneration;tool;trafficking

public_health_relevance:
Project NarrativeTissue regeneration after spinal cord trauma is limited by additional biological events including inflammationwhich induce an inhibitory local microenvironment leading to cellular death and functional deficits.lmmunotherapeutic nanoparticles with different physicochemical factors without using active pharmaceuticalingredients interact with circulating immune cells and reprogram their function to mitigate inflammation andmodify the microenvironment in favor of regeneration. The proposed studies will identify crucial parameters ofnanoparticles for the development of effective nanotherapeutics which will contribute to the development ofpotentially effective practical therapy for spinal cord trauma.


application_id: 11059118
project_number: 5P20GM113226-10
project_title: Project 4 - Smita Ghare PhD
administering_ic: NIGMS
award_notice_date: 2025-05-28
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2027-03-31
study_section: ZGM1-RCB-3
subproject_number: 6814
contact_pi_person_id: 11468892
contact_pi: GHARE, SMITA 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
project_abstract:
Alcoholic liver disease (ALD) carries a high morbidity and mortality and has no FDA approved therapy.Sustained hepatic inflammation is an important factor in progression of alcoholic liver disease and elevatedhepatic and circulating levels of CCL2 and CXCL2 chemokines are seen in both early and later stages of liverdisease. However the molecular mechanisms involved in alcohol-induced upregulation of these chemokinesare not completely elucidated. Emerging evidence indicates that alcohol affects epigenetic regulatorymechanisms and thus significantly contributes to the development of hepatic pathology. Post-translationalmodifications (PTMs) specifically acetylation is important for gene transcription and is maintained by Histonedeacetylases (HDACs) and histone acetyltransferases (HATs). In this regard we have shown that bingealcohol exposure alters expression of hepatic HDAC and also affect global hepatic histone H3 acetylation. Therole of Class I HDACs has been also described in inflammation with a particular pro-inflammatory role forHDAC3. In the context of chemokine expression our preliminary data examining the effects of chronic ethanolon CCL2 upregulation showed that in correlation with increased promoter histone acetylation there was anincrease in the binding of critical transcription factor NFB-p65 to the CCL2 promoter. Further the data showthat a dietary HDAC inhibitor (tributyrin - prodrug of butyrate) attenuates alcohol-induced CCL2 and CXCL2expression neutrophil infiltration and prevents hepatic inflammation and injury. Based on these findings wehypothesize that chronic alcohol-induced alterations in hepatic HDACs drive pathogenicposttranslational modifications of histones and non-histone proteins specifically transcription factorNFB upregulating CCL2 and CXCL2 chemokines expression contributing to liver inflammation andinjury. The major goal of this proposal is to conduct studies that determine the molecular mechanismsunderlying chronic alcohol-induced chemokine upregulation and the development of ALD. Moreover theproposal examines the potential of nutrition-based interventions targeted at HDAC inhibition in mitigatingalcohol-induced chemokine expression and liver inflammation/injury. The specific aims of the proposal are: 1)Examine the role of alcohol-induced promoter histone modifications in regulating pro-inflammatoryCCL2 and CXCL2 chemokine expression in ALD; 2) Determine the role of HDAC mediated regulation ofNFB transactivation function and chemokine expression in ALD; and 3) Evaluate the therapeuticpotential of tributyrin in attenuating CCL2 and CXCL2 chemokine expression and development of ALD.We expect that the results of our study will provide critical molecular insights and facilitate the development oftherapeutic interventions for ALD.

project_terms:
Acetylation;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Attenuated;Binding;Biological Models;Biopsy;Butyrates;CXC Chemokines;CXCL2 gene;Centers of Research Excellence;Chronic;Clinical;Cytokine Activation;DNA Binding;Data;Deacetylation;Development;Doctor of Philosophy;Epigenetic Process;Ethanol;FDA approved;Fatty acid glycerol esters;Genes;Genetic Transcription;Goals;HDAC3 gene;Hepatic;Hepatocyte;Histone Acetylation;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;IL8 gene;Inflammation;Inflammatory;Injury;Intervention;Knockout Mice;Ligands;Liver diseases;Macrophage Activation;Mediating;Modification;Molecular;Morbidity - disease rate;Mus;Myeloid Cells;Neutrophil Infiltration;Nutrition;Organ;Oxidative Stress;Pathogenicity;Pathology;Patients;Plasma;Play;Post-Translational Protein Processing;Preventive;Prodrugs;Regulation;Role;Serum;Severity of illness;Stimulus;Testing;Therapeutic;Therapeutic Intervention;Toxicology;Transactivation;Transcriptional Activation;Upregulation;Work;alcohol effect;alcohol exposure;beta-Chemokines;chemokine;chromatin remodeling;cohort;cytokine;dietary;histone acetyltransferase;histone modification;in vitro Model;in vivo;insight;liver inflammation;liver injury;mortality;non-histone protein;nucleocytoplasmic transport;p65;prevent;promoter;recruit;response;therapeutic development;transcription factor;translational study;tributyrin


application_id: 11059112
project_number: 5P20GM113226-10
project_title: Project 2 - Joshua Hood PhD
administering_ic: NIGMS
award_notice_date: 2025-05-28
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2027-03-31
study_section: ZGM1-RCB-3
subproject_number: 6812
contact_pi_person_id: 7170643
contact_pi: HOOD, JOSHUA 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:
Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related mortality. It is inherentlydifficult to treat given the often-times co-occurrence of underlying cirrhosis which exacerbatesconventional chemotherapeutic toxicity. A sizeable number of patients remain non-responsive oruntreatable to cutting edge immune checkpoint inhibitor therapy necessitating the development of newor augmentative therapies. Given their role in removing foreign nanomaterials as participants of themononuclear phagocyte system coupled to their role in mediating HCC Kupffer cells (KCs) are an idealimmunotherapeutic target for small extracellular vesicles (sEVs). Small EVs are enriched in exosomenanovesicles. Our previous studies demonstrate that melanoma and lung cancer sEVs can directly inducea pro-tumor M2-like M phenotype or be modified with melittin peptide to induce anti-tumor M1-like Ms.Theoretically HCC sEVs might also be modified with melittin to induce anti-tumor M1 KC Ms. The bee venom peptide melittin is a powerful adjuvant for activating M1 immunity. The FDAapproves the use of bee venom injections for bee sting immunotherapy. In this proposal we hypothesizethat (i.) HCC sEVs can be converted into stable melittin adjuvant nanocarriers and (ii.) melittin-modifiedHCC sEVs associate with and induce KCs toward an anti-tumor M1-like phenotype in vivo. In aim 1 HCC sEVs will be converted into stable melittin nanocarriers. A fluorescent redbioluminescent 3D HepG2-Red-Fluc spheroid sEV source model will be developed. We will compare 2Dversus 3D HepG2-Red-Fluc sourced natural and melittinized sEVs for their ability to influence primary KCpolarization in vitro and determine differences in M1/M2 polarizing miRNA content using qRT-pcr. In aim 2 an orthotopic syngeneic model using bioluminescent Hepa1-6-Fluc-Neo cells inimmunocompetent C57L/6 mice will be used. Natural vs. melittinized Hepa1-6-Fluc-Neo sEVs will becompared to determine whether they influence KC M1/M2 polarization. We will also assess whether pre-treatment with melittinized Hepa1-6-Fluc-Neo sEVs inhibits subsequent orthotopic HCC growth. Studieswill be accomplished via utilization of all U of L Hepatobiology & Toxicology COBRE cores. The results of these studies will further our understanding of the relationship between natural HCCsEVs and KC tumor supportive functions and a therapeutic means to antagonize this pathogenicrelationship using melittin-modified KC sEVs will also be evaluated. Translationally sEV populationsmight be harvested from the blood of HCC patients modified into personalized immunotolerantnanomedicines using melittin or other agents and re-administered. The proposed studies also serve as aplatform to pursue pathologic and therapeutic sEV investigations concerning other M driven liverdiseases including hepatitis alcoholic and non-alcoholic-SH and liver fibrosis.

project_terms:
3-Dimensional;Adjuvant;Alcoholic steatohepatitis;Antigen Presentation;Attenuated;Autologous;BAY 54-9085;Bee Venoms;Bees;Biological Assay;Blood;Cancer Etiology;Cancer Vaccines;Cell Line;Cells;Centers of Research Excellence;Cirrhosis;Coupled;Development;Doctor of Philosophy;Effector Cell;Enzyme-Linked Immunosorbent Assay;FDA approved;Growth;Harvest;HepG2;Hepatitis;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune response;Immunity;Immunocompetent;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;In Vitro;Inflammatory;Injections;Investigation;Kupffer Cells;Liver;Liver Fibrosis;Liver diseases;Macrophage;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Melanoma;MicroRNAs;Modeling;Modernization;Mononuclear;Mus;Myeloid-derived suppressor cells;Natural Source;Neoplasm Metastasis;Nivolumab;Participant;Pathogenicity;Pathologic;Patients;Peptides;Phagocytes;Phenotype;Plasma;Population;Primary carcinoma of the liver cells;Process;Proteins;Quantitative Reverse Transcriptase PCR;Reporting;Research;Role;Source;Sting Injury;System;Testing;Therapeutic;Toxicology;Treatment Efficacy;Treatment-related toxicity;Tyrosine Kinase Inhibitor;Vaccine Adjuvant;arginase;cancer therapy;checkpoint therapy;exosome;extracellular vesicles;hepatocellular carcinoma cell line;in vivo;light scattering;mortality;nanocarrier;nanomaterials;nanomedicine;nanovesicle;neoplastic cell;non-alcoholic;nonalcoholic steatohepatitis;polarized cell;problem drinker;recruit;response;spheroids;tumor;tumor growth;zeta potential


application_id: 11059108
project_number: 5P20GM113226-10
project_title: Biorepository and Animal Core
administering_ic: NIGMS
award_notice_date: 2025-05-28
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2027-03-31
study_section: ZGM1-RCB-3
subproject_number: 6810
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:
Project Summary Abstract  Animal Model and Biorepository Core (Core D)The Animal Model and Biorepository Core (Core D) of the Hepatobiology and Toxicology Center provides theessential expertise facilities resources and standardized services required for impactful liver research. TheCore focuses on the needs of the COBREs junior investigators but it also serves other Center members andliver investigators. The Core enhances infrastructure as well as the technical and academic capabilities of theCenter and the Institution as a whole. Core Ds primary functions are to provide COBRE members with accessto: (i) animal models of liver disease (including the characterization of these models); (ii) primary liver cells; and(iii) previously collected de-identified biological specimens from human subjects with liver disease.The Cores experimental model services include: animal exposure; husbandry; necropsy with tissue collectionprocessing and biorepository storage; phenotyping and liver histology; as well as the isolation of primary hepaticcells for ex vivo and in vitro studies. The Core will assist COBRE members in developing new experimentalanimal models and in vitro systems to study liver disease. The Core will serve as a liaison to non-duplicativeanimal research resources at UofLs two other COBRE Centers to maximize overall impact. Core personnel willensure uniformity of husbandry as well as sample collection processing and evaluation so that the same set ofcharacteristics is measured in each model. This uniformity ensures that the data generated within the COBREare consistent and that results of one experiment will be directly comparable with the results of another. TheCores human biorepository enables access to a unique inventory of previously collected de-identified biologicalsamples from subjects with liver diseases (e.g. alcoholic liver disease occupational/environmental liverdiseases liver cancer etc.) in order to promote translational research. Core D will assist COBRE members withthe necessary regulatory approvals for their research. In addition to its function as a service core Core D willpromote the education and training of the COBRE junior investigators and members.To function as a vital integrative component of the COBRE providing services not only for its members but alsofor the Institution as a whole Core D has the following Specific Aims: 1) To foster the development and successof current and future COBRE projects. 2) To educate and train investigators. 3) To develop new protocols andtechniques. 4) To become an integral and self-sustaining component of the COBRE.

project_terms:
Address;Alcoholic Liver Diseases;Animal Experimentation;Animal Model;Animals;Autopsy;Biological;Biology;Centers of Research Excellence;Characteristics;Data;Development;Ensure;Equipment and supply inventories;Evaluation;Experimental Animal Model;Experimental Models;Fees;Fostering;Future;Germ-Free;Gnotobiotic;Goals;Hepatocyte;Histology;Human;Human Resources;IACUC;In Vitro;Individual;Infrastructure;Institution;Institutional Review Boards;Liver;Liver diseases;Maintenance;Malignant neoplasm of liver;Measures;Mission;Modeling;Mus;Occupational;Operative Surgical Procedures;Phenotype;Procedures;Protocols documentation;Regulatory approval;Research;Research Personnel;Resources;Sampling;Service delivery model;Services;Specimen;Standardization;Structure;System;Techniques;Tissue Banks;Toxicology;Training;Training and Education;Translational Research;biobank;biological specimen archives;career development;design;experimental study;flexibility;gut microbiome;human subject;interest;investigator training;meetings;member;metabolic phenotype;sample collection;success


application_id: 11059104
project_number: 5P20GM113226-10
project_title: Bioanalytical Core
administering_ic: NIGMS
award_notice_date: 2025-05-28
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2027-03-31
study_section: ZGM1-RCB-3
subproject_number: 6809
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
project_abstract:
The University of Louisville Hepatobiology and Toxicology COBRE is a multidisciplinary group of investigatorsfocusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/drug interactions.The Bioanalytical Core (Core C) is an integral part of the COBRE and will continue to play a key role in theimplementation and future development of COBRE-funded projects. The Core provides the necessaryexpertise and state-of-the-art equipment for rigorous and comprehensive experimental evaluation of cell andtissue specimens to investigate the pathogenic mechanisms of liver disease. Besides providing requisiteanalytical services a major goal of the Core C is to promote the education and training of the Center memberswith particular attention to the COBRE junior investigators. Core C will specifically communicate with COBREjunior investigators regarding their experimental requirements on a continual basis and appropriatelyparticipate in the planning execution and data interpretation. Core C will also interact with other COBRE Coreson a regular basis in order to avoid duplication of equipment or instrumentation and foster innovative protocoldevelopment and refinement exchange of ideas and integrative analysis of data. In addition to the upgradedexisting equipment (BD FACSCanto II Cellomics and Seahorse analyzers) Core C will also provide technicaland analytical expertise with newly acquired state-of-the-art centralized equipment that includes BZ-X810automated imaging microscope (Keyence) QuickPlex SQ 120 multiplex MSD analyzer and QuantStudio 6 FlexReal-Time PCR System. The Core facility is located in Clinical and Translational Research Building with 2500 sq.ft of operatingspace that is contiguous with the 20000 sq.ft. laboratory space of the Hepatobiology and Toxicology COBRE.Dr. Barve (Director) and the Core C research team have extensive experience in the development andexecution of molecular biochemical and immunological analyses that are critical for the operational andfunctional aspects of Core C. Dr. Barve was/is an investigator (PI Co-PI or Co-I) on several NIH-fundedgrants served for nearly a decade as the Director of the Molecular and Cytokine Core Laboratory of the NIH-funded GCRC and supported the career development of several junior faculty. To remain a vital integrativecomponent of the Center that provides services not only for members but also the Institution as a whole theCore C has the following specific aims: 1) To foster the development sustainability and success of theproposed COBRE projects and pilots; 2) To play an active and significant role in the education and training ofthe investigators; 3) To assist and participate in the development of new experimental protocols; andtechniques and 4) To become an integral and self-sustaining component of the COBRE Center.

project_terms:
Area;Attention;Award;Biochemical;Biological;Biological Assay;Cells;Centers of Research Excellence;Clinical Research;Communication;Communities;Computer software;Continuing Education;Core Facility;Data Analyses;Development;Drug Interactions;Ensure;Environment;Equipment;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Fostering;Funding;Future;Genus Hippocampus;Goals;Grant;HIV;Immunologics;Individual;Infrastructure;Institution;Instruction;Investigation;Journals;Laboratories;Liver;Liver diseases;Maintenance;Methodology;Mission;Molecular;Molecular Target;Pathogenicity;Performance;Phase;Play;Protocols documentation;Reagent;Research;Research Personnel;Resources;Role;Services;Signal Pathway;Specimen;System;Techniques;Technology;Time;Tissues;Toxicology;Training and Education;Translational Research;United States National Institutes of Health;Universities;Whole Organism;career development;cost;cytokine;experience;experimental study;innovation;instrument;instrumentation;investigator training;liver injury;meetings;member;microscopic imaging;multidisciplinary;novel;programs;protocol development;research facility;square foot;success;toxicant


application_id: 11059101
project_number: 5P20GM113226-10
project_title: Omics Core
administering_ic: NIGMS
award_notice_date: 2025-05-28
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2027-03-31
study_section: ZGM1-RCB-3
subproject_number: 6808
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:
Abstract: The primary function of OMICS Core (Core B) is to provide members of the University of LouisvilleHepatobiology and Toxicology COBRE with the expertise resources and facilities needed for metabolomicproteomic and bioinformatic analyses of biological samples collected to study liver injury nutrition gut:liverinteractions and liver:environment/toxicant/drug interactions. Core B personnel will assist with the design ofsample collection protocols will drive the development and the execution of novel and robust chromatographicmethods for sample separation and mass spectrometric methods for the analysis of proteins peptides andmetabolites with a goal of providing a greater understanding of the evolution of molecular mechanisms thatcorrelate with or participate in liver dysfunction. Core B will ensure uniformity and standardization in samplepreparation method development instrument performance data collection data reporting and data sharing.Core B endeavors to contribute to the overall success and utility of the COBRE and to enhance the infrastructureand the technical and academic capabilities of the institution as a whole. In addition to its function as a servicecore Core B will also promote the education and training of the COBRE members and other biomedicalinvestigators with regards to the state-of-the-art omics technologies; with particular attention to the COBRE juniorinvestigators. Furthermore Core B will become an independent and self-supporting entity using a setcomprehensive approaches that have been already implemented and demonstrated their success in our PhaseI COBRE.During the Hepatobiology and Toxicology COBRE Phase II period the goals of Core B will be addressed by thefollowing Specific Aims:1) To support current COBRE and UofL Health Science Center (HSC) projects.2) To educate and train mentees and other investigators.3) To develop new protocols and techniques.4) To become self-sustaining feature of the COBRE and UofL HSC.

project_terms:
Address;Applications Grants;Attention;Award;Bioinformatics;Biological;Biological Assay;Centers of Research Excellence;Chemicals;Chromatography;Clinical Research;Communities;Complex Mixtures;Continuing Education;Data;Data Analyses;Data Collection;Data Reporting;Derivation procedure;Development;Dimensions;Disease;Drug Interactions;Education;Ensure;Environment;Equipment;Fee-for-Service Plans;Funding;Future;Goals;Health Sciences;Hepatology;Human Resources;Individual;Infrastructure;Institution;Intervention Studies;Leadership;Liver;Liver Dysfunction;Liver diseases;Malignant neoplasm of liver;Mass Spectrum Analysis;Methods;Modality;Modeling;Modification;Molecular Evolution;Nutrition;Peptides;Performance;Phase;Preparation;Privatization;Procedures;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;RNA;Reagent;Research;Research Activity;Research Personnel;Research Support;Resources;S10 grant;Sampling;Science;Services;Standardization;Statistical Data Interpretation;Techniques;Technology;Toxicology;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;career;career development;clinical infrastructure;data sharing;design;epitranscriptomics;experimental study;fatty liver disease;innovation;instrument;liver development;liver injury;meetings;member;metabolomics;method development;molecular marker;non-alcoholic;novel;operation;problem drinker;programs;sample collection;small molecule;success;theories;tool;toxicant


application_id: 11059100
project_number: 5P20GM113226-10
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2025-05-28
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2027-03-31
study_section: ZGM1-RCB-3
subproject_number: 6807
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 Hepatobiology and Toxicology COBRE is a multidisciplinary group of investigators focusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/drug interactions alcoholic and non-alcoholic liver injury infectious liver diseases liver cancer and new liver therapies. The purpose of the administrative core is to provide administrative fiscal and scientific oversight for this Phase II COBRE. This includes the overall career development and research goals of the Phase II COBRE (including formative and summative evaluation and specific milestones); the career development plans for junior faculty (including plans for transitioning to independence); plans for replacing key personnel (e.g. Project PIs Core leaders overall PI pilot project PIs); oversight of the pilot projects; oversight of the biostatistical support services; and disseminating information to the lay and scientific communities.  Liver diseases are some of the most common rapidly increasing and poorly recognized health problems afflicting Americans. For example Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis is the most common cause of abnormal liver enzymes in the US affecting about 25% of adults and about 10% of children. Alcoholic Liver Disease is an increasing problem among those who drink. Importantly there is no FDA-approved therapy for either NASH or ALD. Toxicant-Induced Liver Injury is an increasingly recognized industrial/environmental problem. Viral Liver Diseases (Hepatitis A B and C) remain major health problems related to drug abuse and homelessness. Hepatocellular carcinoma and Hepatitis C are major causes for liver related morbidity and liver transplantation in the US. Drug-Induced Liver Injury is the major reason new drugs do not come to market and the major cause of fulminant liver failure in the US. Personalized Medicine is increasingly recognized as an important aspect of drug therapy; and most drugs are metabolized in the liver.  Building on the success of the Phase I COBRE Administrative Core the specific aims of this Phase II COBRE Administrative Core are:  1. continue to provide overall administrative fiscal and scientific oversight  2. enhance and grow the career development enterprise for project PIs  3. enhance and grow the career development/mentor development enterprise for the mentors  4. enhance and grow the research goals of the COBRE  5. continue to provide a process for replacing key personnel  6. continue to provide and enhance a summative and formative evaluation process for the COBRE  including specific milestones  7. continue to provide a robust pilot project program to grow the overall research goals of the COBRE  8. disseminate pertinent information to the scientific and lay community

project_terms:
Acute Liver Failure;Adult;Affect;Alcoholic Liver Diseases;Alcohols;American;Area;Bioinformatics;Biometry;Budgets;Center Core Grants;Centers of Research Excellence;Child;Clinical Trials;Communities;Community Outreach;Country;Development;Development Plans;Diabetes Mellitus;Drug Interactions;Drug abuse;Ensure;Environment;Environmental Health;Enzymes;Evaluation;FDA approved;Faculty;Funding;Goals;Grant;HCV HCC;Health;Hepatitis A;Homelessness;Human Resources;Individual;Industrialization;Kentucky;Letters;Liver;Liver diseases;Malignant neoplasm of liver;Marketing;Mentors;Morbidity - disease rate;National Institute of Environmental Health Sciences;National Institute on Alcohol Abuse and Alcoholism;Obesity;Overweight;Pharmaceutical Preparations;Pharmacology and Toxicology;Pharmacotherapy;Phase;Physicians;Pilot Projects;Population;Process;Public Health;Qualifying;Research;Research Infrastructure;Research Personnel;Rural;Scientist;Services;Structure;Superfund;Teacher Professional Development;Text;Toxicology;United States National Institutes of Health;Universities;Viral hepatitis;career development;drug induced liver injury;faculty mentor;formative assessment;improved;liver injury;liver metabolism;liver transplantation;microbiome;microbiome research;multidisciplinary;non-alcoholic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel therapeutics;opioid abuse;personalized medicine;problem drinker;programs;recruit;research and development;senior faculty;success;toxicant;tumor immunology;viral liver disease


application_id: 11059099
project_number: 5P20GM113226-10
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2025-05-28
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: 2027-03-31
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;HCV HCC;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;Nutrition;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;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: 11058540
project_number: 5R01AG068055-05
project_title: Identifying Associations between Brain Iron Neurocognitive Networks and Protective Factors
administering_ic: NIA
award_notice_date: 2025-03-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 068055
program_official: WAGSTER, MOLLY V
project_start_date: 2021-05-01
project_end_date: 2027-02-28
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
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:
Identifying Associations between Brain Iron Neurocognitive Networks andProtective FactorsAlzheimers disease (AD) involves accumulation of pathological levels of amyloid-beta (A)and phospho-tau proteins. However a significant proportion of individuals with AD pathologydo not have clinical AD indicating contributions of other factors. Novel in-vivo measures arerequired to track other factors contributing to AD-related cognitive declines. Increasingevidence suggests that age-related accumulation of brain iron and its correlates contribute tothe manifestation of memory declines. Our recent neuroimaging results suggest that highbrain iron concentration measured with in vivo quantitative susceptibility mapping (QSM) isassociated poor connectivity within brain memory networks. This proposal seeks to identifyassociations between QSM-based iron concentration and neurocognitive changes toward agoal of improving AD biomarkers. We will also define the interplay between QSM-based ironsignal AD pathology inflammatory markers on cognitive declines. Finally we will test thepossibility that brain iron accumulation may be slowed by an antioxidant rich diet. Wepropose to study 140 healthy older adults using neuroimaging measures including fMRI andQSM measures of CSF and plasma A p-tau and t-tau and inflammatory markers.Additional structural neuroimaging measures will include regional volumes FLAIR imagingfor quantification of WMH volumes and diffusion tensor imaging for quantification ofregionally distributed white matter connectivity. A subset of participants will be complete thesame CSF and imaging measures approximately 3 years later. We aim to identify (1) effectsof QSM-based iron signal on functional and structural brain networks supporting cognition;(2) associations between brain iron inflammatory markers AD pathology and cognitivedeclines and; (3) modifiers of brain iron or its effects on cognition. We will test hypothesesthat high QSM-based brain iron is associated with low connectivity in memory circuitsindependently of AD pathology but may and synergistically interacts with AD over time. Wewill also test the hypothesis that reserve factors will offset the effects of brain iron oncognitive functions via mechanisms of brain maintenance or plastic functional brainreorganization of large-scale brain functional networks in some older adults.

project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Alzheimers disease biomarker;American;Amyloid beta-Protein;Antioxidants;Attenuated;Biological Markers;Brain;Cerebrospinal Fluid;Clinical;Cognition;Cognitive;Cognitive aging;Compensation;Diet;Diffusion Magnetic Resonance Imaging;Disease Progression;Early Diagnosis;Early Intervention;Early identification;Episodic memory;Functional Magnetic Resonance Imaging;Goals;Health;Image;Impaired cognition;Individual;Intake;Iron;Linear Regressions;Liquid substance;MRI Scans;Magnetic Resonance Imaging;Maintenance;Maps;Measures;Mediating;Memory;Memory Loss;Modeling;Neurocognitive;Neurocognitive Deficit;Neuropsychology;Participant;Pathologic;Pathology;Pattern;Performance;Plasma;Positron-Emission Tomography;Predisposition;Regression Analysis;Sampling;Scanning;Short-Term Memory;Signal Transduction;System;Testing;Time;age related;base;behavior measurement;blood-brain barrier crossing;brain based;brain iron;cognitive function;cognitive process;cognitive reserve;functional plasticity;good diet;improved;in vivo;indexing;inflammatory marker;lifestyle factors;neural;neuroimaging;neuroimaging marker;novel;novel marker;older adult;pre-clinical;protective factors;support network;tau Proteins;tau-1;white matter

public_health_relevance:
Project NarrativeNovel biomarkers of Alzheimers disease (AD) are needed to aid early identification ofindividuals at high AD-risk. This study will test the accuracy of brain iron neuroimaging as apredictor AD-related neurocognitive declines. It is anticipated that findings from this study willimprove the ability to detect early AD and track changes in cognitive status during diseaseprogression.


application_id: 11058407
project_number: 5R21NS137256-02
project_title: Combinatorial approach to restore breathing after spinal cord injury
administering_ic: NINDS
award_notice_date: 2025-02-20
opportunity_number: PA-21-219
application_type: 5
activity_code: R21
ic: NS
serial_number: 137256
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2024-03-19
project_end_date: 2027-02-28
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9380335
contact_pi: CHEN, MEIFAN
other_pis: ALILAIN, WARREN JOSEPH
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 / ABSTRACT More than half of human spinal cord injury (SCI) cases occur at the cervical level resulting in permanentrespiratory deficits for which there is no treatment. Injury-induced axon growth of spared respiratory pathways isa form of endogenous neural plasticity that can be harnessed to improve breathing. However experimentalstrategies to promote respiratory axon growth are lacking and the few existing approaches have translationallimitations. Without expanding the repertoire of molecular and/or cellular interventions to enhance axonalplasticity of the respiratory network following injury developing treatment to restore breathing will be unlikely.The objectives of this proposal are: first to determine if endogenous astrocytes can be reprogrammed toenhance structural plasticity of the respiratory system to improve breathing after SCI; and second based onevidence that coupling axon growth-promoting strategy with rehabilitative training can further augment functionalrecovery assess combinatorial effects of astrocyte reprogramming and respiratory training on recovery ofbreathing after SCI. The central hypothesis is that post-injury targeting of astrocytes combined with respiratorytraining will synergistically improve breathing after SCI. This hypothesis will be tested by pursuing two aims: 1)determine the effects of pre-injury astrocyte manipulation alone or in combination with respiratory training onstructural and functional plasticity of the respiratory system; and 2) assess post-injury and location-specificeffects of astrocyte manipulation alone or in combination with respiratory training on respiratory plasticity. Therationale for this proposal is that it will inform on the therapeutic potential of reprogramming endogenousastrocytes to promote axonal plasticity of the respiratory system which may be further harnessed byrehabilitative training to maximize recovery of breathing after SCI.

project_terms:
Acute;Adult;Anatomy;Animal Model;Applications Grants;Astrocytes;Axon;Breathing;Cell Nucleus;Cerebral cortex;Cervical;Cervical spinal cord injury;Ciliary Neurotrophic Factor;Corticospinal Tracts;Coupled;Coupling;Development;Forelimb;Frequencies;Glial Fibrillary Acidic Protein;Growth;Human;Hypoxia;Impairment;Individual;Injury;Intervention;Lateral;Leucine Zippers;Location;Maintenance;Measures;Mechanical Ventilators;Mediating;Modeling;Molecular;Motor;Mus;Neural Pathways;Neuronal Plasticity;Neurons;PF4 Gene;Pathway interactions;Phosphotransferases;Recovery;Recovery of Function;Rehabilitation therapy;Reporting;Respiratory System;Role;Serotonin;Shapes;Spinal Cord;Spinal Injections;Spinal cord injured survivor;Spinal cord injury;Synaptic plasticity;Tamoxifen;Testing;Therapeutic;Tidal Volume;Training;United States;Upregulation;axon growth;axonal sprouting;central nervous system injury;combinatorial;cytokine;functional plasticity;improved;in vivo;ischemic injury;motor recovery;nerve supply;neural network;normoxia;novel;overexpression;programs;regenerative;respiratory;restoration;synergism;translational approach;trend;ventilation

public_health_relevance:
Project NarrativePublic Relevance: Nearly 300000 individuals in the United States have a spinal cord injury and close to 60%are at the cervical level. As a result respiratory motor insufficiency is a major concern and necessitates theneed for a mechanical ventilator in order to breathe and survive. This grant application explores a novelcombinatorial approach to restore breathing by promoting axon growth of respiratory pathways and applyingrespiratory training.


application_id: 11057720
project_number: 5R13DC016831-08
project_title: International Society for Neurogastronomy Symposium
administering_ic: NIDCD
award_notice_date: 2025-04-08
opportunity_number: PA-21-151
application_type: 5
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2030-02-28
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is still a relatively new society whose composition of scientists cliniciansnutritionists agricultural experts food service professionals and chefs naturallypredisposes it to focus on translational issues fundamental to how the chemical sensesimpact human health. The first two specific objectives are to provide a venue andopportunity that brings these groups together and facilitates the synergies that arise whendistinctly different fields interact productively. The third specific objective is to attractstimulate and promote the careers of the young scientists that are the future of the field ofneurogastronomy. The fourth specific objective is to do outreach that serves health andculinary professionals by informing them about the impact that smell and taste has upondiet nutrition and the growing health problems of obesity-related diseases. The fifthspecific objective is to ensure that this new field embraces a culture of diversity weavingthis principle into its early development by recruiting persons of diverse backgrounds to theconference.

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

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


application_id: 11055390
project_number: 5R01AA030775-02
project_title: Influence of Orexin Antagonism on Motivation for Alcohol
administering_ic: NIAAA
award_notice_date: 2025-05-12
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: AA
serial_number: 030775
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
arra_indicator: N
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;Preclinical data;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: 11055285
project_number: 5R01CA272772-03
administering_ic: NCI
award_notice_date: 2025-03-20
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 272772
program_official: SINGH, ANJU
project_start_date: 2023-04-01
project_end_date: 2028-03-31
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-04-01
project_title:
Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer

project_abstract:
Lung cancer kills more people than any other type of cancer including more than 130000 people each year inthe United States. Non-small cell lung cancer (NSCLC) is the most common subtype (82% of all lung cancers)and can arise from squamous or non-squamous lung epithelial cells. Combination treatment with immunotherapy(i.e. monoclonal antibodies targeted to PD-1 or PD-L1) plus concurrent chemotherapy (usually including cisplatinor carboplatin) is now part of the standard of care for many patients with NSCLC. Although in lab-based studieschemotherapy has some effects that are expected to enhance the efficacy of immunotherapies whetherchemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is not wellunderstood at present. Based on our preliminary data we propose to investigate how cisplatin a chemotherapycommonly used to treat NSCLC creates an immunosuppressive tumor microenvironment (TME) that limits theanti-tumor activity of anti-PD-1 immunotherapy. Specifically we hypothesize the following steps: (a) cisplatininduces prostaglandin E2 (PGE2) production in tumor cells; (b) PGE2 leads to upregulation of CD73 enzyme onthe surface of monocytic myeloid-derived suppressor cells (M-MDSCs); (c) CD73 catalyzes the production ofextracellular adenosine from AMP (derived from ATP released from dying cells); and (d) adenosine inhibits theactivation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo-immunotherapy. Furthermore we propose a novel therapeutic strategy for overcoming this adenosine-mediatedimmunosuppression and sensitizing tumors to chemo-immunotherapy whereby co-treatment with recombinantpolyethylene glycol-conjugated adenosine deaminase enzyme (PEG-ADA) will convert immunosuppressiveadenosine into immunostimulatory inosine. In Specific Aim 1 of this project we will test our predictions about thekey cellular and molecular players in this pathway including cisplatin-induced PGE2 secretion CD73 expressionon M-MDSC adenosine production and suppression of anti-tumoral T cell activity. We will use a variety of in vivosystems that provide a faithful representation of human NSCLC including an orthotopic murine lung cancermodel and humanized mice with patient-derived xenografts (PDX). In Specific Aim 2 we will test theeffectiveness of selectively deleting CD73 in M-MDSCs or co-treating with PEG-ADA as approaches to increasethe anti-tumor/immunostimulatory activities of chemo-immunotherapy (anti-PD-1 + cisplatin) in transgenic mousemodels of non-squamous and squamous NSCLC. We will also examine tumor samples from NSCLC patientswho have progressed on anti-PD-1/chemotherapy for correlative evidence of this novel mechanism. Completionof these aims will identify novel and actionable immunosuppressive mechanisms that mediate relapse andtherapeutic resistance in metastatic NSCLC patients. Our studies will establish adding PEG-ADA (a drug that isFDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that canbe quickly translated into improved NSCLC treatment regimens.

project_terms:
Address;Adenosine;Attenuated;CD8-Positive T-Lymphocytes;Cancer Model;Cancer Patient;Carboplatin;Cell Physiology;Cells;Cisplatin;Clinical;Combination immunotherapy;Combined Modality Therapy;Cytotoxic agent;Data;Dinoprostone;Disease;Effectiveness;Energy-Generating Resources;Enzymes;Epithelial Cells;Eragrostis;FDA approved;Generations;Glucose;Health;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immuno-Chemotherapy;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Inosine;KRASG12D;Life;Lung;Malignant neoplasm of lung;Mediating;Metabolic;Modeling;Molecular;Monoclonal Antibodies;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nucleotidases;Nutrient;Outcome;PTGS2 gene;Paracrine Communication;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Polyethylene Glycols;Polyunsaturated Fatty Acids;Production;Purine Nucleosides;Recombinants;Relapse;Resistance;Risk;Sampling;Signal Induction;Signal Pathway;Surface;System;T-Lymphocyte;Testing;Therapeutic;Transgenic Mice;Translating;Treatment Failure;Treatment Protocols;Tumor Immunity;United States;Upregulation;Xenograft procedure;adenosine deaminase;anti-PD1 antibodies;cancer cell;cancer therapy;cancer type;chemotherapy;clinically relevant;effectiveness testing;effector T cell;extracellular;human disease;humanized mouse;immunogenic cell death;improved;in vivo;innovation;monocyte;mortality;mouse model;neoplastic cell;novel;novel therapeutic intervention;patient derived xenograft model;programmed cell death ligand 1;programmed cell death protein 1;randomized clinical trials;response;standard of care;therapy resistant;tumor;tumor ablation;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
Project NarrativeCancer therapy with a combination of cytotoxic drugs and with immune checkpoint inhibitors (ICIs)agentsthat reinvigorate the suppressed immune system to attack cancer cells (e.g. anti-PD-1 antibody)hasrevolutionized the treatment of metastatic lung cancer nevertheless therapeutic resistance is observed in asignificant proportion of patients and a critical determinant of unresponsiveness in these patients is the intra-tumoral accumulation of adenosine a molecule that actively suppresses the effectiveness of immunotherapies.To deplete the intra-tumoral adenosine we have explored the use of an FDA approved drug [PEGylated]-Adenosine Deaminase (PEG-ADA). Our proposed studies will confirm if depletion of adenosine with PEG-ADAcan induce anti-tumor immunity and sensitize lung cancer to chemo-immunotherapy and such a therapeuticstrategy can further extend the life of patient with a disease that is now a major health problem worldwide.


application_id: 11054625
project_number: 5R01CA279748-03
project_title: Immunotherapeutic targeting of MIF-dependent chaperone activity
administering_ic: NCI
award_notice_date: 2025-03-14
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;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-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: 11054271
project_number: 1R03HS030011-01A1
project_title: Prediction of Practice Change in Primary Care Following Guideline Updates
administering_ic: AHRQ
award_notice_date: 2024-09-11
opportunity_number: PA-23-115
application_type: 1
activity_code: R03
ic: HS
serial_number: 030011
suffix: A1
program_official: EDEN, AIMEE
project_start_date: 2024-09-30
project_end_date: 2026-09-29
study_section: Healthcare Effectiveness and Outcomes Research[HEOR]
contact_pi_person_id: 12670848
contact_pi: HENDRIX, NATHANIEL DAVID
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079659108
primary_uei: GEBSQDRBMFN5
duns_number: 079659108
uei: GEBSQDRBMFN5
fips: US
organization_id: 4602601
organization_name: AMERICAN BOARD OF FAMILY MEDICINE, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 405111338
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYThe central idea of evidence-based medicine is that clinical decisions should be made on the basis of thebest available research. Few practicing clinicians can stay current with the vast quantity of clinical researchrelevant to their patients though. This is especially true for primary care providers who care for patientswith a broad range of conditions. Treatment guidelines are therefore an essential mechanism fordisseminating research and promoting high-quality clinical care among physicians who cannot directlyengage with published clinical research. Still the time to widespread guideline implementation is too long.Delaying the uptake of guidelines has been associated with worse patient outcomes particularly amongpatients from marginalized groups. Using the American Family Cohort the nations largest clinical repositoryof electronic health records from primary care we will analyze the response to four guideline updates thathave different barriers to implementation: expansion of screening for Hepatitis C virus; vaccination of olderadults against pneumococcus with newly approved vaccines; provision of preexposure prophylaxis (PrEP)for Human Immunodeficiency Virus; and initiation of screening for colorectal cancer at age 45 among peopleof average risk. Our analyses will support the dissemination of guidelines into primary care in two distinctways. First we will assess the predictors of time to practice change in the direction of more guideline-concordant care for each of the four guideline update case studies as determined by change-point analysis.We will use a multi-level model to then predict time to practice change integrating patient provider andpractice site characteristics. This will allow guideline developers to forecast the uptake and potential impact including impact on disparities  of potential guideline updates. Next we will develop phenotypes ofclinicians based on their response to guideline updates by using latent class analysis to identify distinctivepatterns of practice change across the combination of all four guideline updates. This latent class analysiswill show how enabling factors and barriers to implementation can interact to generate predictable patternsof guideline response. In sum our second aim will support market segmentation and the individualization ofeducational outreach that can improve the efficiency and impact of dissemination activities.

public_health_relevance:
PROJECT NARRATIVEGuidelines for treating diseases are an important way that primary care providers learn about new research.However it takes too long for guidelines to be adopted into practice which harms patients. We will buildtools to help create more impactful guidelines and to support educational outreach on guideline updates.


application_id: 11053608
project_number: 5R01EY032645-03
administering_ic: NEI
award_notice_date: 2025-04-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: EY
serial_number: 032645
program_official: COOK, TIFFANY
project_start_date: 2023-03-01
project_end_date: 2028-02-29
study_section: Pathophysiology of Eye Disease - 1 Study Section[PED1]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: GREGG, RONALD G
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2025-03-01
project_title:
Preclinical evaluation of a homing endonuclease gene therapy for adRP in models of P23H retinopathy.

project_abstract:
Autosomal dominant Retinitis pigmentosa (adRP) is a blinding eye disease that results in loss of rods andeventually cone photoreceptors. A large fraction of adRP is caused by mutations in the rhodopsin (Rho) geneand the most common mutation in North America causes a P23H mutation in rhodopsin. Patients typicallypresent with mid- to late-stage disease when many rod photoreceptors already have degenerated.We will evaluate genome editing using a meganuclease genome editing tool (Rho1-2) that is specific for thesequence causing the P23H mutation in several preclinical animal models of P23H adRP. We will deliver AAV5-GRK1-Rho1-2 via subretinal injection to infect photoreceptors. We will measure efficacy the ability of Rho1-2 toalter rod degeneration and functional decline. We will quantitatively determine Rho1-2 efficiency the proportionof P23H alleles with insertions/delections (indels) specificity the proportion of P23H to WT alleles with indelsand its safety the absence of indels in other genes throughout the human genome (off target editing).In Pig P23H adRP models we will evaluate Rho1-2 editing efficacy because of the similarities between pigs andhumans in eye size and retinal structure and because the pig has a cone rich visual streak. We will use the samenon-invasive tools used in the clinic to measure retinal function (full field electroretinograms) and structure(spectral domain OCT). We will use two existing transgenic pig lines that harbor the entire P23H hRHO genebut differ in their time course resulting in a fast or slow loss of rods and rod function. We will match treatmenttime with the natural history of rod structural and functional decline compare Rho1-2 editing efficacy in early-mid- and late-stage P23H adRP and define its temporal treatment window. In Humanized adRP mouse modelswe will evaluate Rho1-2 editing efficiency and specificity because they contain WT and P23H human alleles inthe appropriate genomic context. In human retinal organoids we will evaluate Rho1-2 editing safety (off-targetcutting throughout the genome) because they contain human photoreceptors as well as the rest of the humangenome in a relevant context..Taken together the results of our experiments will determine if Rho1-2 should move forward for eventual use inhuman clinical trials and will define endpoints for those trials.

project_terms:
Accounting;Affect;Alleles;Animal Euthanasia;Animal Model;Animals;Behavior;Biological Models;Blindness;Canis familiaris;Cells;Clinic;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Cone;Development;Disease;Double Strand Break Repair;Electroretinography;Engineering;Eye;Eye diseases;Family suidae;Frequencies;GRK1 gene;Gene Expression;Gene Mutation;Genes;Genome;Genome-wide Unbiased Identification of DSBs Enabled by sequencing;Genomics;Goals;Homing;Human;Human Genome;Intervention;Measures;Methodology;Modality;Modeling;Morphology;Mus;Mutate;Mutation;Natural History;Night Blindness;Nonhomologous DNA End Joining;North America;Organoids;Outcome;Patient Selection;Patients;Photoreceptors;Pre-Clinical Model;Proteins;Rare Diseases;Research Personnel;Rest;Retina;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinitis Pigmentosa;Rhodopsin;Rod;Safety;Selection Criteria;Site;Specificity;Structure;Technology;Therapeutic;Time;Transgenic Organisms;Vertebrate Photoreceptors;Viral Packaging;Visual;alternative treatment;autosome;deep sequencing;efficacy evaluation;efficacy testing;endonuclease;experimental study;functional decline;gene editing technology;gene therapy;genome editing;human model;humanized mouse;in silico;individualized medicine;insertion/deletion mutation;interest;mouse model;mutant;neglect;nonhuman primate;nuclease;off-target site;optimal treatments;porcine model;pre-clinical;preclinical evaluation;retinal rods;safety assessment;subretinal injection;timeline;tool;zinc finger nuclease

public_health_relevance:
In retinitis pigmentosa (RP) rod photoreceptors die leading to blindness. Patients typically come to the clinicwith mid/late-stage disease after many rods have died. We will test the efficacy efficiency specificity andsafety a gene therapy for this autosomal dominant orphan disease caused the P23H mutation in rhodopsin.


application_id: 11053522
project_number: 5R01NS127974-03
administering_ic: NINDS
award_notice_date: 2025-05-19
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: 2025-04-01
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;Arteries;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: 11052611
project_number: 5R01HL163589-02
project_title: Targeting Endothelial Cell Mineralocorticoid Receptor Against Aortic Aneurysm in Females
administering_ic: NHLBI
award_notice_date: 2025-06-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163589
program_official: STABLEY, JOHN N
project_start_date: 2024-06-01
project_end_date: 2028-05-31
study_section: Atherosclerosis and Vascular Inflammation Study Section[AVI]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: GONG, MING C
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 SummaryAbdominal aortic aneurysm (AAA) is a severe vascular disease affecting millions of Americans with highmorality. Currently no medication has been approved to treat this devastating disease. Women are less andlater to develop AAA than men. Nevertheless AAA in women is more aggressive. It grows faster. It is morelikely to rupture at smaller diameters resulting in higher mortality with worse morbidity after surgical repair.Smoking promotes AAA in both men and women but women who smoke are at higher risk for AAA than men.Estrogen (E2) has long been believed to protect premenopausal women from AAA. However its effect on AAAin animal models and human clinical trials is controversial. Several AAA animal models have been developedand have contributed to our current understating of AAA. However one of the common limitations of theseanimal models is to use young animals to study AAA which occurs mainly in older people. To fill this significantgap we developed a relatively new AAA mouse model that requires using older male mice activation ofmineralocorticoid receptor (MR) by aldosterone (Aldo) and high salt intake to induce AAA. Surprisingly wefound that Aldo and salt (Aldo-salt) only induced AAA in male mice but not in female mice unless female micewere subjected to ovariectomy (Ovx) or nicotine. Mechanistically MR was upregulated by Aldo-salt with Ovx ornicotine in endothelial cells (EC) in the aorta with accumulation in the nucleus indicating E2 may protectfemale mice from AAA via suppressing MR expression and/or nuclear translocation in EC in the aorta.Interestingly Per2 a core circadian gene interacts with ER and MR and is required for E2 to suppress MRexpression. Moreover genetic deletion of MR in EC but not smooth muscle cell and myeloid cells inhibitedAldo-salt-induced AAA concordant with a reduction in ICAM1 upregulation in EC and neutrophil (N)infiltration in the aorta. Based on the literature and robust evidence from our preliminary data we hypothesizethat E2 inhibits Aldo-salt-induced MR protein upregulation and nuclear translocation via ER/Per2/MRinteraction in EC in the aorta thus protecting female mice from ICAM1 upregulation N infiltration and aorticaneurysm. Aim 1 is to define the mechanism by which E2 protects Aldo-salt-induced aortic aneurysm byinhibiting MR protein upregulation and nuclear translocation via ER in EC in the aorta in female mice with Ovxand nicotine; Aim 2 is to determine whether targeting the Per2/MR/ICAM1/N signaling can protect femalemice with Ovx or nicotine from Aldo-salt-induced aortic aneurysm. To achieve these goals 12-week-old or 12-month-old C57BL/6 iECERKO Per2KO iECPer2KO iECMRKO and WT control female mice will besubjected to Ovx or nicotine and then treated with E2/progesterone (P4)/dihydrotestosterone (DHT)/ICAM1/Ly6G antibody (Ab). The effect of hormone therapy genetic deletion and Ab blocking on aging/Aldo-salt-induced AAA will be determined. The proposed studies will shed new mechanistic insight into the pathologiesof AAA in women and provide preclinical evidence to help identify new therapeutic targets against AAA.

project_terms:
Abdominal Aortic Aneurysm;Accounting;Affect;Aging;Aldosterone;American;Aneurysm;Animal Model;Animals;Antibodies;Aorta;Aortic Aneurysm;Atherosclerosis;Blocking Antibodies;Cell Nucleus;Cessation of life;Clinical Trials;Data;Diameter;Disease;Endothelial Cells;Estrogens;Exhibits;Female;Genes;Genetic;Goals;Hormone replacement therapy;Human;Hypertension;ICAM1 gene;Infiltration;Intercellular adhesion molecule 1;Literature;Mineralocorticoid Receptor;Modeling;Molecular;Morality;Morbidity - disease rate;Mus;Myeloid Cells;Neutrophil Infiltration;Nicotine;Nuclear Translocation;Older Population;Operative Surgical Procedures;Ovariectomy;Pathology;Pharmaceutical Preparations;Postmenopause;Premenopause;Progesterone;Research;Risk Factors;Role;Rupture;Scheme;Signal Transduction;Smoke;Smoking;Sodium Chloride;Stanolone;Testing;Therapeutic;United States;Upregulation;Vascular Diseases;Woman;circadian;eplerenone;high risk;high salt diet;hormone therapy;insight;juvenile animal;male;men;mortality;mouse model;neutrophil;new therapeutic target;novel therapeutics;old mice;pre-clinical;receptor;receptor expression;repaired;sex;sexual dimorphism

public_health_relevance:
Project NarrativeAbdominal aortic aneurysm (AAA) is a severe vascular disease affecting millions of Americans. Womendevelop AAA less and later than men but AAA in women is more aggressive with more rapid expansion ahigher tendency to rupture and higher mortality following rupture. This application aims to investigate themechanisms that underlie AAA in female mice and to identify new therapeutic targets to develop new drugs totreat AAA.


application_id: 11052556
project_number: 5R01AA028905-04
project_title: Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease
administering_ic: NIAAA
award_notice_date: 2025-05-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AA
serial_number: 028905
program_official: LIN, LI
project_start_date: 2022-06-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-DKUS-R(04)]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis tosteatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity mortality andhealth care costs in the US and worldwide. However there is no FDA-approved therapy for any stage of ALD.There is also an incomplete understanding of the mechanisms and mediators of disease progression andseverity. Soluble epoxide hydrolase (s-EH) a master enzyme that regulates the metabolism of endogenousbioactive lipids (e.g. epoxy-fatty acids Ep-FAs) has recently been recognized as an emerging therapeutic targetin multiple diseases. The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition atdifferent stages of ALD severity and to provide a mechanistic foundation for using s-EH inhibition as a noveltherapy for alcohol-induced liver pathology. Aim 1. To test the therapeutic effectiveness of s-EH inhibitionas a novel therapeutic strategy for ALD. We will: i) test whether modulation of s-EH activity by pharmacologicalinhibition or s-EH (Ephx2) genetic ablation can effectively attenuate or prevent EtOH-induced liver injury inexperimental ALD; ii) evaluate whether s-EH inhibition leads to stabilization of blood and liver Ep-FAs; and iii)correlate changes in Ep-FA levels with markers of liver injury. Systemic and targeted liver-specific delivery of s-EH inhibitors (t-TUCB and TPPU) and WT and Ephx2 -/- mice (global and liver-specific) will be used in multipleanimal models of ALD which produce different stages of disease severity and which recapitulate differentfeatures of human ALD. This allows for a rigorous evaluation of the effects of s-EH inhibition at different stagesof ALD severity. Treatment and prevention paradigms will be applied. Aim 2. To explore mechanism(s)underlying the beneficial effects of s-EH inhibition in experimental ALD. We will determine whether Ep-FAstabilization mediated by s-EH inhibition plays a critical role in attenuation of EtOH-induced liver injury. We willtest whether n3 vs n6 Ep-FAs exert a greater beneficial effect by enhancing M2 macrophage polarizationincreasing a pro-restorative/pro-resolving macrophage phenotype and by Ep-FAs-PPAR-CXCL1-mediatedreduction of neutrophil infiltration. s-EH inhibitors WT transgenic fat-1 mice (which endogenously convert n6PUFAs to n3 PUFAs) and hepatocyte-specific Ppar-/- mice will be used. In vivo and in vitro studies will beperformed. Aim 3. To evaluate EtOH-induced alterations in s-EH and Ep-FAs in human ALD. Utilizing de-identified human plasma and whole blood samples we will: i) evaluate alterations in plasma Ep-FAs andestablish relationships between biomarkers of liver injury and systemic inflammation in patients with alcohol-associated hepatitis (AH); ii) determine the effects of n3-PUFA dietary supplementation on plasma Ep-FAs inheavy drinking individuals; and iii) test whether s-EH inhibition and Ep-FAs (including both n3 and n6 Ep-FAs)can effectively decrease basal and LPS-stimulated pro-inflammatory cytokine production in whole blood andperipheral blood monocytes obtained from AH patients.

project_terms:
Ablation;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Experiments;Animal Model;Anti-Inflammatory Agents;Attenuated;Biological Markers;Blood;Blood specimen;CXCL1 gene;Cirrhosis;Dietary Supplementation;Disease;Disease Progression;Enzymes;Epoxide hydrolase;Epoxy Compounds;Etiology;Evaluation;FAT gene;FDA approved;Fatty Acids;Fatty Liver;Fibrosis;Foundations;Genetic;Glycols;Goals;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis;Hepatocyte;Human;In Vitro;Individual;Infection;Inflammation;Inflammatory;Injury;Kidney;Lipids;Liver;Liver diseases;Lung;Macrophage;Mediating;Mediator;Messenger RNA;Metabolic Diseases;Metabolism;Morbidity - disease rate;Mus;Names;Neutrophil Infiltration;Obesity;Omega-3 Fatty Acids;Organ failure;PPAR gamma;Pathogenesis;Pathology;Patients;Phenotype;Plasma;Play;Prevention;Preventive;Production;Property;Resolution;Role;Severity of illness;Steatohepatitis;Testing;Therapeutic;Transgenic Organisms;Treatment Efficacy;Whole Blood;attenuation;chemokine;cytokine;effective therapy;in vivo;inhibitor;liver injury;monocyte;mortality;neutrophil;non-alcoholic fatty liver disease;novel;novel therapeutic intervention;novel therapeutics;organ regeneration;peripheral blood;pharmacologic;preservation;prevent;receptor;systemic inflammatory response;therapeutic effectiveness;therapeutic evaluation;therapeutic target;therapeutically effective;tissue regeneration

public_health_relevance:
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis tosteatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity mortality andhealth care costs in the US and worldwide. However there is no FDA-approved therapy for any stage of ALD.The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition at different stages of ALDseverity and to provide a mechanistic foundation for using s-EH inhibition as a novel therapy for alcohol-inducedliver pathology.


