# projects

application_id: 10573161
project_number: 5P20GM121327-07
project_title: Circulating tumor cell-neutrophil clusters in breast cancer metastasis
administering_ic: NIGMS
award_notice_date: 2022-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6636
contact_pi_person_id: 12106844
contact_pi: LIU, XIA X
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 SUMMARYMetastasis causes a majority of breast cancer (BCa)-related deaths. Among all types of BCas triple-negativebreast cancers (TNBCs) are more aggressive and have a poorer prognosis. To metastasize cancer cells mustenter into the circulatory system. These circulating tumor cells (CTCs) are considered the seeds of metastasis.Recently both our preliminary data and other studies have shown that neutrophils can interact with asubpopulation of CTCs (named CTC-neutrophil clusters) to facilitate metastasis. However the features ofneutrophil-associated CTCs and how CTC-associated neutrophils facilitate metastasis has yet to be determined.The overall objective of this proposal is to identify and characterize neutrophil-associated CTCs and how theinteraction promotes metastasis with the hope of developing a novel therapeutic strategy to inhibit metastasisby blocking CTC-neutrophil cluster formation. We found that the intercellular adhesion molecule 1 (ICAM-1)which is well-known to bind to Mac-1 on neutrophils is overexpressed in lung metastases and knockdown ofICAM-1 inhibits TNBC metastasis. In addition ICAM-1+ TNBC cells produce high level of soluble urokinaseplasminogen activator receptor (uPAR). Since uPAR is a potent chemoattractant for recruitment of neutrophilsand facilitates Mac-1-mediated adhesion we hypothesize that ICAM-1+ CTCs are prone to associate withneutrophil by increasing suPAR production to enhance their metastatic ability. Furthermore our preliminaryfindings indicate that Mac-1 expression is upregulated in circulating neutrophils from tumor-bearing mice. Sinceboth phospholipase A2 and arachidonate 5-lipoxygenase the key enzymes in arachidonic acid (AA) metabolismcan upregulate Mac-1 expression we also hypothesize that enhanced AA metabolism in circulating neutrophilsis required for their interaction with CTCs to promote metastasis. We propose 2 Specific Aims: 1) to determinethe molecular mechanisms by which ICAM-1 promotes BCa metastasis particularly whether uPAR facilitatesICAM-1 and Mac-1 mediated CTC and neutrophil interaction using both mouse and human TNBC models; 2) todissect the role of AA metabolism in the pro-metastatic activity of circulating neutrophils using blood samplesfrom both TNBC mouse models and BCa patients. The results from this proposal will not only reveal newmechanisms of metastasis but also have significant implications for understanding how AA metabolismregulates pro-metastatic function of neutrophils which will pave the way for the design of next-generationneutrophil-based immunotherapy.

project_terms:
Adhesions;Arachidonate 5-Lipoxygenase;Arachidonic Acids;Binding;Biological Assay;Blood specimen;Brain;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Breast cancer metastasis;Cancer Center;Cardiovascular system;Cells;Centers of Research Excellence;Cessation of life;Chemotactic Factors;Chemotaxis;Circulation;Data;Development;Diagnosis;Dinoprostone;Disease;Distant;Endothelial Cells;Enzymes;Exhibits;Goals;Human;Immune;Immunotherapy;In Vitro;Intercellular adhesion molecule 1;Kentucky;Lung;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Lung;Molecular;Mus;Names;Neoplasm Circulating Cells;Neoplasm Metastasis;Neutrophil Infiltration;Nonmetastatic;Organ;Phenotype;Phospholipase A2;Play;Production;Prognosis;Property;Prostaglandin-Endoperoxide Synthase;Role;Site;Sorting;Testing;Therapeutic;Tissues;Universities;Urokinase Plasminogen Activator Receptor;Western Blotting;cancer cell;design;healthy volunteer;improved;in vivo;innovation;intravital imaging;knock-down;lung colonization;malignant breast neoplasm;metastatic process;mouse model;neutrophil;next generation;novel;novel therapeutic intervention;overexpression;recruit;single-cell RNA sequencing;stem cells;synergism;targeted treatment;triple-negative invasive breast carcinoma;tumor;tumor metabolism;tumorigenic;uptake


application_id: 10573152
project_number: 5P20GM121327-07
project_title: Imaging Core
administering_ic: NIGMS
award_notice_date: 2022-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6635
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
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 SUMMARYThe Imaging Core of the Center for Cancer and Metabolism (CCM) is the technical service and support corefor CCM project research laboratories and pilot project recipients. The integrated services of the Core rangefrom the imaging capabilities of simple microscopes to imaging analysis by sophisticated and advancedimaging methodologies. The Imaging Core personnel assist users to operate the instruments and analyzeimaging data. The Core provides advice for the current PIs in this Center of Biomedical Research Excellence(COBRE) application to use the Imaging Core for their specific studies. The Imaging Core has providedtremendous help to the projects in Phase I of COBRE support and will continue to make its services readilyavailable and easily accessible to all COBRE laboratories in order to generate high quality data. Toward thegoals of providing efficient and high-quality imaging services and of establishing a robust imaging infrastructurewithin the CCM we have added new features and new imaging systems to the Core. Our specific aims are: 1)to provide project-specific training and consultation for COBRE investigators; 2) to develop and adapt state-of-the art imaging techniques to enhance the research of early-stage and pilot project investigators; and 3) todevelop and implement new methods to enhance CCM imaging services and make such services available toCOBRE and non-COBRE users. This Core will provide an easily accessible facility where investigators canevaluate their tissue and/or cellular samples using various types of imaging systems. Dr. Jianhang Jia theDirector of the Imaging Core is a highly productive investigator who has successfully obtained substantialextramural research support including an NIGMS Maximizing Investigators' Research Award (MIRA) (R35)award for established investigators that relies extensively on sophisticated imaging capabilities. He has workedclosely with all graduated COBRE PIs making significant contributions to their successes in obtainingindependent research support. Dr. Jia has guided the development of the four CCM research projects in thisPhase II application and he will continue to advise CCM investigators on the design of experiments that useimaging modalities.

project_terms:
Aging;Animal Disease Models;Area;Award;Bioinformatics;Bioluminescence;Biomedical Research;Biometry;Cancer Center;Centers of Research Excellence;Clinical;Complex;Computer software;Consult;Consultations;Data;Dedications;Development;Disease Progression;Distant;Equipment;Evaluation;Experimental Designs;Extramural Activities;Faculty;Floor;Fluorescence;Goals;Human Resources;Image;Imaging Device;Imaging Techniques;Individual;Infrastructure;Kentucky;Laboratories;Laboratory Research;Link;Malignant Neoplasms;Medicine;Metabolic;Metabolism;Methodology;Methods;Microscope;Mission;Monitor;Mus;National Institute of General Medical Sciences;Neoplasm Metastasis;Organ;Pathology;Phase;Pilot Projects;Positioning Attribute;Productivity;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Scientist;Services;Site;Slide;System;Tissues;Training;Transfection;Universities;Work;advanced analytics;analytical tool;animal facility;anticancer research;cancer therapy;cell motility;cost effective;design;digital;flexibility;imaging capabilities;imaging modality;imaging study;imaging system;in vivo;in vivo imaging;in vivo imaging system;instrument;metabolomics;multidisciplinary;novel;optical imaging;programs;skills;success;treatment response;tumor initiation;tumor metabolism;tumorigenesis


application_id: 10573134
project_number: 5P20GM121327-07
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6633
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
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 SUMMARYThe University of Kentucky (UK) Center for Cancer and Metabolism (CCM) is a unique multidisciplinary Centerof Biomedical Research Excellence (COBRE) embedding a strategically developed sustainable centerinfrastructure that cultivates cutting-edge research focused on the role of metabolic dysregulation in cancerdevelopment and progression. The Administrative Core provides critical scientific and administrative leadershipto advance the goals of the CCM: to develop and sustain a thematically focused multidisciplinary centerinfrastructure dedicated to defining the role of altered metabolism in the development and treatment of cancerand to use this innovative center structure to develop promising early-stage investigators with enhanced cancerresearch skills. The goal of the Administrative Core is to increase the scientific productivity of the centers facultyby delivering efficient administrative services across scientific projects and cores as well as pilot projects throughan organizational / leadership framework that supports flexible team-based mentoring and provides for clearaccountability. The Administrative Core is the central coordinating hub responsible for integrating highlycomplementary disciplinary strengths at UK in cancer metabolism and informatics and leveraging sophisticatedmetabolomics tools and advanced cancer imaging capabilities in support of data-intensive research focused oncancer metabolism. The core has primary responsibility for facilitating the CCMs scientific vision operating onprinciples grounded in transformational leadership and shared administrative oversight. Administrative Corefunctions are operationalized through the following 3 specific aims: 1) to provide overall operational managementof the center; 2) to facilitate research training mentoring and career development activities to develop early-stage investigators in cancer and metabolism and expand research in this area through pilot projects; and 3) toconduct overall planning and evaluation of CCM activities and resources. The core implements all administrativeactivities of the CCM: oversees daily center activities; manages program communications fiscal processesmeeting organization and advisory committee input; facilitates and expedites interactions among projects andcores; manages the pilot project program; and leads program and project evaluation efforts. The core overseesa total of 4 projects 2 scientific cores a biostatistics and bioinformatics support component that is integratedinto each project and 4 pilot projects each year. In addition the core ensures highly effective well-planned team-based mentorship including basic and clinical perspectives and external expertise for early-stage investigators.The core supports CCM investigators through their career development milestones including tenure andpromotion stages. In implementing these activities effectively the Administrative Core contributes substantiallyto development of a sustainable biomedical research infrastructure dedicated to advancing a cancer metabolismmultidisciplinary theme.

project_terms:
Accountability;Address;Administrative Efficiency;Administrator;Advanced Malignant Neoplasm;Advisory Committees;Area;Biochemistry;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Clinical Sciences;Communication;Communication Programs;Coupled;Data;Data Science;Dedications;Development;Disparate;Effectiveness;Ensure;Evaluation;Faculty;Fostering;Goals;Health;Incidence;Informatics;Infrastructure;Kentucky;Knowledge;Leadership;Malignant Neoplasms;Mediator;Mentors;Mentorship;Metabolic;Metabolism;Molecular Medicine;Monitor;National Cancer Institute;Obesity;Oncogenic;Pharmacologic Substance;Pilot Projects;Play;Process;Productivity;Program Evaluation;Research;Research Infrastructure;Research Personnel;Research Training;Resource Sharing;Resources;Role;Scientist;Seasons;Senior Scientist;Services;Structure;System;Translational Research;Universities;Vision;anticancer research;biomedical informatics;cancer therapy;career development;clinical center;flexibility;imaging capabilities;improved;innovation;meetings;metabolomics;mortality;multidisciplinary;next generation;novel;programs;skills;success;synergism;therapeutic target;tool;tumor metabolism


application_id: 10573133
project_number: 5P20GM121327-07
project_title: University of Kentucky Center for Cancer Metabolism
administering_ic: NIGMS
award_notice_date: 2022-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: REVILLEZA, MARIA JAMELA R
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3(C2)
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: ST CLAIR, DARET K
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:
PROJECT SUMMARYThe University of Kentucky (UK) Center of Biomedical Research Excellence on Cancer and Metabolism (CCM)was established in March 2017 by a multidisciplinary team of basic and clinical scientists engaged in cutting-edge research on metabolic dysregulations in cancer an emerging hallmark of disease responsible for tumordevelopment drug resistance and distant metastasis. The overarching goal of the Phase II CCM is to continueefforts to expand a thematically focused multidisciplinary infrastructure dedicated to defining the contribution ofmetabolism in the development and treatment of cancer and to use this novel multidisciplinary platform todevelop promising project leaders with enhanced skills in an exciting new area of cancer research. With adedicated team of mentors combining basic and clinical expertise in redox biology cancer cell signalingepigenetics systems biochemistry and clinical trials as well as core strengths in advanced metabolomics andsophisticated cancer imaging we will accomplish this overall goal by conducting high-quality basic andtranslational research addressing metabolic reprogramming governing tumor initiation metastasis drugresistance and recurrence. This objective will be met by achieving 2 Specific Aims. Specific Aim 1 is to expandthe critical mass of investigators conducting CCM thematic research. We will recruit coach and solidify thecommitment of a cadre of promising project leaders to conduct cancer and metabolism research utilizing a highlyeffective mentoring system and provide these scientists with cutting-edge research core facilities and services.Proposed new synergies will be developed through 4 well-crafted research projects; an Administrative Core;innovative research cores in metabolism and imaging; strong biostatistics and bioinformatics support; andcollaborations with other UK research centers to facilitate the translation of basic findings in cancer metabolisminto early therapeutic and/or intervention approaches. Specific Aim 2 is to advance an independent sustainablemultidisciplinary thematic biomedical infrastructure and research program on cancer and metabolism bystrengthening key scientific cores. We propose to expand the scope and capacity of these vital cores by acquiringand installing new state-of-the-art equipment introducing new technologies and service as well as providingtraining sessions workshops and symposiums. Kentucky ranks highest in rates of overall cancer incidence andmortality [1]. In Phase I the CCM had a transformative impact in career research and retention of the nextgeneration of scientists who address metabolic dysregulations underpinning the causal links between metabolicdisorders and cancer development a major health threat in the nation. Importantly the Phase II application willbuild upon these accomplishments to propel CCM to a nationally recognized center in cancer and metabolismresearch that will also address the regions critical needs.

project_terms:
Address;Applications Grants;Area;Basic Science;Biochemistry;Bioinformatics;Biology;Biometry;Cancer Center;Cell Survival;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Core Facility;Coupled;Data;Dedications;Development;Disease;Distant Metastasis;Drug resistance;Early Diagnosis;Educational workshop;Environment;Epigenetic Process;Equipment;Extramural Activities;Faculty;Fees;Fostering;Foundations;Funding;Goals;Grant;Growth;Health;Image;Incidence;Infrastructure;Institution;Interdisciplinary Study;Intervention;Kentucky;Link;Malignant Neoplasms;Mediator;Mentors;Metabolic;Metabolic Diseases;Metabolism;Methodology;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Phase;Pilot Projects;Positioning Attribute;Productivity;Protein Array;Quality of life;Recurrence;Research;Research Personnel;Research Project Grants;Research Support;Role;Scientist;Services;Signal Transduction;System;Therapeutic;Training;Translational Research;Translations;United States National Institutes of Health;Universities;Vital capacity;animal imaging;anticancer research;base;cancer cell;cancer imaging;cancer initiation;cancer prevention;cancer therapy;career;defined contribution;early detection biomarkers;editorial;improved;in vivo;innovation;metabolomics;mortality;multidisciplinary;new technology;next generation;novel;prevent;programs;recruit;skills;success;symposium;synergism;therapeutic target;therapy resistant;tool;tumor;tumor initiation;tumor metabolism;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEKentucky ranks highest in rates of overall cancer incidence and mortality [1]. To address this major health issuethe University of Kentucky Center of Biomedical Research Excellence on Cancer and Metabolism will sustain arobust infrastructure to continue to conduct basic and translational research to better define the metabolicdysregulations governing tumor development metastasis drug resistance and recurrence. This will be achievedthrough the cultivation and expansion of a cadre of promising project leaders by providing research supportmentoring and access to state-of-the-art metabolic and imaging core facilities.


application_id: 10572240
project_number: 1K99AA030627-01
project_title: Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH
administering_ic: NIAAA
award_notice_date: 2022-09-21
opportunity_number: PAR-21-271
application_type: 1
activity_code: K99
ic: AA
serial_number: 030627
program_official: LIN, LI
project_start_date: 2022-09-21
project_end_date: 2024-08-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
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_terms:
ATP Synthesis Pathway;Affect;Alcoholic liver damage;Alcohols;Animal Model;Animals;Apoptosis;Binding;Bioenergetics;Biogenesis;Biological Assay;Biological Markers;Cardiolipins;Cells;Cessation of life;Clinical;Clinical Trials;Culture Media;Data;Dextrins;Dose;Enzymes;Ethanol;Euthanasia;Evaluation;Experimental Animal Model;Foundations;Galactosamine;Genes;Genus Hippocampus;Hepatic;Hepatic Insufficiency;Hepatitis;Hepatocyte;Human;Immune;Impairment;In Vitro;Inflammation;Inflammatory Response;Injections;Injury;Lead;Lipids;Liver;Liver Mitochondria;Liver Regeneration;Liver diseases;Maintenance;Maltose;Measurement;Mediating;Mitochondria;Mitochondrial Myopathies;Modeling;Mus;Natural regeneration;Oxidative Phosphorylation;Oxides;Partial Hepatectomy;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Pharmacology;Phase;Phospholipids;Plasma;Population;Prevention;Process;Prognosis;Proliferating;Proliferation Marker;Proteins;Regimen;Research;Research Personnel;Respiratory Chain;Rodent;Role;Safety;Sampling;Solid;Structure;Supplementation;TNF gene;Tail;Testing;Therapeutic;Training;Translations;Treatment Efficacy;Veins;Vesicle;Viral;Viral Genome;alternative treatment;chronic liver disease;cytochrome c;cytokine;disorder control;feeding;hepatocyte injury;improved;in vitro Model;ineffective therapies;lipidomics;liver cell proliferation;liver function;liver transplantation;male;mitochondrial dysfunction;mitochondrial membrane;mortality;novel;oxidation;particle;patient prognosis;pre-clinical;preclinical study;preservation;prevent;problem drinker;regeneration function;response;restoration;single-cell RNA sequencing;therapeutically effective;treatment arm;treatment strategy


application_id: 10571912
project_number: 5K08AI151100-05
project_title: Defining the impact of zinc on Streptococcus agalactiae biofilm and colonization
administering_ic: NIAID
award_notice_date: 2023-02-08
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: AI
serial_number: 151100
program_official: GU, XIN-XING
project_start_date: 2020-03-09
project_end_date: 2025-02-28
study_section: Microbiology and Infectious Diseases B Research Study Section[MID-B]
contact_pi_person_id: 12264080
contact_pi: DOSTER, RYAN S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryDuring pregnancy zinc deficiency is associated with an increased risk of infection. Streptococcus agalactiaealso known as Group B Streptococcus (GBS) colonizes 20-30% of pregnant women. GBS vaginal colonizationincreases the risk for stillbirth preterm labor and neonatal sepsis. One strategy that GBS may use to stablycolonize the reproductive tract is to produce biofilm and we have found that GBS biofilm production issuppressed in the presence of zinc. This proposal tests the hypothesis that GBS biofilm production isnegatively regulated by zinc and this biofilm contributes to stable colonization of host tissues by limiting innateimmune responses against GBS. To test this hypothesis Aim 1 will use mutagenesis and transcriptomicapproaches to identify genetic pathways regulating GBS biofilm. Aim 2 will define the impact of zinc-regulatedbiofilm at the host-microbial interface by evaluating GBS mutants lacking cadD a zinc efflux transporter whichresults in impaired biofilm production. We will examine these interactions using in vitro models of humanvaginal epithelial cells explanted human fetal membranes and an Instrumented Fetal Membrane Organ on aChip (IFMOC) model under conditions that modify zinc availability. Aim 3 will use a mouse vaginal colonizationmodel to define how the zinc transporter cadD impacts vaginal colonization in settings of zinc deficiency orsupplementation. Completion of these Aims will shed new light on how zinc impacts GBS-host interactions thatculminate in colonization (and infection) of the reproductive tract.Dr. Ryan Doster is an Instructor in the Division of Infectious Diseases at Vanderbilt University Medical Center.His past work investigated gestational tissue innate immune responses to infection. This project will expand hisresearch focus to mechanisms of GBS colonization. This project complements Dr. Dosters clinical training inpediatrics and adult infectious diseases medicine. Under the mentorship of Dr. David Aronoff Dr. JenniferGaddy and a multidisciplinary Scholarship Oversight Committee Dr. Doster will master techniques includingbacterial mutagenesis transcriptomics and modeling infection within the reproductive tract to determine howzinc alters bacterial physiology and pathogenesis. Vanderbilt offers cutting-edge technology and expertise inthese areas through Vanderbilt Technologies for Advanced Genomics and other shared research corefacilities. These studies and a strong career development program will prepare Dr. Doster for transition to anindependent researcher investigating the pathogenesis of bacterial infections during pregnancy.

project_terms:
Academic Medical Centers;Adult;Area;Bacterial Infections;Bacterial Physiology;Cells;Communicable Diseases;Complement;Core Facility;Data;Development;Epithelial Cells;Epithelium;Event;Female;Fetal Membranes;Future;Genetic;Genetic Transcription;Genomics;Glucose;Goals;Human;Immune response;Impairment;In Vitro;Infection;Inflammatory Response;Innate Immune Response;Link;Medicine;Mentors;Mentorship;Microbial Biofilms;Microscopy;Modeling;Morbidity - disease rate;Mus;Mutagenesis;Newborn Infant;Nutrient;Pathogenesis;Pathway interactions;Pediatrics;Perinatal;Perinatal Infection;Physicians;Pregnancy;Pregnant Women;Premature Birth;Premature Labor;Production;Program Development;Regulator Genes;Regulatory Pathway;Research;Research Personnel;Resolution;Risk;Risk Factors;Role;Scholarship;Scientist;Stimulus;Streptococcal Infections;Streptococcus Group B;Supplementation;Techniques;Technology;Testing;Tissue membrane;Tissues;United States;Vagina;Woman;Work;Zinc;Zinc deficiency;Zinc supplementation;career;career development;clinical training;dietary;early onset;host colonization;human model;in vitro Model;in vivo;infection risk;innovation;instructor;instrument;intraamniotic infection;intrauterine infection;microbial host;mortality;mouse model;multidisciplinary;mutant;neonatal infection;neonatal sepsis;novel strategies;organ on a chip;pathogen;premature;prevent;reproductive tract;response;stillbirth;transcriptome;transcriptomics;zinc-binding protein

public_health_relevance:
Project NarrativeZinc deficiency increases the risk for infections during pregnancy. Perinatal bacterial infections often originatein the vagina where asymptomatic bacterial colonization leads to ascending intrauterine infection followed bypreterm labor stillbirth or neonatal infection. As part of a long-term goal to identify novel approaches toprevent and treat of perinatal infections this proposal will investigate how zinc alters the ability of a commonperinatal pathogen Group B Streptococcus to colonize and infect the female reproductive tract.


application_id: 10571404
project_number: 1R21AG080176-01
project_title: Role of P4HA1 in Endocrine Resistance of Breast Cancer
administering_ic: NIA
award_notice_date: 2023-02-24
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AG
serial_number: 080176
program_official: CARRINGTON-LAWRENCE, STACY
project_start_date: 2023-03-01
project_end_date: 2023-09-17
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 16148369
contact_pi: XIONG, GAOFENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Tamoxifen is the oldest and the most widely used selective estrogen receptor modulators. Fulvestrant is aselective estrogen receptor down-regulator which blocks and damages estrogen receptors. Fulvestrant isintroduced to clinical as second-line therapy post disease progression after tamoxifen. Endocrine treatment isthe first-line therapy for estrogen receptor positive breast cancer patients. However 30%-50% of the breastcancer patients with five to ten years of treatment acquire resistance to endocrine therapy. Resistance toendocrine therapy and recurrence is the leading cause of mortality in breast cancer patients. Prolyl hydroxylation(P4H) is an enzyme hydroxylates proline into 4-hydroxyproline of collagens and other proteins with the -X-Pro-Gly- sequences as collagens in the endoplasmic reticulum. P4HA1 the alpha subunit of P4H1 is responsiblefor both peptide binding and catalytic activity. In this study we found that increased expression of P4HA1 wasdetected in endocrine therapy resistant luminal breast cancer cells compared with endocrine therapy sensitivecells. High P4HA1 expression significantly correlates with short relapse-free survival in luminal breast cancerpatients. Inactivation of P4HA1 protein sensitized endocrine resistance luminal cancer cells to 4-Hydroxytamoxifen (4OHT) or fulvestrant treatment accompanied by increased reactive oxygen species (ROS)and endoplasmic reticulum (ER) stress. These preliminary data indicate that P4HA1 is an important regulator forendocrine resistance of breast cancer. We hypothesize that inhibition of P4HA1 sensitizes luminal breast cancercells to endocrine therapy by inducing ROS-ER stress pathway. To investigate the importance of P4HA1 forendocrine resistance we will introduce P4HA1 protein expression in endocrine sensitive luminal breast cancercell lines. We will examine resistance to 4OHT or fulvestrant treatment ER stress level as well as ROS levelsin P4HA1-overexpression cells under 4OHT or fulvestrant treatment. We will perform rescue experiments inP4HA-silenced endocrine resistant cells using ROS inhibitor. For the in vivo study we will use endocrine resistantluminal breast cancer cell lines orthotropic xenograft model and resistance luminal breast cancer patient-derived-xenograft (PDX) models. We will determine whether inactivation of P4HA1 renders these endocrineresistant tumors sensitive to tamoxifen or fulvestrant treatment in vivo and examine whether the overwhelmedER stress and ROS levels are associated with endocrine sensitivity in tumors. In summary this investigation willuncover a novel uncanonical role of P4HA1 in endocrine resistance by regulation ROS-ER stress pathway andexplore P4HA1 as a novel therapeutic target for combinatorial therapy for endocrine resistant luminal breastcancer patients.

project_terms:
4-Hydroxy-Tamoxifen;Binding;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer cell line;Cells;Clinical;Collagen;Data;Disease Progression;Drug Combinations;Endocrine;Endoplasmic Reticulum;Enzymes;Estrogen Receptors;Estrogen Therapy;Estrogen receptor positive;Estrogens;Fulvestrant;Goals;Hydroxylation;Hydroxyproline;Investigation;Malignant Neoplasms;Molecular;Pathway interactions;Patient-derived xenograft models of breast cancer;Peptides;Proline;Proteins;Reactive Oxygen Species;Recurrence;Regimen;Regulation;Relapse;Resistance;Role;Sampling;Selective Estrogen Receptor Modulators;Stress;Tamoxifen;Testing;Therapeutic;Xenograft Model;acquired treatment resistance;cancer cell;clinical practice;combinatorial;endoplasmic reticulum stress;experimental study;hormone therapy;in vivo;inhibitor;knock-down;malignant breast neoplasm;mortality;new therapeutic target;novel;overexpression;patient derived xenograft model;protein expression;therapeutic target;therapy resistant;tumor;tumor growth

public_health_relevance:
Resistance to endocrine therapy and recurrence are the leading causes of mortality in breast cancer patients.Prolyl hydroxylation (P4H) is an enzyme that hydroxylates proline into 4-hydroxyproline of collagens. Thisinvestigation will uncover a novel uncanonical role of P4HA1 in endocrine resistance by regulation ROS-ERstress pathway and explore P4HA1 as a novel therapeutic target for endocrine resistant luminal breast cancer.


application_id: 10571366
project_number: 1R21AI173735-01
project_title: Addressing genetic tractability and species-specific infection biology in Chlamydia pneumoniae
administering_ic: NIAID
award_notice_date: 2022-11-07
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 173735
program_official: UPADHYAY, MEENU MISHRA
project_start_date: 2022-11-07
project_end_date: 2024-10-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Chlamydia species represent a paradigm for understanding successful obligate intracellularparasitism. While C. trachomatis and C. pneumoniae are both prevalent human pathogens C.pneumoniae respiratory infections are likely most common. Acute C. pneumoniae infectionsmanifest as community acquired pneumonia bronchitis and sinusitis while additionalinflammatory sequelae are associated with chronic infection. Advances in genetic tractabilityhave facilitated considerable progress in characterizing C. trachomatis pathogenesis.Unfortunately similar progress has lagged for C. pneumoniae leading to a paucity in detailsregarding molecular mechanisms of infection and precluding informative approaches leveragingcomparative studies. To overcome this barrier we will engineer plasmid systems enabling allelicreplacement and ectopic gene expression for C. pneumoniae. These new technologies will beapplied in proof-of-principle studies to address functional aspects manifested by a pair ofdivergent type III secreted effectors employed by C. pneumoniae to manipulate host cellbiology. At the end of these studies we will have established new approaches that will benefitthe entire Chlamydia research community and advance the understanding of how chlamydialspecies have evolved to accomplish common developmental requirements.

project_terms:
Acceleration;Acute;Address;Alleles;Biology;Bronchitis;Cell Separation;Cells;Cellular biology;Chlamydia;Chlamydia trachomatis;Chlamydophila pneumoniae;Communities;Comparative Study;Complement;Data;Development;Disease;Ectopic Expression;Endocytosis;Engineering;Epithelial Cells;Epitopes;Exhibits;Filopodia;Foundations;Future;Gene Deletion;Gene Duplication;Gene Expression;Genes;Genetic;Genetic Techniques;Genital;Genitalia;High Prevalence;Human;Infection;Inflammatory;Invaded;Light;Maintenance;Mediating;Molecular;Mucous Membrane;Mutagenesis;Pathogenesis;Pathogenicity;Phagocytes;Phenotype;Plasmids;Prevalence;Probability;Process;Proteins;Recruitment Activity;Research;Respiratory Disease;Respiratory Tract Infections;Reverse engineering;Role;Sinusitis;System;Techniques;Technology;Work;cell type;chronic infection;community acquired pneumonia;constitutive expression;design;efficacy testing;expression vector;gene product;genetic manipulation;human pathogen;inducible gene expression;intracellular parasitism;member;mutant;new technology;novel strategies;obligate intracellular parasite;pathogen;protein function;receptor mediated endocytosis;recruit;respiratory pathogen;seropositive;sorting nexins;tissue tropism;trafficking;vector

public_health_relevance:
Chlamydia pneumoniae an agent of human respiratory disease relies on specializedmechanisms that exert anti-host activities essential to pathogenesis. Understanding thosemechanisms requires a tractable means of genetic manipulation. This proposal contains workdesigned to develop mutagenesis and expression techniques for C. pneumoniae that will beimportant for the study of disease.


application_id: 10570927
project_number: 5R42MD015915-03
administering_ic: NIMHD
award_notice_date: 2022-12-01
opportunity_number: PA-20-265
application_type: 5
activity_code: R42
ic: MD
serial_number: 015915
program_official: DAGHER, RADA K
project_start_date: 2020-09-23
project_end_date: 2025-11-30
study_section: Special Emphasis Panel[ZRG1-EMNR-D(11)B]
contact_pi_person_id: 79003066
contact_pi: DRONAWAT, SUNDEEP
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 081302037
primary_uei: D263NL49YK14
duns_number: 081302037
uei: D263NL49YK14
fips: US
organization_id: 10059076
organization_name: FETAL LIFE, LLC
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-12-01
project_title:
Portable Affordable Innovative and Smart Device-Coupled Electronic Fetal Monitoring System to Improve Rural Access to Obstetrics Services and Improve Outcomes in Rural Communities

project_abstract:
PROJECT SUMMARYTo ensure fetal well-being obstetricians monitor fetal heartrate (FHR) and uterine contractions on a weekly tobi-weekly basis towards the end of pregnancy and during labor. Such monitoring is performed with an electronicfetal monitor (EFM) to decrease the development of complications while minimizing the need for unnecessaryobstetric interventions. This is especially important for women with high-risk pregnancies. Inadequate monitoringincreases the risk of morbidity mortality and poor infant outcomes. Unfortunately many women especially inrural and minority communities face many barriers like sufficient time and resources to adequate prenatal carelike EFM. Furthermore EFMs used in hospitals are not portable and can be prohibitively expensive for mid- tolow-resource communities. On the other hand monitors for home use measure only 1 parameter and thereforenot approved for clinical decision making. Fetal Lifes solution is a novel EFM system based on a patent-pendingengineering design. Our innovation enables us to manufacture an EFM system as accurate as a hospital EFMbut at a fraction of the cost while maintaining a portable size with telemonitoring capabilities. Commercializingthis system will increase accessibility to necessary healthcare by reducing the cost and time required for prenatalcare for patients and healthcare providers.In a successful Phase I program Fetal Life met all Phase I milestones resulting in: 1) development of a prototypeof the system (devices plus patient-facing mobile app) and 2) confirmation that the system is usable by pregnantpatients and can detect contraction and FHR signals. Completion of the Phase I program was critical tosupporting the proposed Phase II program that will focus on completing and validating the EFM system withtelemonitoring capabilities for 510(k) clearance. Phase II efforts will include completing the system with theaddition of the healthcare provider-facing app and validating its accuracy with in vitro testing (Aim 1)manufacturing and completing standard safety testing (Aim 2) and validating accuracy and usability of thesystem in a statistically powered study with pregnant subjects (Aim 3). Successful completion of the Phase IIprogram will provide critical performance and safety data necessary for a 510(k) filing and key data supportingits use for telehealth both of which are required for successful market deployment.

project_terms:
3D Print;Appointment;Biological;Caring;Clinic;Clinical;Code;Companions;Computer software;County;Coupled;Data;Data Set;Development;Device Designs;Devices;Diabetes Mellitus;Discipline of obstetrics;Electronics;Engineering;Ensure;Evaluation;Face;Fetal Heart Rate;Fetal Monitoring;Fetal health;Frequencies;Funding;Gel;Gynecology;Health Personnel;Healthcare;High-Risk Pregnancy;Home;Hospitals;Improve Access;In Vitro;Intervention;Legal patent;Life;Low income;Manikins;Marketing;Maternal Health Services;Measurement;Measures;Medical Device;Minority;Monitor;Morbidity - disease rate;Mothers;Outpatients;Participant;Patient Care;Patients;Performance;Personal Satisfaction;Phase;Pregnancy;Pregnant Women;Prenatal care;Procedures;Resource-limited setting;Resources;Risk;Risk Factors;Rural;Rural Community;Safety;Signal Transduction;Small Business Technology Transfer Research;Study Subject;Surveys;System;Technology;Testing;Time;United States National Institutes of Health;Universities;Uterine Contraction;Woman;barrier to care;biomaterial compatibility;clinical decision-making;clinical practice;cohort;commercialization;cost;cytotoxicity;data exchange;data sharing;engineering design;fetal;health care availability;health care quality;heart rate monitor;human subject;improved;improved outcome;in vitro testing;infant outcome;innovation;manufacture;maternal outcome;minority communities;mobile application;monitoring device;mortality;novel;obstetric care;obstetric services;portability;pregnant;programs;prototype;remote health care;remote monitoring;rural underserved;safety testing;skin irritation;telehealth;telemonitoring;underserved community;usability;vibration

public_health_relevance:
PROJECT NARRATIVEMeasuring fetal heartrate and uterine contractions is a common procedure performed by obstetricians to ensuremother and fetal health during pregnancy and labor. However many pregnant mothers especially in rural andminority communities do not have the resources or time to reach an obstetrician and currently available at-homeproducts are not used to make clinical decisions. Fetal Health will lower the barriers to healthcare access forrural mothers by developing a portable and affordable telemonitoring product that can measure fetal heartrateand uterine contractions and simultaneously send both sets of data to a remote doctor to make critical decisionsin real time that will ultimately improve mother and fetal health.


application_id: 10570330
project_number: 7K23DE025313-06
project_title: Study of Pathways in the Link Between Type 2 Diabetes and Periodontitis
administering_ic: NIDCR
award_notice_date: 2022-03-04
opportunity_number: PA-21-268
application_type: 7
activity_code: K23
ic: DE
serial_number: 025313
program_official: FRIEDEN, LESLIE A
project_start_date: 2022-02-11
project_end_date: 2022-04-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9341498
contact_pi: ANDRIANKAJA, OELISOA M
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT:Lipid lowering agents (LLA) such as statins are known to have pleiotropic anti-inflammatory effects and haverecently been seen to reduce the occurrence of periodontal tissue destruction. However no study hasthoroughly assessed the potential role of LLA use in reducing inflammatory responses in periodontal disease(PD) development especially among type 2 diabetic (T2D) individuals in whom hyperinflammatory condition ispresent. We propose to assess the anti-inflammatory effects of LLA through activation or up-regulation ofperoxisome proliferator-activated receptors- alpha (PPAR-) and/or PPAR- on the occurrence of PD amongoverweight or obese T2D individuals. We hypothesize that diabetic individuals taking LLA such as statins willhave high systemic levels of PPAR- which in turn may lower local and systemic inflammatory responses toPD pathogens thereby reducing the occurrence of PD compared with adult diabetic individuals who do not takestatins. More specifically we will assess whether LLA use especially statins reduces periodontalmeasurements determined by probing pocket depth (PPD) clinical attachment loss (CAL) and bleeding onprobing (BOP) among diabetic adults. We will also evaluate whether the trends in the effects of statins onthese periodontal destructions are mediated by the reduction of both gingival crevicular fluid (GCF) and serumlevels of IL-1 IL-17 and TNF- and GCF levels of bone related factors such as OPG and RANKL.Furthermore we will explore in our secondary aim whether the anti-inflammatory effects of statins areassociated with up-regulation of PPAR- expression. We expect that the mRNA expression levels of PPAR-among diabetic individuals who take statins would be higher than those in controls without the medications. The proposed study will retrospectively recruit a total of 260 diabetic adults aged 40 to 65 yearsdivided into two groups: 130 adults taking statins and 130 adults not taking the medications. Detailedinformation of statin use type frequency dosage and duration use will be collected to assess statin exposure.Periodontal status of each participant will be assessed as a main outcome and the GCF and serum levels ofIL-1 IL-17 and TNF- as well as GCF levels of OPG and RANKL as secondary outcomes. For the secondaryaim a total of 40 participants (20 diabetic individuals with statins and 20 diabetic individuals without statins)matched by age gender BMI and smoking status will be drawn from the total population (N=260) to assessthe potential effect of statins on the up-regulation of PPAR- expression to investigate its influence on PDoccurrence among T2D individuals. Findings from this retrospective study will be highly relevant for publichealth given the high prevalence of PD among T2D patients and could be used for developing prevention orsupport possible local statins delivery for PD therapeutic strategies in the future.

public_health_relevance:
NARRATIVE:The proposed study will assess mechanisms which may explain the link between type 2 diabetes (T2D) andperiodontal disease (PD) by evaluating the relationship between regular statin use and change in local andsystemic markers of inflammation. Findings from this study will be highly relevant for public health given thehigh prevalence of PD among T2D patients and would be informative for developing strategies for preventionof PD as well as to help develop local statins for PD therapeutic strategies in the future.


application_id: 10570191
project_number: 5R21AR078447-02
project_title: Magnetic nanocomplexes-induced immunomodulation for fracture healing
administering_ic: NIAMS
award_notice_date: 2023-01-25
opportunity_number: PAR-19-173
application_type: 5
activity_code: R21
ic: AR
serial_number: 078447
program_official: MARQUITZ, ARON
project_start_date: 2022-02-10
project_end_date: 2024-12-31
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
contact_pi_person_id: 14341515
contact_pi: TONG, SHENG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Non-healing fractures are a cause of severe disability and have devastating effects on the quality of life.Currently there are no reliable first-line therapies that stimulate healthy bone formation and prevent nonunion.There is a growing body of evidence supporting the indispensable role of macrophages in fracture healing.Also macrophage dysfunction is a critical component in the pathogenesis of non-healing or poorly healingfractures. Immunomodulatory strategies that apply biochemical factors are gaining traction to regulatemacrophage phenotypes. However they have limited success due to complications with specificity efficacyand systemic toxicity. Here we propose to develop a magnetic iron-oxide nanocomplexes (MNC)-based therapy for promotingfracture healing. The cytoskeletal dynamics of macrophages are intricately linked to their inflammatoryresponse. Our studies confirmed that the cytoskeletal dynamics of macrophages are determined by theirphenotype. Studies also show that mere manipulation of cytoskeletal dynamics using physical cues withoutany exogenous factors is shown to transform macrophage phenotype. This phenotype modulation is due tothe nuclear translocation of the transcription factor MRTF-A and changes in chromatin compaction caused bycytoplasmic-to-nuclear redistribution of histone deacetylase-3 (HDAC3). We hypothesize that intracellularmagnetic force can elicit transcriptional control of macrophage phenotype and promote fracture healing viaMRTF-A release and HDAC3 redistribution. In SA1 we will engineer magnetic nanocomplexes for targeted internalization and mechanisticallyelucidate intracellular force-induced modulation of the cytoskeleton and corresponding change in macrophagephenotype. In SA2 we will validate macrophage targeting of MNC and elucidate their therapeutic potential in amurine critical-sized femoral defect. The proposed research will be a paradigm shift in wound healing and willalso provide crucial insights into the mechanobiology of macrophages that are valuable for diagnostic andtherapeutic interventions.

project_terms:
Actins;Acute;Adopted;Area;Binding;Biochemical;Biocompatible Materials;Biomechanics;Bone Regeneration;Bone Resorption;Cells;Chromatin;Chronic;Cues;Cytoplasm;Cytoskeleton;Defect;Diagnostic;Drug Delivery Systems;Endothelium;Engineering;Exhibits;Exogenous Factors;Exposure to;F-Actin;Femur;Fostering;Fracture;Functional disorder;G Actin;Gene Expression;Genes;HDAC3 gene;Immune response;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Kinetics;Link;Macrophage;Macrophage Activation;Magnetism;Metabolic;Methodology;Methods;Modeling;Morphology;Multipotent Stem Cells;Mus;Natural regeneration;Nuclear;Nuclear Translocation;Organ failure;Osteogenesis;Pathogenesis;Pathology;Patients;Peptides;Phenotype;Physiology;Polymers;Process;Quality of life;Regenerative Medicine;Research;Role;Signal Transduction;Site;Specificity;Surface;TLR4 gene;TNF gene;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;Traction;Transcriptional Regulation;Trauma;Traumatic injury;Up-Regulation;Work;age related;bone;bone fracture repair;bone healing;cancer imaging;clinical translation;cyclooxygenase 2;density;design;disability;healing;immunomodulatory therapies;immunoregulation;inflammatory modulation;insight;iron oxide;magnetic field;monomer;nanocomplexes;nanomaterials;polymerization;prevent;programs;regenerative therapy;success;systemic toxicity;tissue regeneration;transcription factor;uptake;wound healing

public_health_relevance:
Regenerative medicine holds much promise for treating various ailments including organ failures age-related pathologies and trauma-related injuries. While most of the current research focus is on developingbiomaterials and methods for controlling the fate of multipotent stem cells little is known about the hostresponse primarily due to macrophages and the interconnectivity between inflammation and functionalintegration. This proposed research will investigate the mechanobiology of macrophages and developmethodologies that harness the bodys natural processes for augmenting bone regenerative therapies.


application_id: 10569675
project_number: 5P20GM130456-04
project_title: Developing immunotherapeutic nanoparticles for spinal cord injury
administering_ic: NIGMS
award_notice_date: 2023-03-07
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 7564
contact_pi_person_id: 14321924
contact_pi: PARK, JONGHYUCK
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:
Traumatic spinal cord injury (SCI) leads to primary injury followed by secondary injuries including inflammation which create an inhibitory environment. Regeneration is limited due to additional tissue damages and an inhibitory environment leading to various neurological deficits. The goal of this proposal is to develop a non-invasive acute intervention with the goal of modulating inflammatory responses to reprogram an inhibitory environment after SCI. Particularly the SCI demographic shifts toward a more equal balance among males and females indicating that improved therapeutics are needed since the difference in physiological factors between sexes play important roles in pharmacological treatments and functional recovery after SCI. In this study Poly(lactide-co-glycolide) (PLG)-based multiple nanoparticle (NP) formulations will be designed with various physicochemical factors to identity sex-specific key functionality of NPs to reprogram inflammation thereby facilitating functional recovery in females and males respectively after SCI. Specific aim 1 will investigate NP-induced innate cells modulation following SCI to identify sex-specific key properties of NPs. The distinct physicochemical properties of NPs will differently limit inflammation after SCI. Specific aim 2 will assess NPs-mediated long-term dynamic responses in the spinal cord and their effects on anatomical and functional recovery in both sexes after SCI. Intravenously (IV) administered NPs will bind to pro-inflammatory subsets of immune populations and direct their trafficking to the spleen. NP-positive innate cells within the injured tissues will lead to a sustained response facilitating an environment that improves recovery after SCI. Successful completion of proposed aims will provide efficient sex-specific NP designs to maximize functional recovery after SCI. In addition NPs are made of FDA-approved material that enables NPs to be administered in triage or on site to patients diagnosed with SCI without direct intervention into the spinal cord. This study will provide a potentially practical therapy for the entire SCI population.

project_terms:
Acute;Anatomy;Binding;Cells;Centers of Research Excellence;Clinical Trials;Diagnosis;Environment;Equilibrium;FDA approved;Female;Formulation;Glycolic-Lactic Acid Polyester;Goals;Hospitals;Immune;Immunotherapeutic agent;Impairment;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Intravenous;Mediating;Natural regeneration;Neurologic Deficit;Patients;Pharmacologic Substance;Pharmacological Treatment;Physiological;Play;Population;Property;Quality of life;Recovery;Recovery of Function;Research;Role;Site;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Spleen;Staging;Therapeutic;Tissues;Triage;acute care;design;improved;inflammatory modulation;injured;innovation;intravenous administration;loss of function;male;nanoparticle;programs;response;severe injury;sex;trafficking

public_health_relevance:
Spinal cord injury (SCI) severely impairs the quality of life for patients causing permanent loss of function below the injury. The proposed nanoparticle-mediated strategy will provide a non-invasive acute care platform that can be given immediately intravenously in the pre-hospital environment. Successful completion of the proposed studies will have the potential to develop an over-the-counter transformational platform that can lead to fast-track staging of clinical trials for SCI patients.


application_id: 10569674
project_number: 5P20GM130456-04
project_title: Immunomodulatory Therapy for Bone Regeneration
administering_ic: NIGMS
award_notice_date: 2023-03-07
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 6618
contact_pi_person_id: 14078198
contact_pi: TIRUVANNAMALAI ANNAMALAI, RAMKUMAR
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:
Inflammation plays a vital role during bone formation resorption and fracture healing. The process of fracture healing is biologically entangled with that of acute inflammation and innate immunity. A proper sequence and dose of inflammatory signals are critical for proper bone healing. Macrophages one of the first cells that infiltrate the fracture site are indispensable for fracture healing as they promote osteoblastic differentiation and vascularization. Also it is well recognized that mechanical conditions influence callus development and the type and extent of osteogenesis during fracture. But most work on the macrophage response in the context of fracture healing has focused on activation mediated by biochemical signals. The biophysical parameters of the fracture microenvironment especially matrix mechanics and their influence on macrophage immunophenotypes are largely overlooked. Our overall goal is to elucidate the influence of biophysical cues on macrophage function to develop an immunomodulatory platform reducing the burden of bone diseases in patients.  Macrophages respond to changes in extracellular matrix mechanics through actin-cytoskeletal reorganization nuclear deformation and gene expression. We hypothesize that biophysical forces in the form of substrate mechanics elicit transcriptional control of macrophages via a transcriptional activator MRTF-A release (during actin polymerization) and redistribution of a cell signaling mediator HDAC3 (chromatin compaction). The two independent aims for this project are: 1) Elucidate the actin cytoskeleton-mediated transcriptional control in macrophages in a murine fracture model 2) Engineer immunomodulatory materials with suitable viscoelastic mechanics to guide the transcriptional machinery of macrophages to promote bone regeneration.  Overall our proposed research provides insights into the role of the innate immune response in fracture healing and develops next-generation immunomodulatory materials for therapeutic bone regeneration. Hence our research aligns well with the CPRI COBRE mission to facilitate translational chemical biology research to advance treatments and strategies to address significant health challenges.

project_terms:
Actins;Acute;Address;Biochemical;Biology;Biophysics;Bone Diseases;Bone Regeneration;Bone callus;Cells;Centers of Research Excellence;Chemicals;Chromatin;Cues;Cytoskeletal Modeling;Cytoskeleton;Development;Dose;Engineering;Extracellular Matrix;Fracture;Gene Expression;Genetic Transcription;Goals;HDAC3 gene;Health;Immunophenotyping;Infiltration;Inflammation;Inflammatory;Innate Immune Response;Macrophage;Mechanics;Mediating;Mediator;Mission;Modeling;Mus;Natural Immunity;Nuclear;Osteogenesis;Patients;Pharmacologic Substance;Play;Polymers;Process;Research;Role;Signal Transduction;Site;Therapeutic;Transcription Coactivator;Transcriptional Regulation;Vascularization;Work;biophysical properties;bone fracture repair;bone healing;immunomodulatory therapies;immunoregulation;innovation;insight;next generation;osteoblast differentiation;polymerization;response;viscoelasticity


application_id: 10569670
project_number: 5P20GM130456-04
project_title: Chemical biology of type IV secretion systems
administering_ic: NIGMS
award_notice_date: 2023-03-07
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8071
contact_pi_person_id: 11309989
contact_pi: SHAFFER, CARRIE
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 SUMMARYBacteria have evolved specialized nanomachines to deliver microbial cargo across the cell envelope. Oneversatile translocation apparatus the type IV secretion system (T4SS) can be strategically deployed to injectmacromolecular substrates into target bacterial or eukaryotic recipient cells. Despite their importance in bacterialpathogenesis and dissemination of antibiotic resistance determinants the mechanisms by which the T4SSassembles and transports payload remain largely undefined. To address this knowledge gap the long-term goalof this proposal is to develop and apply robust molecular tools to accelerate fundamental studies of T4SSnanomachines. The cag T4SS of the gastric bacterium Helicobacter pylori has emerged as an important systemfor understanding how a single molecular machine can transport diverse cargo into target cells. Whereas someT4SS have the capacity to secrete hundreds of proteins or DNA-protein complexes into the host cell the abilityto translocate a diverse repertoire of lipid nucleic acid protein and polysaccharide substrates distinguishes thecag T4SS from other systems. Notably the bacterial oncoprotein CagA is rapidly delivered to host gastric cellsvia cag T4SS mechanisms. Translocated H. pylori effector molecules activate innate defenses and dysregulatesignaling pathways that influence progression of gastric disease; consequently colonization by cag T4SS-positive H. pylori significantly augments the risk for gastric cancer. As a result of its central role in bacterialpathogenesis the T4SS represents an ideal target for antimicrobials. In this application we propose to identifyand mechanistically characterize novel small molecule-based T4SS modulators. Iterative structure-activityrelationship studies will be used to develop chemical scaffolds and pharmacophores with optimized anti-virulencepotential. Probe development will take advantage of expertise and assay platforms in the Shaffer lab and willleverage synergistic resources in the proposed CPRI Computational Core (ligand-binding model developmentrational design virtual screening) CPRI Translational Core (high throughput assay support novel compoundrepositories and ADMET profiling) and the Organic Synthesis Core (medicinal chemistry and scale-up).Prioritized and validated chemical probes will be used in conjunction with biochemical and genetic approachesto interrogate cag T4SS regulation and dynamic steps in substrate translocation. Using a similar multidisciplinaryapproach we will determine how the H. pylori cag T4SS apparatus assembles at the bacteria-host cell interface.Collectively these studies will stimulate new basic research directions and will provide important insight into howthe T4SS nanomachine orchestrates the delivery of specific molecular cargo to target cells to drive microbialpathogenesis. Furthermore this work will generate powerful chemical tools that are broadly applicable toinfectious disease research and will identify potent lead compounds with the potential to disarm T4SS functionin a variety of medically-relevant pathogens.

project_terms:
2-hydroxypyridine;Acceleration;Address;Antibiotic Resistance;Bacteria;Bacterial Genome;Basic Science;Biochemical;Biogenesis;Biological;Biological Assay;Biology;C10;Cells;Cellular biology;Centers of Research Excellence;Chemicals;Clinical;Collaborations;Complement;Complex;DNA;Destinations;Development;Discipline;Engineering;Epithelial Cells;Escherichia coli;Eukaryotic Cell;Exhibits;Faculty;Fostering;Foundations;Genetic;Goals;Helicobacter pylori;Impairment;Infection;Infectious Diseases Research;Knowledge;Lead;Libraries;Ligand Binding;Lipids;Lipopolysaccharide Biosynthesis Pathway;Mechanics;Mediating;Medical;Microscopy;Molecular;Molecular Machines;Molecular Probes;Nucleic Acids;Nucleoproteins;Oncoproteins;Organic Synthesis;Outcome;Pathogenesis;Pathogenicity Island;Peptidoglycan;Pharmaceutical Chemistry;Pharmacologic Substance;Phenotype;Pilum;Plant Model;Play;Polysaccharides;Prokaryotic Cells;Proteins;Regulation;Research;Research Design;Resolution;Resources;Rhizobium radiobacter;Risk;Role;Series;Signal Pathway;Stomach;Stomach Diseases;Structure-Activity Relationship;System;Systems Biology;Therapeutic;Toxin;Type IV Secretion System Pathway;Validation;Virulence;Work;antimicrobial;appendage;carcinogenicity;cell envelope;design;extracellular;genetic approach;high throughput screening;inhibitor;innovation;insight;interdisciplinary approach;malignant stomach neoplasm;microbial;microbiome;model development;mutant;nanomachine;novel;pathogen;pathogenic bacteria;pharmacophore;protein complex;rational design;repository;response;scaffold;scale up;screening;small molecule;system architecture;tool;tumorigenic;virtual screening


application_id: 10569468
project_number: 3P40OD019794-08S1
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2022-02-25
opportunity_number: PAR-17-006
application_type: 3
activity_code: P40
ic: OD
serial_number: 019794
suffix: S1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-D(50)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
OVERALL COMPONENT - PROJECT SUMMARYThis application seeks support to continue operations of the Ambystoma Genetic Stock Center (AGSC) at theUniversity of Kentucky (UK). The AGSC is the only federally funded resource center that distributes Mexicanaxolotls (Ambystoma mexicanum) a salamander that provides living materials in support of biomedicalresearch nationally and internationally. Most notably axolotls are unique among vertebrates in being able toregenerate numerous tissues and body parts. These include the spinal cord limbs jaw retina brain heartand tail all of which can be regenerated at any point during embryonic larval and adult life. Also axolotls areused by researchers that work in additional areas including neurobiology ecotoxicology developmentphysiology cell biology genetics genomics and evolution. This is an exciting time for the axolotl as itsincredibly large genome (32 Gb) was recently sequenced and assembled. New and assessable resources areallowing cutting edge technologies like gene-editing and single cell RNA sequencing to be performed for thefirst time approaches that are rapidly accelerating discoveries using axolotl models. In just the past 4 yearsNIH support for axolotl research has tripled and there has been a significant increase in transgenic and knock-out lines in the community. PIs in the salamander community recently came together to discuss futureopportunities and challenges and the enabling role the AGSC will play in moving community efforts forward.During the previous funding period the AGSC moved internally from the College of Arts and Sciences to theCollege of Medicine (COM) at UK. This move has strengthened the AGSC in several significant ways thatclearly demonstrate long term commitment by the host institution for this irreplaceable resource. Specificallyfunding was made available to replace re-circulating systems and create a more user friendly website tofacilitate axolotl stock purchasing and more efficiently disseminate information that is useful for working withaxolotls. Additionally COM-UK has extensive experience working with university core research centers andthus provides a more stable administrative environment to support AGSC business activities and to betterensure regulatory compliance and animal health and welfare. Over the next 5 years the AGSC will build uponcurrent momentum by maintaining and generating high quality axolotl stocks that are needed by a growingnumber of NIH-funded investigators. Husbandry and management practices will be modified to increaseavailability of post-embryonic stocks that are seeing increasing demand by researchers. Also transgenic andknock-out stocks will be prioritized for import into the AGSC and cryopreservation methods will be developed topreserve and more efficiently manage stocks. The AGSC will continue to serve as an informatics hub whereinvestigators obtain information about the collection technical procedures potential collaborators andresearch findings. Overall the project will ensure distribution and long-term sustainability of axolotl resourcesto NIH-funded investigators.!

project_terms:
Adolescent;Adult;Ambystoma;Ambystoma mexicanum;Animals;Area;Arts;Awareness;Biological;Biomedical Research;Body part;Brain;Breeding;Businesses;Cellular biology;Collaborations;Collection;Communities;Computers;Cryopreservation;Custom;Development;Disease;Embryo;Embryonic Development;Ensure;Environment;Evolution;Funding;Future;Genes;Genetic;Genome;Genomics;Health;Heart;Hour;Human;IACUC;Informatics;Infrastructure;Institution;International;Jaw;Kentucky;Knock-out;Life;Limb structure;Louisiana;Medicine;Methods;Modeling;Natural regeneration;Neurobiology;Newsletter;Online Systems;Organ Model;Physiology;Play;Population;Practice Management;Procedures;Protocols documentation;Reproducibility;Research;Research Personnel;Research Support;Resources;Retina;Role;Salamander;Science;Shipping;Site;Spinal Cord;System;Tail;Technology;Time;TimeLine;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Work;animal resource;college;cost;experience;genetic resource;knowledge base;learning strategy;meetings;operation;organ regeneration;preservation;single-cell RNA sequencing;sperm cell;sperm cryopreservation;tissue repair;user-friendly;web site;welfare


application_id: 10569026
project_number: 5R01DK124774-03
administering_ic: NIDDK
award_notice_date: 2023-01-28
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 124774
program_official: SILVA, CORINNE M
project_start_date: 2021-04-01
project_end_date: 2026-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-02-01
project_title:
Circadian Regulation of Metabolic Risk in Mice and Women: Role of Estrogen and Time-Restricted Feeding

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

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

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


application_id: 10567211
project_number: 1R01NS129987-01
project_title: The role of SOCE in microglia and secondary degeneration after SCI
administering_ic: NINDS
award_notice_date: 2023-01-31
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 129987
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2023-02-01
project_end_date: 2027-12-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11601659
contact_pi: STIRLING, DAVID PAUL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Neurological outcome after spinal cord injury (SCI) is dependent on the extent of primary injury andthe delayed secondary degeneration of spared white matter (WM) and grey matter. Although Ca2+ overload isestablished as a key mediator of secondary injury therapeutically targeting external sources of Ca2+ to datehave failed to improve neurological recovery in pre-clinical studies and following human SCI. This proposal willassess the role of store-operated Ca2+ entry (SOCE) directly in spinal cord neurons and microglia after SCIusing cell type specific knockout of key SOCE mediators. Although SOCE plays a vital role in maintaining Ca2+homeostasis and is necessary to sustain intracellular Ca2+ at critical levels for immune cell function wepropose that aberrant and excessive SOCE causes secondary degeneration of WM. The role of SOCE in WMinjury microglial activation and function remains poorly understood. Furthermore the precise role of theessential SOCE components including stromal interaction molecule (stim 1 and -2) and Orai 1-3 (form theCa2+ channel pore) in microglial function and neuronal injury remains unclear. Our preliminary data support animportant role for SOCE in mediating secondary degeneration microglial activation and proinflammatorycytokine release and worsening neurological recovery. We hypothesize that dysregulation of SOCE mediatesbystander secondary axonal degeneration following SCI by increasing Ca2+ permeability through Stim and/orOrai channels causing Ca2+ overload in axons. In addition we hypothesize that SOCE regulates microglialactivation and release of proinflammatory factors that negatively impacts neurological recovery after SCI. Ourspecific Aims are to 1. Determine the role of SOCE in secondary degeneration and neurological recoveryfollowing SCI. 2. Determine the role of microglial SOCE in secondary degeneration wound healing andneurological recovery after SCI. To accomplish these aims we will use two photon excitation intravital imagingto visualize the dynamic response of spinal cord axons and microglia after SCI in real time. We will use bothpharmacological SOCE inhibitors and cell type specific knockout of key SOCE mediators directly in spinalneurons and microglia. The most efficacious approach will then be assessed using behavioral testing amountof spared WM and grey matter and wound healing. The technology and approach may help advance the fieldas live imaging of axons over time allows unequivocal determination of the fate of injured axons and whetherthey can be rescued in real-time with treatment. Furthermore it allows direct visualization of microgliasimultaneously with axons and their interactions as these events are unfolding in the injured spinal cord. Thisproposal is innovative and uses advanced imaging techniques to explore overlooked areas of SCI research.The approach taken may also unveil novel drug targets and repurpose FDA approved drugs found to inhibitSOCE (e.g. teriflunomide). The underlying mechanisms of WM injury may also be relevant to otherneurological diseases of the nervous system such as multiple sclerosis stroke and TBI.

project_terms:
Acute;Afferent Neurons;Anti-Inflammatory Agents;Area;Axon;Biological Process;Blood;Breeding;Calcium;Cell physiology;Chronic;Cicatrix;Data;Drug Targeting;Environment;Event;FDA approved;Growth;Growth Factor;Histology;Homeostasis;Human;Image;Imaging Techniques;Immune;Inflammation Mediators;Inflammatory;Injury;Knock-out;Knockout Mice;LoxP-flanked allele;Mediating;Mediator;Microglia;Molecular;Mouse Strains;Multiple Sclerosis;Mus;Myelogenous;Myeloid Cells;Nerve Degeneration;Nervous System;Neurodegenerative Disorders;Neurologic Deficit;Neurological outcome;Neuronal Injury;Neurons;Nitrogen;Outcome;Oxygen;Pain;Pathologic;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Phenotype;Physiological;Play;Process;Production;Recovery;Recovery of Function;Reporter;Reporting;Research;Role;STIM1 gene;Secondary to;Signal Transduction;Site;Source;Spinal;Spinal Cord;Spinal cord injury;Stroke;Technology;Time;Tissue Preservation;Tissues;Vertebral column;Visualization;Wallerian Degeneration;axon injury;axonal degeneration;behavior test;cell type;cytokine;cytotoxic;drug repurposing;effective therapy;experimental study;functional improvement;functional outcomes;glial activation;gray matter;improved;in vivo;inhibitor;innovation;intravital imaging;intravital microscopy;nervous system disorder;neuroinflammation;neurological recovery;neuroprotection;new therapeutic target;novel;pharmacologic;preclinical study;prevent;recruit;response;therapeutic target;two-photon;white matter;white matter injury;wound healing

public_health_relevance:
Project NarrativePatients often suffer from permanent neurological deficits due to secondary degeneration of axons after spinalcord injury and there are no effective therapies to treat these problems. The molecular mechanisms that causesecondary bystander axonal loss following spinal cord injury remain poorly understood; however growingscientific evidence suggests a key role of calcium overload and neuroinflammation in this process. We willexplore the role of aberrant store-operated calcium entry (SOCE) as mediating direct secondary bystanderdegeneration and indirectly by targeting SOCE in microglia.


application_id: 10565857
project_number: 5R01DA047368-05
project_title: A Translational Determination of the Mechanisms of Maladaptive Choice in Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2023-03-03
opportunity_number: PA-18-060
application_type: 5
activity_code: R01
ic: DA
serial_number: 047368
program_official: FEDOTA, JOHN RAPHAEL
project_start_date: 2019-04-15
project_end_date: 2025-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: BECKMANN, JOSHUA ;WESLEY, MICHAEL J
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:
ABSTRACT Opioid use disorder (OUD) is characterized by the decision to use opioids at the expense of other activities.Lab-based efforts to address this problem have therefore included opioid choice self-administration proceduresthat incorporate a non-drug alternative to model this defining feature. Studies using these procedures havetypically scheduled competing reinforcers so that the probabilities are certain. However such deterministicoutcomes are not representative of real-world experiences in which the consequences from drug-related choicesare often unpredictable. Importantly decision-making in a dynamic uncertain context significantly alters thevalue of choice options and requires continuous updating of option values which engages learning processesand related corticostriatal networks that function abnormally in OUD. Decision-making in dynamic environmentshas been successfully modeled using probabilistic reinforcement-learning choice (PRLC) tasks. The integrationof these tasks with reinforcement-learning (RL) computational modeling has been used to capture moment-to-moment changes in the mechanisms of dynamic choice and the application of neuroscience techniques hasbegun to identify the underlying neurobiology. This approach has uncovered biologically-based decision-makingabnormalities in multiple brain disorders but has yet to be systematically applied to the experimental study ofOUD The translation of combined RL and neuroscience approaches to OUD is logical considering themaladaptive choice behavior that typifies the disorder the varying reinforcement probabilities in opioid usersnatural environments and the learning impairments that have been documented in individuals with OUD. Thusthere are critical gaps in our understanding of the mechanisms underlying dynamic opioid use decisions and astrong scientific premise for applying an RL framework to fill these gaps. This project proposes rigorous PRLCtasks RL modeling neurorecording/fMRI neuroimaging techniques and complementary translational studydesigns in rats and humans. The first set of cross-species experiments will demonstrate the impact of opioidexposure and withdrawal on dynamic decision-making and reveal the neurobehavioral and neurobiologicalprocesses underlying abnormal task performance. The second set of experiments will use a PRLC task in whichintravenous remifentanil a prototypical opioid agonist with a favorable safety profile is available as an alternativeto a non-drug reinforcer to determine the behavioral and neural profiles associated with drug choice as well asthe increases and decreases in drug choice that occur during withdrawal and in the presence of a largemagnitude alternative reinforcer respectively. This project will have a significant impact on the field byestablishing the experimental application of reinforcement-learning theory to the study of maladaptive dynamicdrug-use decision-making in OUD to reveal behavioral and neural mechanisms that can be targeted for futureprevention and treatment development.

project_terms:
Abate;Abstinence;Address;Animals;Area;Back;Behavioral;Behavioral Mechanisms;Brain Diseases;Brain region;Choice Behavior;Chronic;Clinical;Cognition;Computer Models;Corpus striatum structure;Cues;Decision Making;Disease;Drug usage;Environment;FDA approved;Food;Foundations;Functional Magnetic Resonance Imaging;Future;Half-Life;Human;Impairment;Individual;Intravenous;Knowledge;Learning;Mental disorders;Methods;Modeling;Neurobiology;Neurologic;Neurosciences;Opioid;Opioid agonist;Outcome;Oxycodone;Performance;Pharmaceutical Preparations;Prevention;Prevention strategy;Probability;Probability Learning;Procedures;Process;Psychological reinforcement;Rattus;Research;Research Design;Safety;Schedule;Self Administration;Signal Transduction;Task Performances;Techniques;Time;Translating;Translations;Update;Withdrawal;experience;experimental study;human subject;innovation;learning engagement;neural;neuroadaptation;neurobehavioral;neuroimaging;neuromechanism;non-drug;novel;opioid exposure;opioid use;opioid use disorder;opioid user;opioid withdrawal;participant safety;reinforcer;remifentanil;theories;therapy development;translational study;treatment strategy

public_health_relevance:
PROJECT NARRATIVE Opioid use disorder (OUD) is characterized by the decision to use opioids at the expense of other activitiesbut lab-based studies have not modeled naturalistic dynamic decision-making. This translational rat and humanproject will use an innovative reinforcement-learning approach and neuroscience methods to uncover themechanisms of maladaptive dynamic choice in OUD in order to reveal novel prevention and treatment targets.


application_id: 10563194
project_number: 5R01NS112693-04
project_title: Mitochondrial Uncoupling Prodrug as a Translational Therapy for TBI
administering_ic: NINDS
award_notice_date: 2024-02-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 112693
program_official: AWWAD, HIBAH OMAR
project_start_date: 2020-03-15
project_end_date: 2026-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: KILBAUGH, TODD JUSTEN
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Traumatic brain injury (TBI) results in cognitive impairment which can be long-lasting after moderate to severeTBI. Currently there are no FDA-approved therapeutics to treat the devastating consequences of TBI andimprove recovery. A wealth of experimental evidence shows that mitochondrial dysfunction is poised to be apivotal link in the neuropathology of brain injury. We previously have targeted bioenergetic impairment withmitochondria-directed therapeutics including mild mitochondrial uncouplers which have shown to beneuroprotective. These uncouplers facilitate the movement of protons from the mitochondrial inner-membranespace into the mitochondrial matrix thereby reducing the mitochondrial membrane potential (). Whilecomplete uncoupling of mitochondria would be detrimental we have published data showing that transient ormild uncoupling confers neuroprotection in preclinical models of TBI. Recently we demonstrated that a prodrugof 24-dinitrophenol (DNP) MP201 a mitochondrial uncoupler with better pharmacodynamic properties includinghigher tolerability and extended elimination time rescues acute mitochondrial bioenergetics reduces oxidativedamage increases brain-derived neurotropic factor (BDNF) and is neuroprotective. We hypothesize that theoptimal dosage and timing of therapeutic intervention of MP201 is neuroprotective across species following focalcontusion brain injury. Our proposed studies will explore how MP201 administration can improve acutelongitudinal and chronic outcomes paired with critical biomarkers including platelet physiology andneurochemical profiles. To achieve this we will use innovative techniques across multiple institutions to assesssynaptic and non-synaptic mitochondria in both porcine and murine models of TBI. Additionally we will extendour findings to examine therapeutic efficacy measuring longitudinal cortical morphology (T2/DTI scanning)neurometabolite profiles (MRS scanning) platelet signature (as a novel biomarker and biosensor) and cognitivebehavior. Finally we will explore the underlying mechanism behind the long-term neuroprotection imparted byMP201 after TBI examining BDNF levels and mitochondrial restoration. With strong preliminary data and utilizingmany innovative and clinically-relevant techniques we anticipate this proposal will generate ground-breakingdata. Overall this proposal will highlight highly translatable therapy by MP201 to alleviate negative outcomes ofTBI.

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

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


application_id: 10563171
project_number: 5R01NS112304-03
project_title: Propriopsinal neuron function in normal and post-SCI locomotion
administering_ic: NINDS
award_notice_date: 2023-03-28
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 112304
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2026-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: DANNER, SIMON MICHAEL
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits many ofthe functional details of those circuits and their contributions to recovery following spinal cord injury (SCI)remain to be determined. Recent development of powerful molecular tools enables functional dissection ofneural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling. We will combine thesetools with sophisticated gait and kinematic analyses that includes the full repertoire of speed dependent gaitsto provide the functional and anatomical information necessary for building and refining an advanced neuro-biomechanical computer model of the rat spinal cord body and limbs. We will focus on two classes of spinalcord interneurons the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons thatinterconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements andinvestigate their role in the intact spinal cord and after SCI using both hemisection and contusion models. Ourpreliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gaitexpression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisinglysilencing these neurons after an incomplete contusion injury results in better overground locomotion a resultthat is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-basedtrans-synaptic labeling we will determine the sensory descending and propriospinal inputs onto both LAPNsand LDPNs. We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as newanatomical data (Aim 2) to build and refine our computational model (Aim 3). Then in vivo experiments andcomputer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissuralLAPNs and LDPNs play in locomotor behavior including the full range of locomotor gaits and in recoveredfunction after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of longpropriospinal neurons represents an important step towards the development of new therapeutic tools forrecovery after SCI.

project_terms:
Adult;Anatomy;Animals;Axon;Behavior;Binding;Biomechanics;Cervical;Characteristics;Computer Models;Computer Simulation;Contusions;Data;Data Set;Development;Dissection;Experimental Models;Forelimb;Gait;Goals;Hindlimb;Injury;Interneurons;Ipsilateral;Knowledge;Label;Lateral;Left;Limb structure;Locomotion;Mediating;Modeling;Molecular;Movement;Musculoskeletal System;Neurons;Physiological;Play;Population;Publishing;Rattus;Recovery;Reverse engineering;Role;Running;Sensory;Source;Speed;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Structure;Structure-Activity Relationship;Synapses;Techniques;Testing;Thoracic spinal cord structure;Validation;Vertebral column;Viral;Virus;Walking;animal data;biomechanical model;central pattern generator;design;experimental study;in silico;in vivo;kinematics;model development;neural circuit;neurotransmission;novel;novel therapeutics;predictive modeling;sensory input;tool

public_health_relevance:
Project Narrative This multi-PI project focuses on the role of the long ascending and descending propriospinalneurons (LAPNs LDPNs) in the control of locomotion and recovery after a spinal cord injury. We will use acombination of viral based synaptic silencing retrograde and trans-synaptic tracing and comprehensive gaitand kinematic analysis to aid the development of a neuro-biomechanical computer model and to generateimportant new knowledge of spinal locomotor circuitry.


application_id: 10561694
project_number: 5R01EY030933-04
project_title: Blood outer retina barrier regulation
administering_ic: NEI
award_notice_date: 2023-01-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EY
serial_number: 030933
program_official: SHEN, GRACE L
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractMutations in rod photoreceptor-specific genes in retinitis pigmentosa (RP) cause diminishedperipherial and night-time vision. But it is secondary loss of cone function leading todiminished high-resolution daylight vision utilized for reading facial recognition and other dailytasks that is most debilitating. Events leading to loss of cone function in RP are still beingunraveled. Like other neurons photoreceptors depend upon glucose which they use forenergy as well as ongoing synthesis to replace visual pigment-rich membraneous outersegments (OS) as they undergo daily light-induced phagocytosis. The RPE serves as ablood-outer retinal barrier transporting glucose and nutrients from the choroid circulationto adjacent photoreceptors. We provide evidence that glucose transport from the RPE tophotoreceptors for new OS synthesis is linked to OS phagocytosis. As abundant mutantrod OS are lost and phagocytosis diminishes in RP glucose transport becomes short-circuited leading to cone starvation. We will examine the signaling pathway regulatingglucose transport from the RPE and linked metabolome/epigenome changes in thesecells during RP progression in both mice and pigs a large animal model of RP wherecones are concentrated into a visual streak.

project_terms:
AKT inhibition;Adaptor Signaling Protein;Age;Animal Model;Apical;Arrestins;Automobile Driving;Back;Binding;Birth;Blood;Catheters;Cell Death;Cells;Choroid;Circulation;Clathrin;Complex;Cone;Cytoplasm;Cytoskeletal Modeling;DNA;Dark Adaptation;Development;Disease Progression;Down-Regulation;Endocytosis;Environment;Epigenetic Process;Epithelial Cells;Event;Face;Family;Family suidae;Feedback;Feeds;GLUT 4 protein;GLUT-1 protein;Gene Expression;Genes;Glucose;Glucose Transport Induction;Glucose Transporter;Hypoglycemia;Injections;Insulin;Integrins;Investigation;Label;Light;Link;Lipids;Macrophage;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Mutation;Neurons;Nutrient;Pathway interactions;Peripheral;Phagocytosis;Phagocytosis Induction;Phosphatidylserines;Phosphorylation;Photoreceptors;Proteins;Reading;Regulation;Resolution;Retina;Retinal Pigments;Retinitis Pigmentosa;Rod;Rod Outer Segments;Signal Pathway;Signal Transduction;Starvation;Structure of retinal pigment epithelium;Surface;Transplantation;Vision;Visual;Work;alpha ketoglutarate;blood glucose regulation;coated pit;cofactor;enhancing factor;epigenome;experimental study;functional loss;glucose metabolism;glucose transport;glucose uptake;histone demethylase;inhibitor;loss of function;metabolome;mutant;overexpression;prevent;receptor;recruit;response;restoration;retinal rods;scaffold;subretinal injection;uptake

public_health_relevance:
Project NarrativeAlthough many mutations in retinitis pigmentosa (RP) arise in rod-specific genes it issecondary loss of cone function leading to diminished high-resolution daylight vision that ismost debilitating. We provide evidence glucose transport from RPE to photoreceptors isdiminished in RP causing their starvation and loss of function. A pathway regulatingglucose transport is identified and we link its deregulation to RPE metabolome changesin RP.


application_id: 10561398
project_number: 1R01HL166225-01
project_title: Targeting smooth muscle cell BMAL1 as a new therapeutic strategy against restenosis
administering_ic: NHLBI
award_notice_date: 2022-12-13
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 166225
program_official: FLEG, JEROME L
project_start_date: 2023-01-01
project_end_date: 2026-12-31
study_section: Integrative Vascular Physiology and Pathology Study Section[IVPP]
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 Summary/AbstractCoronary heart disease (CHD) is the single leading cause of death in the United States. Coronaryrevascularization including coronary artery bypass graft and percutaneous coronary intervention is the mostcommon modality in patients with CHD. However it is often associated with a high incidence of restenosis.Although the rate of restenosis is reduced significantly by using bare-metal stent (BMS) and particularly withdrug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stentthrombosis with DES has been encountered as a major significant gap in the field. The current applicationproposes to bridge this gap and specifically investigates the role of the smooth muscle cell (SMC) BMAL1 inneointimal hyperplasia in mouse models of arterial injury. BMAL1 is a core molecular component of thecircadian clock. It has long been believed that loss of function of BMAL1 is detrimental to well-being. Howeverthis dogma was challenged by our recent report that genetic deletion of Bmal1 in SMCs (SM-Bmal1-KO)protects mice from aldosterone or angiotensin II-induced abdominal aortic aneurysm. Consistent with thisfinding our preliminary demonstrate that SMC-specific Bmal1 deletion also protects mice femoral artery wireinjury- or carotid artery ligation-induced neointimal hyperplasia. While the underlying mechanism remainselusive our preliminary data reveal arachidonic acid metabolism is most significantly affected by SMC-specificBmal1 deletion. Interestingly among enzymes implicated in arachidonic acid metabolism cytosolicphospholipase A2 alpha (cPLA2) is most downregulated by SMC-specific Bmal1 deletion. Mechanistically ourpreliminary data illustrate that BMAL1 binds to the mouse cPLA2 promoter and SMC BMAL1 is required forvascular injury-induced cPLA2 upregulation in neointima. Given the potential role of cPLA2 in VSMCproliferation and neointimal hyperplasia we hypothesize that upregulation of BMAL1 in SMCs by vascularinjury promotes cPLA2 expression thus mediating the initiation and progression of neointimal hyperplasia andsignificantly contributing to the development of restenosis after coronary revascularization. Aim 1 will test thehypothesis that upregulation of SMC BMAL1 by vascular injury is critical for the onset and progression ofneointimal hyperplasia. Aim 2 will define the mechanism by which SMC BMAL1 regulates cPLA2 and therebymediates vascular injury-induced neointimal hyperplasia. To achieve the goals SM-Bmal1-KO SM-cPLA2-KO and SM-Bmal1/cPLA2-KO mice will be subjected to femoral artery wire injury or carotid artery ligation toinduce neointimal hyperplasia and to determine the mechanism by which SMC BMAL1 and cPLA2 mediatevascular injury-induced neointimal hyperplasia. Results from the proposed studies will provide new mechanisticinsight on how SMC BMAL1 mediates vascular injury-induced neointimal hyperplasia via cPLA2. Moreoverresults from the proposed studies will provide preclinical evidence that inhibiting the BMAL1/cPLA2 signalingat the lesion site is a new therapeutic strategy against restenosis after coronary revascularization.

project_terms:
ARNTL gene;Abdominal Aortic Aneurysm;Adopted;Affect;Aging;Aldosterone;Alzheimer's Disease;American;Angiotensin II;Arachidonic Acids;Arterial Injury;Atherosclerosis;Binding;Biological Assay;Carotid Arteries;Cause of Death;Cell Proliferation;Cells;Clinical Research;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Cytosolic Phospholipase A2;Data;Development;Diabetes Mellitus;Endothelial Cells;Enzymes;Female;Genetic;Genetic Transcription;Goals;Hyperplasia;Hypertension;Immune response;Incidence;Injury;Knockout Mice;Lesion;Ligation;Malignant Neoplasms;Mediating;Messenger RNA;Metabolism;Metals;Modality;Molecular;Mus;Pathway Analysis;Patients;Personal Satisfaction;Pharmaceutical Preparations;Platelet-Derived Growth Factor;Proliferating;Reporting;Risk;Role;Scheme;Signal Transduction;Site;Sleep;Smooth Muscle Myocytes;Stents;Testing;Thrombosis;Time;United States;Up-Regulation;Vascular Smooth Muscle;Vascular remodeling;Vascularization;Woman;chromatin immunoprecipitation;circadian pacemaker;cost;femoral artery;insight;loss of function;male;men;mouse model;new therapeutic target;novel therapeutic intervention;novel therapeutics;overexpression;percutaneous coronary intervention;pleiotropism;pre-clinical;promoter;restenosis;stent thrombosis;transcription factor;transcriptome sequencing;vascular inflammation;vascular injury

public_health_relevance:
Project narrativeCoronary revascularization (i.e. stent placement) has been adopted worldwide and is the most commonmodality in patients with coronary heart diseases in the United States. However it is also among the mostcostly and is often associated with a high incidence of restenosis (repeat narrowing of a coronary artery). Thisapplication aims to elucidate the mechanisms responsible for restenosis and thus identify new therapeutictargets to develop new drugs to treat restenosis after coronary revascularization.


application_id: 10560925
project_number: 1R01AI172873-01
project_title: Neutrophil Heterogeneity and Immunopathogenesis of COVID-19 ARDS
administering_ic: NIAID
award_notice_date: 2022-12-30
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 172873
program_official: JOFFE, AARON MICHAEL
project_start_date: 2023-01-01
project_end_date: 2027-12-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: HUANG, JIAPENG ;URIARTE, SILVIA M
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryCoronavirus disease 2019 (COVID-19) is a potentially life-threatening disease caused by the novel viralpathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the 10%-20% of COVID-19patients hospitalized approximately 1/3 develop acute respiratory distress syndrome (ARDS). COVID-19-induced ARDS results from a combination of virally induced lung injury and the rapid influx of immune cells thatrelease inflammatory mediators leading to a hyper-activated state known as cytokine storm. Understanding thepathophysiology of COVID-19 ARDS is critical to finding effective therapeutic interventions. Accumulatingevidence indicates critical roles for neutrophils in both ARDS and immunothrombosis in COVID-19. Multi-omicsstudies identified dramatic neutrophil heterogeneity in COVID-19 including emergence of a large number oflow density neutrophils (LDN). We reported a novel population of LDN present in both the circulation and lungsof severe COVID-19 patients which expresses intermediate levels of CD16 (CD16Int LDN). CD16Int LDNspontaneously form neutrophil extracellular traps (NETs) activate platelets in vivo and in vitro and haveheightened degranulation. Our preliminary data show that LDN subsets from severe COVID-19 patients arefunctionally distinct from mature normal density neutrophils (NDN). Based on these findings we postulatethat differential functional responses of heterogeneous neutrophil populations collaborate to inducesystemic and pulmonary inflammation leading to ARDS in COVID-19 patients. Three specific Aims areproposed to further dissect the underlying mechanisms. Aim 1 will comprehensively characterize neutrophilsubsets from severe/critical COVID-19 patients using proteomics and transcriptomics approaches. Theinformation gained from those studies will be used to refine our CyTOF antibody panel and prospectivelymeasure dynamic changes of neutrophil subsets over the disease course in COVID-19 patients. Aim 2 willdetermine neutrophil subset functional changes during disease progression and their contributions todysregulated inflammatory response and coagulopathy in severe/critical COVID-19 patients. Neutrophildegranulation NET formation phagocytosis chemotaxis T cell suppressive activity and cytokine/chemokinerelease will be examined. We will also determine if LDN subsets and NDN or their derived products promotecoagulopathy in COVID-19 patients. Aim 3 will determine the relative contributions of neutrophil host defensesystems to development of acute lung injury. We will also use a hACE2 Tg mouse model to determine theroles of neutrophil respiratory burst granule exocytosis and NET formation to SARS-CoV-2-induced acutelung inflammation. Successful completion of this proposal will provide novel insights into COVID-19-inducedARDS pathophysiology by defining the functional roles of different neutrophil subsets and by establishingwhich host defense systems of neutrophils as a therapeutic target for inhibiting inflammatory lung injury andimmunothrombosis in COVID-19.

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


application_id: 10560120
project_number: 3P30ES030283-03S1
project_title: University of Louisville Center for Integrative Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2022-06-02
opportunity_number: PA-21-071
application_type: 3
activity_code: P30
ic: ES
serial_number: 030283
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY OF THE FUNDED PARENT GRANTThe University of Louisvilles (UofL) Center for Integrative Environmental Health Science (CIEHS) brings togethera multidisciplinary group of investigators working together to develop a framework to understand the complexitiesof and to integrate the interactions between environmental toxicants life style factors life stage genetics andgender and their roles in human health and disease. The CIEHS is uniquely positioned to build transdisciplinaryteams to tackle these problems by virtue of the multidisciplinary expertise of its members and its geographiclocation. The Louisville Regional Community composed of Metropolitan Louisville and the counties of westernKentucky is a unique mix of urban and rural environments with industrial and agricultural exposures that is amicrocosm of the United States. The region is plagued by rates of chronic disease (e.g. cardiovascular diabetescancer etc.) all with environmental etiologies that are among the highest in the nation. The CIEHS facilitatesresearch and training focused on: (1) exposure to industrial chemicals present in the urban and rural KYenvironments (metals VOCs PCBs vinyl chloride etc.) (2) lifestyle factors (diet alcohol socioeconomicstressors obesity etc.) and the modifications to response by life stage genetics and gender in development ofchronic adult diseases. CIEHS is organized into three multi-disciplinary research interest groups (multi-organtoxicology cancer and neurodevelopmental toxicology). The Integrated Health Science Facility Core promotestranslation of basic science including assistance with both adult and pediatric clinical trials. The CommunityEngagement Core promotes multi-directional communication between CIEHS investigators and communitygroups with special focus on rural health care providers and youth groups. The Pilot Project Program providesresources supporting new environmental health investigators collaborations between CIEHS members andestablished investigators bringing new skill sets to environmental health problems new avenues ofenvironmental health research by CIEHS members and community-engaged and community-led research incollaboration with CIEHS members. A Career Development Program provides mentorship and support to newjunior as well as mid-level investigators. These activities are supported by two facility cores (biostatistics andinformatics and integrated toxicomics and environmental measurements). The CIEHS provides leadership inenvironmental health research promotes investigation of the interactions of chronic exposure to environmentaltoxicants and lifestyle factors in pathogenesis and develops the next generation of environmental healthresearchers. Our studies utilize model systems in the laboratory the larger ecosystem by investigation ofpollution effects on wildlife and the human laboratory provided by the Louisville Regional Community incollaboration with community partners.

project_terms:
Address;Adult;Agriculture;Alcoholic Fatty Liver;Alcohols;Animals;Basic Science;Biochemical;Biological Assay;Biological Models;Biometry;Blood;Cardiovascular system;Cell Cycle;Cells;Center Core Grants;Chemicals;Childhood;Chromosomal Instability;Chronic;Chronic Disease;Clinical Trials;Collaborations;Communication;Communities;Core Facility;County;Data;Development;Diabetes Mellitus;Diet;Disease;Disease Outcome;Disease Progression;Doctor of Philosophy;Ecosystem;Educational process of instructing;Environment;Environmental Hazards;Environmental Health;Environmental Pollutants;Etiology;Exposure to;Fatty Liver;Foundations;Funding;Future;Gender;Genetic;Geographic Locations;Goals;Growth;Health;Health Personnel;Health Sciences;Hepatic;Hepatocyte;High Fat Diet;High School Student;Human;Industrialization;Informatics;Interdisciplinary Study;Interest Group;Investigation;Kentucky;Knowledge;Laboratories;Leadership;Life;Lipids;Liver;Liver diseases;Malignant Neoplasms;Measurement;Measures;Medicine;Mentors;Mentorship;Metabolic;Metals;Modification;Morbidity - disease rate;National Institute of Environmental Health Sciences;Neoplastic Cell Transformation;Obesity;Organ;Outcome;Pathogenesis;Pathologic;Persons;Pilot Projects;Pollution;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Positioning Attribute;Predisposition;Prevalence;Primary carcinoma of the liver cells;Program Development;Public Health;Rattus;Research;Research Personnel;Research Training;Resources;Risk Assessment;Risk Factors;Risk Management;Role;Rural;Rural Community;Severity of illness;Testing;Tissues;Toxic Environmental Substances;Toxicology;Training;Translations;United States;Universities;Vinyl Chloride;Youth;career development;chromium hexavalent ion;chronic liver disease;citizen science;community based participatory research;community based research;community engagement;community involvement;drinking water;environmental toxicology;epidemiologic data;epidemiology study;experience;fatty liver disease;human disease;improved;in vivo Model;lifestyle factors;lipid metabolism;member;metropolitan;mortality;multidisciplinary;neoplastic;next generation;non-alcoholic fatty liver disease;novel;parent grant;pollutant interaction;preventive intervention;programs;ranpirnase;recruit;response;rural environment;rural healthcare;simple steatosis;skills;socioeconomics;stressor;urban setting;voucher

public_health_relevance:
PROJECT NARRATIVE OF THE FUNDED PARENT GRANTThe goal of the University of Louisville Center for Integrative Environmental Health Sciences is to understandhow exposure to environmental toxicants interacts with life style factors and how these co-exposures impacthuman health and disease as modified by life stage and gender. This knowledge will provide better preventionand intervention strategies to improve the health of the people in western Kentucky.


application_id: 10559703
project_number: 5R01AA028246-03
administering_ic: NIAAA
award_notice_date: 2023-02-02
opportunity_number: PA-18-390
application_type: 5
activity_code: R01
ic: AA
serial_number: 028246
program_official: FREEMAN, ROBERT
project_start_date: 2021-03-15
project_end_date: 2026-01-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14470701
contact_pi: RAY, ANNE ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-02-01
project_title:
Cross-Tailoring Integrative Alcohol and Risky Sex Feedback for College Students: A Hybrid Type 1 Effectiveness-Implementation Trial

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

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

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


application_id: 10559475
project_number: 5R01EB028792-03
administering_ic: NIBIB
award_notice_date: 2022-11-29
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EB
serial_number: 028792
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2020-03-15
project_end_date: 2024-11-30
study_section: Imaging Guided Interventions and Surgery Study Section[IGIS]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-12-01
project_title:
Perioperative Diffuse Optical Imaging of Tissue Blood Flow and Oxygenation for Optimization of Mastectomy Skin Flap Viability

project_abstract:
ABSTRACTMastectomy is performed on approximately half of women with breast cancer. Postmastectomy breastreconstruction has benefits for body image sexuality self-esteem and quality of life. Poor clinical prognosesafter breast reconstruction often involve mastectomy skin flap necrosis (MSFN) or other complicationsassociated with the lack of blood flow and oxygenation to wound tissue volumes. MSFN and wound dehiscenceleads to a number of challenges including wound management problems delays to adjuvant therapy estheticcompromise implant extrusion patient distress and financial loss. A technology that allows surgeons toperioperatively assess and optimize preservation of skin flaps while avoiding complications is essential to ensuresuccessful clinical outcomes. Although alternative techniques have been explored to identify ischemic-hypoxictissues at risk of necrosis none have achieved universal acceptance as each technique has a few challengingissues that decrease its clinical usefulness. Moreover no single technique provides both blood flow andoxygenation information which are essential for precise assessment of skin flap viability. Our recent innovativedevelopment of near-infrared speckle contrast diffuse correlation tomography (scDCT) technique provides anoninvasive (dye-free) and noncontact means for continuous 2D/3D imaging of blood flow distributionsthroughout large/thick tissue volumes such as mastectomy skin flaps. We propose to extend this scDCTprototype to a next generation multi-wavelength scDCT (MW-scDCT) device for perioperative imaging of bothblood flow and oxygenation distributions in mastectomy skin flaps. New high-speed algorithms for 2D mappingand 3D image reconstruction will be developed to accommodate rapid online assessment of skin flaphemodynamics. This MW-scDCT system will be tested/optimized using standard tissue-simulating phantoms(Aim 1) and calibrated/validated against a commercial dye-based fluorescence angiography device (SPY Elite)in swine (Aim 2) and patients (Aim 3) undergoing mastectomy with expander-implant based breastreconstruction. The in vivo studies will determine the capability of our MW-scDCT for intraoperative prediction ofMSFN regions/volumes and postoperative optimization of incremental expander volumes to reduce risks ofMSFN and other complications. We expect that combined measurements of preoperative baseline andintraoperative alteration in skin flap flow and oxygenation will provide a more accurate assessment of skin flapviability than a one-time single-parameter measurement (i.e. blood flow blood oxygenation or fluorescenceperfusion). Study outcomes will provide the rationale for designing MW-scDCT guided clinical trials ofmastectomy with breast reconstruction to reduce postoperative complications and healthcare costs. Moreoverthis noninvasive (dye-free) noncontact continuous and cost-efficient imaging system has the potential forperioperative use in many other clinical settings especially where contact measurements may not be possiblesuch as for continual and longitudinal monitoring of burns wounds and other types of tissue flaps.

project_terms:
Adjuvant Therapy;Algorithms;Area;Blood;Blood capillaries;Blood flow;Body Image;Brain;Brain Hypoxia-Ischemia;Breast;Burn injury;Calibration;Clinical;Clinical Trials;Color;Dermal;Development;Devices;Diagnosis;Diffuse;Distress;Dyes;Ensure;Esthetics;Excision;Family suidae;Fluorescence;Fluorescence Angiography;Health Care Costs;Hemorrhage;Heterogeneity;Human;Image;Imaging Techniques;Implant;Incidence;Indocyanine Green;Interruption;Judgment;Laboratories;Lateral;Mammaplasty;Maps;Mastectomy;Measurement;Measures;Metabolic;Monitor;Necrosis;Operative Surgical Procedures;Optics;Outcome;Outcome Study;Oxygen;Patients;Pattern;Perfusion;Perioperative;Postoperative Complications;Postoperative Period;Quality of life;Risk;Risk Reduction;Rodent;Sexuality;Skin;Speed;Surface;Surgeon;System;Techniques;Technology;Temperature;Testing;Thick;Three-Dimensional Image;Three-Dimensional Imaging;Tissue imaging;Tissues;Woman;breast surgery;clinical prognosis;cost efficient;design;diffuse optical spectroscopy and imaging;hemodynamics;image reconstruction;imager;imaging system;in vivo;innovation;malignant breast neoplasm;multimodality;next generation;non-invasive optical imaging;novel;operation;preclinical study;preservation;prevent;prototype;self esteem;surgery outcome;tomography;translational study;wound;wound treatment

public_health_relevance:
PROJECT NARRATIVEClinical prognoses after surgical breast reconstruction often involve mastectomy skin flap necrosis or othercomplications associated with lack of blood flow and oxygenation to wound tissue volumes. The objective of thisproject is to design and optimize a novel noninvasive optical imaging technique which will enable rapid online3D imaging of both blood flow and oxygenation distributions throughout the entire volume of mastectomy skinflaps to perioperatively assess ischemic-hypoxic tissue regions/volumes. Outcomes from this translational studyin swine and patients undergoing mastectomy with expander-implant based breast reconstruction will provideessential information for intraoperative guidance of compromised tissue excision and postoperative optimizationof incremental expander fill volumes to reduce postmastectomy complications and healthcare costs.


application_id: 10557832
project_number: 5R01AR071789-05
project_title: Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
administering_ic: NIAMS
award_notice_date: 2023-02-01
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 071789
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2018-09-21
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)S]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Children born with severe homocystinuria due to homozygous cystathionine beta synthase deficiency (CBS-/-)exhibit poor body weights skeletal muscle myopathy and die in teenage. Although mice with homozygous CBSmutation die shortly after birth the heterozygous CBS-/+ survives. Our preliminary data suggests thatenzymes CBS and cystathionine gamma-lyase (CSE) that irreversibly remove homocysteine (Hcy) byconverting to hydrogen sulfide (H2S) are decreased in skeletal muscle. Although lowering of Hcy levels andgeneration of H2S is beneficial the mechanism by which HHcy causes of skeletal muscle wasting and frailty isunknown. The long-term goal of this project is to understand the mechanism of muscle wasting in HHcy andevaluate the potential beneficial effects of H2S signaling in reversing skeletal muscle wasting and myopathy.The central hypothesis of this proposal is that HHcy causes skeletal muscle deterioration bycompromising vasculogenesis by enhancing muscle atrophy and by limiting skeletal muscleregeneration and H2S reverses these changes. We will test this hypothesis by following three specific aims:Specific Aim #1: To determine whether the HHcy inhibits muscle specific AKT HIF-1 and AMPKsignaling and impairs vasculogenesis and H2S reverses impaired vasculogenesis.Specific Aim #2: To determine whether the HHcy attenuates PGC-1 signaling and instigates atrogeneexpression and causes muscular atrophy and H2S mitigates muscle atrophy.Specific Aim #3: To determine whether the HHcy enhances TGF-1 signaling and myostatin levelsthereby suppresses muscle regeneration and H2S ameliorates these changes.

project_terms:
Angiography;Atrophic;Attenuated;Biological Assay;Birth;Body Weight;CRISPR/Cas technology;Cell Differentiation process;Cell Line;Cell Proliferation;Child;Chronic;Collagen;Cystathionine beta-Synthase;Cysteine Desulfhydrase;Data;Deposition;Deterioration;Diameter;Endothelial Cells;Enzymes;Exhibits;FOXO1A gene;Fatigue;GDF8 gene;Generations;Genes;Genetic Transcription;Goals;Heterozygote;Homocysteine;Homocystinuria;Hydrogen Sulfide;Hyperhomocysteinemia;Hypoxia;Image;Immunohistochemistry;Impairment;In Vitro;Ischemia;Isolated limb perfusion;Lasers;Ligation;Measures;Mediating;Metabolic;Modality;Mus;Muscle;Muscle Fibers;Muscular Atrophy;Mutation;Myopathy;Natural regeneration;Phosphorylation;Plasma;Predisposition;Proliferating;Proto-Oncogene Proteins c-akt;Roentgen Rays;Role;Signal Transduction;Signaling Molecule;Skeletal Muscle;Starvation;Teenagers;Testing;Therapeutic;Tissues;Transcript;Transduction Gene;Transgenic Mice;Transgenic Organisms;Vascular Endothelial Growth Factors;attenuation;density;design;femoral artery;frailty;hypoxia inducible factor 1;in vivo;knock-down;limb ischemia;muscle regeneration;novel;prevent;response;satellite cell;skeletal muscle wasting;small molecule;tissue oxygenation;vasculogenesis

public_health_relevance:
Narrative: This proposal is aimed to understand the mechanistic role of metabolic alterations (i.e.HHcy) in muscular damage and to evaluate the therapeutic potential of this novel gaseous signalingmolecule H2S. This study will also reveal that the H2S generation itself is enough to counter the HHcymediated detrimental effects necessary to benefit therapeutic modalities.


application_id: 10557547
project_number: 1P20GM148326-01
project_title: Sustained eIF5A hypusination at the core of brain metabolic dysfunction in TDP-43 proteinopathies
administering_ic: NIGMS
award_notice_date: 2023-05-15
opportunity_number: PAR-19-313
application_type: 1
activity_code: P20
ic: GM
serial_number: 148326
project_start_date: 2023-05-15
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
subproject_number: 8911
contact_pi_person_id: 12103073
contact_pi: SELENICA, MAJ-LINDA B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ ABSTRACT TAR DNA-binding protein 43 (TDP-43) pathology is associated with clinical dementia and occurs in morethan half of clinically diagnosed Alzheimers disease (AD) patients (1 2). The discovery of limbic-predominantTDP-43 encephalopathy (LATE) emphasized the importance of age-related TDP-43 proteinopathy with orwithout co-morbid AD pathological hallmarks. The lack of disease-modifying agents against TDP-43 pathologycreates an urgent need to identify novel therapeutic pathways against TDP-43 proteinopathy. Interestinglyregional disruption of glucose uptake and utilization is linked to the progression of AD neuropathology (3-5) andyet there is no consensus on the effect of TDP-43 on glucose and energy homeostasis in the diseased brain (6).This proposal will address this significant gap in knowledge by studying the impact of the eIF5A hypusinationpathway on the brains metabolic state in TDP-43 pathology. eIF5A is an initiation/elongation factor and the onlyprotein undergoing hypusination (eIF5AHyp). Deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase(DOHH) activity convert a single lysine to a hypusine moiety. Our feasibility data finds that TDP-43 pathology inAD brain and TDP-43 mouse models induces DHS expression and hypusine levels. Additionally we show thatenhanced hypusination exacerbates TDP-43 pathology dysregulates brain glucose homeostasis and exertsmitochondrial bioenergetic defects. Our central hypothesis states that DHS-targeted strategies reducinghypusine levels will ameliorate TDP-43 neuropathogenesis by restoring brain glucose metabolism andmitochondrial bioenergetics upstream of cognitive decline and neurodegeneration. In Aim 1 we willestablish how conditional deletion of the DHS (DHSko) in the adult forebrain of the TDP-43 transgenic mousemodel will affect the brain metabolic transcriptomic profile via NanoString analysis and determine biologicalsignatures that define the eIF5AHyp - TDP-43 phenotype. We will also utilize the CNS-Met Metabolomics Core tomeasure brain metabolite levels while biochemically determining metabolic proteins enzymes and TDP-43pathology. We will further elucidate how DHSko can rescue LTP cognitive performance and neurodegenerationassociated with TDP-43 phenotype of a novel TDP-43 animal model. In Aim 2 we will define the role of eIF5AHypon the mitochondrial bioenergetics of neurons and astrocytic-responsive neurons. We will establish how DHSinhibition rescues mitochondrial bioenergetics and restores metabolite balance in primary cells. We will alsodetermine the cellular and mitochondrial TDP-43 accumulation and mitochondrial structure integrity. Overall theproposed studies will provide evidence that the eIF5AHyp pathway in the TDP-43 phenotype is upstream ofirreversible stages of dementia. It also offers the first detailed mechanisms of how reducing hypusine restoresglucose dysregulation and mitochondrial dysfunction maintaining neuro-astrocytic support and healthy neuronalactivity while rescuing the pathological phenotype in animal models of TDP-43 proteinopathy.

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


application_id: 10557544
project_number: 1P20GM148326-01
project_title: CNS-Met Metabolomics Core
administering_ic: NIGMS
award_notice_date: 2023-05-15
opportunity_number: PAR-19-313
application_type: 1
activity_code: P20
ic: GM
serial_number: 148326
project_start_date: 2023-05-15
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
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;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;nervous system disorder;neuroinflammation;neurotransmitter biosynthesis;operation;personalized medicine;prospective;response;sample fixation;skills;skills training;success


application_id: 10557543
project_number: 1P20GM148326-01
project_title: CNS-Met Administrative Core
administering_ic: NIGMS
award_notice_date: 2023-05-15
opportunity_number: PAR-19-313
application_type: 1
activity_code: P20
ic: GM
serial_number: 148326
project_start_date: 2023-05-15
project_end_date: 2028-02-29
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
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;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;nervous system disorder;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: 10557542
project_number: 1P20GM148326-01
project_title: Center of Biomedical Research Excellence in CNS Metabolism
administering_ic: NIGMS
award_notice_date: 2023-05-15
opportunity_number: PAR-19-313
application_type: 1
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: Special Emphasis Panel[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 Physiology;Neurologic Dysfunctions;Neurons;Neurosciences;Neurosciences Research;Obesity;Outcome;Oxidation-Reduction;Parkinson Disease;Phase;Pilot Projects;Positioning Attribute;Process;Research;Research Personnel;Research Project Grants;Resources;Rest;Role;Scientist;Severity of illness;Structure;Synapses;System;Techniques;Therapeutic;Training;Translations;Traumatic Brain Injury;United States National Institutes of Health;Universities;biomarker discovery;brain metabolism;cohort;collaborative environment;college;data science resource;defined contribution;design;glucose metabolism;imaging capabilities;insight;instrumentation;interest;investigator training;metabolome;metabolomics;mitochondrial metabolism;multidisciplinary;nervous system disorder;neuroinflammation;neuronal excitability;neuropathology;neurophysiology;neurotransmission;neurotransmitter biosynthesis;novel;programs;protein TDP-43;recruit;skills;success;sustainability framework;synergism;systems research;translational impact

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


application_id: 10557187
project_number: 5R01EY028911-05
project_title: Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing
administering_ic: NEI
award_notice_date: 2023-01-30
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: EY
serial_number: 028911
program_official: MCKIE, GEORGE ANN
project_start_date: 2019-02-01
project_end_date: 2026-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(81)S]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary An intact and fully differentiated corneal epithelium is critical for proper vision and to keep foreign objects(bacteria viruses small particles) out of the eye. However damage to the corneal epithelium is one of themost common ocular problems presented in primary care facilities and arises from a variety of factorsincluding trauma disease and a side-effect of drugs. Despite the prevalence discomfort and potential forblindness associated with perturbation of the corneal epithelium there are no FDA-approved agents thatpromote the restoration and homeostasis of this tissue. The long-term goal of our research is to develop newcompounds that promote corneal epithelial wound healing and homeostasis. The overall objective of thisapplication is to chemically optimize a recently identified c-Cbl antagonist to increase its affinity and potencywhile decreasing cytotoxicity. To accomplish this we will test the central hypothesis that compounds thatdisrupt EGFR:c-Cbl interactions will prevent EGFR ubiquitylation divert the activated EGFR from the lysosomeand prolong EGFR signaling. Based on preliminary studies this prolongs EGFR activity and increases therestoration and maintenance of corneal epithelium via cell migration proliferation and differentiation. Therationale for these studies is that knockdown of c-Cbl and inhibits EGFR ubiquitylation prolongs EGFR activityand enhances corneal epithelial wound healing. Following an in silico screen of 25000000 compounds wehave identified several lead compounds that bind c-Cbl and inhibit ligand-mediated EGFR ubiquitylation. Weseek to develop the top compound into a therapeutic agent with the following specific aims. In Aim 1 we willstructurally optimize our lead compound to increase its affinity for c-Cbl and disrupt EGFR:c-Cbl binding.Multiple rounds of chemical modifications to our lead compound will be used to identify new derivatives thatbind recombinant c-Cbl with high affinity and disrupt EGFR:c-Cbl interactions. In Aim 2 we will test the highestaffinity compounds for disruption of c-Cbl-mediated ubiquitylation and trafficking of the EGFR. The topcandidates will be tested for their ability to block ligand-mediated EGFR ubiquitylation and lysosomaldegradation and if they prolong EGFR signaling in corneal epithelial cells. In Aim 3 we will determine whetherinhibitors of EGFR ubiquitylation promote corneal epithelial wound healing. The top compounds will beassayed for corneal epithelial wound healing using in vitro ex vivo and in vivo assays. Our proposed studiesare innovative in our opinion because we will by-pass the limitation of EGFR occupancy and target a novelprotein (c-Cbl) and molecular mechanism (receptor desensitization). These studies are significant becauseaccelerating re-epithelialization and homeostasis of compromised corneas will decrease patient distressminimize infections and reduce the incidence of blindness. Corneal epithelial homeostasis is a major publichealth issue with limited treatments. Our goal is to develop our lead compounds for the topical treatment ofcompromised corneal epithelium to restore tissue homeostasis.

project_terms:
Acceleration;Address;Advanced Development;Affinity;Anatomy;Animal Model;Antineoplastic Agents;Bacteria;Binding;Biochemical;Biological Assay;Biology;Biomedical Engineering;Blindness;Bypass;Calorimetry;Cell Proliferation;Cell model;Cetuximab;Chemical Injury;Chemical Structure;Chemicals;Complex;Cornea;Corneal Diseases;Corneal Injury;Data;Development;Diabetes Mellitus;Disease;Distress;Drug Side Effects;Drug usage;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial Cells;Epithelium;Event;Eye;Eye Infections;FDA approved;Generations;Goals;Growth Factor Receptors;Health care facility;Homeostasis;Human;In Vitro;Incidence;Infection;Investigation;Laboratories;Lead;Ligands;Light;Lysosomes;Maintenance;Measures;Mediating;Membrane;Mission;Modeling;Modification;Molecular;Operative Surgical Procedures;Oryctolagus cuniculus;Pain;Patients;Prevalence;Primary Care;Procedures;Proliferating;Proteins;Public Health;Reagent;Receptor Signaling;Recombinants;Recurrence;Research;Retina;Rodent;Signal Transduction;Structure;Testing;Therapeutic;Therapeutic Agents;Tissue Model;Tissues;Topical application;Trauma;Virus;Vision;Work;antagonist;cancer type;cell growth;cell motility;cell replacement therapy;corneal epithelial wound healing;corneal epithelium;corneal surgery;cytokine;cytotoxicity;desensitization;drug development;drug-like compound;experience;heat injury;improved;in silico;in vivo;inhibitor;innovation;interest;knock-down;limbal;nanomolar;novel;novel therapeutics;particle;pharmacologic;preservation;prevent;receptor;restoration;side effect;stem cell replacement;tissue culture;trafficking;ubiquitin-protein ligase;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 secondary effects ofdiabetes. This innovative line of investigation seeks to develop a first generation compound that will extend theduration of epidermal growth factor receptor signaling to maintain and promote a healthy corneal epithelium.This project is relevant to the NEIs mission because these findings will advance the development of newstrategies to promote corneal epithelial wound healing and minimize the chances of eye infection andsubsequent blindness.


application_id: 10556877
project_number: 5P20GM125504-05
project_title: The role of sugar transport in C. difficile colonization and disease
administering_ic: NIGMS
award_notice_date: 2022-02-24
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
program_official: MCGUIRL, MICHELE
project_start_date: 2022-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3(C1)
subproject_number: 8734
contact_pi_person_id: 14774031
contact_pi: COLLINS, JAMES TRISTAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Clostridioides difficile infection (CDI) is still the most common cause of healthcare-associated infection despite a concerted effort to reduce the incidence. Increasingly C. difficile is found in the community among persons with no recent healthcare contact. The long-term goal of this project is to identify novel therapeutic targets which can be exploited to treat CDI and control the spread of C. difficile. The overall objectives in this application are to (i) elucidate the specificity and redundancy of the sugar transporters under positive selection in C. difficile (ii) determine their role in disease and iii) examine the impact of dietary sugar on asymptomatic carriage. The central hypothesis is that C. difficile has evolved to better occupy niche space within the gastrointestinal tract (GIT) by taking advantage of the modem sugar-rich diet. The rationale for this project is that determining the specificity and importance of sugar transporters and downstream metabolism in C. difficile carriage and infection sets up a robust scientific framework whereby new prophylaxis and treatment strategies can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Elucidate the specificity redundancy and influence on toxin production of evolving sugar transport genes 2) Determine the effect of evolving sugar transport genes on community invasion and disease and 3) Investigate the role of sugars in niche establishment and asymptomatic carriage. The research proposed in this application is innovative because it focuses on the metabolic adaptation of C. difficile to carbohydrates and their role in asymptomatic carriage as well as disease. This focus has the potential to lead to novel prophylactic strategies that can be used against C. difficile before the emergence of the disease. The proposed research is significant as it will provide a solid scientific justification for the continued examination of metabolism as a virulence mechanism in C. difficile and provide a framework for the future study of novel prophylactic intervention and treatment options.

project_terms:
Carbohydrates;Clostridium difficile;Communities;Diet;Dietary Sugars;Disease;Future;Gastrointestinal tract structure;Genes;Goals;Healthcare;Incidence;Infection;Infection Control;Inflammation;Intervention;Lead;Metabolic;Metabolism;Modems;Pathogenicity;Persons;Production;Prophylactic treatment;Research;Role;Solid;Specificity;Testing;Toxin;Virulence;healthcare-associated infections;innovation;microbiome research;new therapeutic target;novel;prophylactic;sugar;treatment strategy


application_id: 10555721
project_number: 3R01AG068215-03S1
project_title: Administrative Supplement to Sleep Fragmentation and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2022-08-29
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: AG
serial_number: 068215
suffix: S1
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BACHSTETTER, ADAM D;DUNCAN, MARILYN J.;O'HARA, BRUCE FREDERICK;SUNDERAM, SRIDHAR
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Chronic sleep disruption resulting from work schedules noise exposure family obligations sleep disorders orlifestyle choices is a pervasive feature of contemporary life. Sleep problems affect up to 40% of AD patientsmay precede cognitive impairments by more than a decade and worsen as the disease progresses. As well asaffecting mood and well-being sleep disruption may drive the development of AD neuropathology for instanceby reducing clearance of amyloid- (A) and by promoting a neurotoxic proinflammatory state involvingastrocytes and microglia. Sleep disruption can include reduced total sleep (sleep restriction [SR]) loss of deepsleep (also known as slow-wave sleep [SWS] marked by large amplitude low frequency electrical activity)and fragmentation of sleep (SF) into shorter bouts. Fragmentation of the daily sleep-wake rhythm is associatedwith greater risk of incident AD and earlier cognitive decline in older humans. In spite of these correlativestudies whether or how chronic SF impacts the progression of AD has not been experimentally investigated.SF may be a better model of the sleep disruption associated with AD than the traditional approach of SR. Ourstudies of AD mouse models show that spontaneously occurring SF is associated with more severe Aaccumulation and that experimentally-induced SF leads to A accumulation and neuroinflammation. BesidesSF loss of SWS may exacerbate AD and improving SWS may be beneficial in mild cognitive impairment(MCI) or even in AD. Since sleep disruption adversely affects the development of AD-related neuropathology itis surprising that sleep enhancement (SE) strategies to consolidate sleep and increase SWS have not beenadequately explored to slow or reverse these effects. Our overall working hypothesis is that a change in thequality of sleep especially sleep fragmentation and loss of SWS is more important than the quantity of sleep.Further we hypothesize that the mechanism underlying these effects is primarily neuroinflammation at least inpart mediated by A peptide deposition. We will use a unique well-characterized mouse model that exhibitsAD-related A pathology neuroinflammation and cognitive deficits. This project has three specific aims: (1)that SF will accelerate (and SE decelerate) AD progression; (2) that increases in A accumulation mediatesSF-induced neuroinflammation neuropathology and cognitive decline; and (3) that increases inneuroinflammation mediate SF-induced neuropathology and cognitive decline. We will use multiple novelapproaches including thermoneutral temperature manipulation and a unique anti-inflammatory compound thathas recently entered early stage clinical trials. Thus these studies will elucidate the underlying mechanisms bywhich sleep disruption is linked to AD and will lay the groundwork for new therapeutic strategies.

project_terms:
Abeta clearance;Administrative Supplement;Affect;Alzheimer's Disease;Alzheimer's disease patient;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Chronic;Cognitive deficits;Correlative Study;Dementia;Deposition;Development;Disease;Disease Progression;Exhibits;Family;Frequencies;Human;Impaired cognition;Life;Life Style;Link;Mediating;Microglia;Modeling;Moods;Personal Satisfaction;Phase I Clinical Trials;Postmenopause;Risk;Schedule;Sleep;Sleep Deprivation;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Societies;Temperature;Woman;Work;abeta accumulation;age related;base;beta amyloid pathology;improved;mild cognitive impairment;mouse model;neuroinflammation;neuropathology;neurotoxic;noise exposure;novel strategies;novel therapeutic intervention;sex;sleep quality;sleep quantity

public_health_relevance:
Age-related dementia is a significant and growing burden on our society  the most well known of which isAlzheimers disease (AD)  and chronic sleep disruption is a pervasive feature of contemporary life that isassociated with and exacerbated in AD. This project will examine the idea that sleep quality is more importantthan sleep quantity and will specifically investigate sex-based factors that make women more susceptible toboth AD and post-menopausal sleep disorders.


application_id: 10553003
project_number: 5P20GM130456-03
project_title: Developing immunotherapeutic nanoparticles for spinal cord injury
administering_ic: NIGMS
award_notice_date: 2022-02-09
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: FRINCU, CRINA
project_start_date: 2022-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9(C1)
subproject_number: 7564
contact_pi_person_id: 14321924
contact_pi: PARK, JONGHYUCK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Traumatic spinal cord injury (SCI) leads to primary injury followed by secondary injuries including inflammation which create an inhibitory environment. Regeneration is limited due to additional tissue damages and an inhibitory environment leading to various neurological deficits. The goal of this proposal is to develop a non-invasive acute intervention with the goal of modulating inflammatory responses to reprogram an inhibitory environment after SCI. Particularly the SCI demographic shifts toward a more equal balance among males and females indicating that improved therapeutics are needed since the difference in physiological factors between sexes play important roles in pharmacological treatments and functional recovery after SCI. In this study Poly(lactide-co-glycolide) (PLG)-based multiple nanoparticle (NP) formulations will be designed with various physicochemical factors to identity sex-specific key functionality of NPs to reprogram inflammation thereby facilitating functional recovery in females and males respectively after SCI. Specific aim 1 will investigate NP-induced innate cells modulation following SCI to identify sex-specific key properties of NPs. The distinct physicochemical properties of NPs will differently limit inflammation after SCI. Specific aim 2 will assess NPs-mediated long-term dynamic responses in the spinal cord and their effects on anatomical and functional recovery in both sexes after SCI. Intravenously (IV) administered NPs will bind to pro-inflammatory subsets of immune populations and direct their trafficking to the spleen. NP-positive innate cells within the injured tissues will lead to a sustained response facilitating an environment that improves recovery after SCI. Successful completion of proposed aims will provide efficient sex-specific NP designs to maximize functional recovery after SCI. In addition NPs are made of FDA-approved material that enables NPs to be administered in triage or on site to patients diagnosed with SCI without direct intervention into the spinal cord. This study will provide a potentially practical therapy for the entire SCI population.

project_terms:
Acute;Anatomy;Binding;Cells;Centers of Research Excellence;Clinical Trials;Diagnosis;Environment;Equilibrium;FDA approved;Female;Formulation;Glycolic-Lactic Acid Polyester;Goals;Hospitals;Immune;Immunotherapeutic agent;Impairment;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Intravenous;Lead;Mediating;Natural regeneration;Neurologic Deficit;Patients;Pharmacologic Substance;Pharmacological Treatment;Physiological;Play;Population;Property;Quality of life;Recovery;Recovery of Function;Research;Role;Site;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Spleen;Staging;Therapeutic;Tissues;Triage;acute care;base;design;improved;injured;innovation;loss of function;male;nanoparticle;response;severe injury;sex;trafficking

public_health_relevance:
Spinal cord injury (SCI) severely impairs the quality of life for patients causing permanent loss of function below the injury. The proposed nanoparticle-mediated strategy will provide a non-invasive acute care platform that can be given immediately intravenously in the pre-hospital environment. Successful completion of the proposed studies will have the potential to develop an over-the-counter transformational platform that can lead to fast-track staging of clinical trials for SCI patients.


application_id: 10552010
project_number: 5R21AI169423-02
project_title: Extracellular vesicles released in response to Yersinia pestis
administering_ic: NIAID
award_notice_date: 2022-12-08
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 169423
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2022-01-18
project_end_date: 2024-12-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: URIARTE, SILVIA M
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:
SUMMARY Extracellular vesicles (EVs) are membrane-bound vesicles released by cells that are potent vehiclesfor intercellular communication. The signaling capacity of EVs is mediated by incorporation of differentbiomolecules (e.g. proteins lipids nucleic acids and carbohydrates) within individual vesicles.Neutrophils produce EVs upon recognition of a variety of stimuli but the biological properties of EVschange depending on the stimuli encountered. Thus depending on stimulation neutrophil-derived EVshave been shown to induce both pro- and anti-inflammatory responses in recipient cells. Neutrophilscan also produce a subset of EVs that are directly microbiostatic to bacteria and fungi. However theEV response by neutrophils has only been characterized for very few bacterial species and thereforewe have a limited understanding of the full potential of neutrophil-derived EVs in response to differentbacterial infections. Yersinia pestis is the causative agent of the human disease known as plague. Y.pestis evades immune cell recognition via direct interactions with innate immune cells that disrupt thenormal responses by these cells. Specifically Y. pestis uses a type three secretion system (T3SS) todirectly secrete bacterial proteins (called Yops) into host cells which disrupt specific host cell signalingpathways. The outcomes of Yop translocation into host neutrophils include: blocking phagocytosisinhibition of the generation of reactive oxygen species and decreased production of pro-inflammatorycytokines by neutrophils. Recently we and others have shown that Y. pestis is able to block neutrophilgranule exocytosis in a T3SS-dependent manner. Together these data show that Y. pestis efficientlyalters endocytic and exocytic activities by neutrophils. Despite its ability to disrupt endocytic andexocytic pathways the ability of Y. pestis to alter the production of EVs by host cells has not beenpreviously investigated. With a growing appreciation for EVs in inflammation and bacterial clearanceour lack of a proper understanding of the EVs released by innate immune cells in response to Y. pestisrepresents a critical knowledge gap in the immune response to Y. pestis. Based on previously publishedstudies and our preliminary data we hypothesize that Y. pestis actively alters the production of EVs byinnate immune cells and that this alteration has a direct impact on how EVs can influence the immuneresponse to the bacterium. To test this hypothesis in Aim 1 we will define the composition of thepayloads packaged into EVs by neutrophils in response to Y. pestis infection and whether the T3SSand Yop effectors alter the production of EVs. In Aim 2 we will determine the impact of EVs isolatedfrom neutrophils infected with Y. pestis or a Y. pestis strain lacking the Yop effectors on immune cellresponse to Y. pestis infection. Completion of these Aims will provide for the first time a comprehensivedescription of the EVs produced by human neutrophils in response to infection with Y. pestis.

project_terms:
Anti-Inflammatory Agents;Antigen Presentation;Autoimmunity;Bacteria;Bacterial Infections;Bacterial Proteins;Binding;Biological;Biology;Carbohydrates;Cell Communication;Cells;Characteristics;Classification;Cytoplasmic Granules;Data;Exocytosis;Future;Generations;Goals;Grant;Growth;Human;Immune;Immune Evasion;Immune response;Immune signaling;Individual;Infection;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Innate Immune System;Knowledge;Lipids;Macrophage;Malignant Neoplasms;Mediating;Membrane;Molecular;Nucleic Acids;Outcome;Pathogenesis;Pathologic;Pathway interactions;Patients;Phagocytosis;Physiological;Plague;Population;Production;Property;Proteins;Publishing;Reactive Oxygen Species;Reporting;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Site;Stimulus;System;Testing;Therapeutic;Therapeutic Intervention;Time;Vesicle;Yersinia pestis;cytokine;exosome;extracellular vesicles;fungus;human disease;improved;intercellular communication;monocyte;mutant;neutrophil;novel;novel strategies;recruit;response;tool;vesicular release

public_health_relevance:
PROJECT NARRATIVEExtracellular vesicles (EVs) are released by cells to mediate cell-to-cell communication and contribute toestablishing the proper immune response during infection. Our goal is to define how Yersinia pestis thecausative agent of plague alters EV production by immune cells to disrupt cell communication and inhibit therecruitment of immune cells to the site of infection (referred to as inflammation). Because inducing inflammationduring early stages of plague can improve the therapeutic window for a patient defining mechanisms used byY. pestis to inhibit inflammation is not only important for our understanding the pathogenesis of this bacteriumbut will help us to identify new approaches to improve current plague therapy.


application_id: 10551214
project_number: 5R01CA223164-05
project_title: Integrin alpha6beta4 regulation of cancer epigenetics
administering_ic: NCI
award_notice_date: 2022-12-23
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 223164
program_official: AULT, GRACE S
project_start_date: 2019-01-01
project_end_date: 2024-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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:
How DNA demethylation machinery can be targeted to specific genomic loci is still poorly understood yethas important implications for tumor biology. Mounting evidence suggests that the microenvironmentinfluences epigenetics; however the mechanisms guiding these events have not been elucidated. We havedemonstrated that integrin 64 dramatically alters the transcriptome toward an invasive phenotype. Theintegrin regulates this process in part by substantially changing the epigenome through the regulation of DNAdemethylation of select CpG rich regions and loci. Thus we expect that understanding how integrin 64regulates the cancer epigenome holds the key to how site-specific and mechanotransduced epigenetics areregulated. Investigations into how integrin 64 regulates DNA demethylation (funded by an NCI R21) led toour discovery that integrin 64 utilizes and stimulates the base excision repair (BER) pathway to mediatethese epigenetic events but not in cells in which the link between integrin 64 and the nucleus iscompromised. We have also identified specific mutations in integrin 4 subunit that preventing the integrin frombinding to intermediate filaments and anchoring under the nucleus thus indicating a pathway for integrin-mediated alterations in nuclear function. Based on our preliminary data and supporting literature wehypothesize that integrin 64 coordinates signal and mechano-transduction to the nucleus that drives BERand results in DNA demethylation of select loci which in turn enhances tumor invasion and metastasis. We willtest our central hypothesis through completion of the following three aims: 1) Determine how integrin 64cytoskeletal linkages impacts invasion metastasis and epigenetics 2) Elucidate how integrin 64 regulatesBER-mediated DNA demethylation and 3) Define changes in the epigenome mediated by integrin 64signaling. We expect that by elucidating the genes and pathways used by integrin 64 to modulate thedemethylation of select genes we will provide critical insight into how specific sites within the genome aredemethylated to foster an invasive and metastatic transcriptome.

project_terms:
Actins;Apoptosis;Base Excision Repairs;Basement membrane;Bioinformatics;Biometry;Breast;Carcinoma;Cell Nucleus;Cells;Chromatin;Clinical;Complex;Cytokeratin;Cytoskeleton;Cytosol;DNA;DNA Methylation;DNA Repair;DNA Sequence Alteration;Data;Enhancers;Environment;Epigenetic Process;Event;Fostering;Funding;GADD45A gene;Gene Expression Regulation;Genes;Genome;Heterogeneity;Histones;Integrin Binding;Integrin alpha6beta4;Integrin beta4;Integrins;Intermediate Filaments;Invaded;Investigation;Keratin;Laboratories;Laminin;Link;Literature;Malignant Neoplasms;Mediating;Methodology;Methylation;Modeling;Modification;Molecular;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Oncogenic;Pathway interactions;Phenotype;Post-Translational Protein Processing;Process;Property;Regulation;Research;Resistance;Role;Signal Transduction;Site;Solid;Specificity;Testing;Therapeutic;Therapeutic Intervention;Tumor Biology;Tumor Cell Invasion;Untranslated RNA;Vimentin;Work;breast pathology;cell motility;demethylation;emerin;epigenome;falls;genome-wide;genomic locus;innovation;insight;leukemia/lymphoma;mechanotransduction;migration;next generation sequencing;novel;plectin;prevent;promoter;recruit;repair enzyme;sensor;transcriptome;transcriptomics;transmission process;triple-negative invasive breast carcinoma;tumor;tumor microenvironment

public_health_relevance:
In this study we will use the collective expertise of our team and take advantage of the recent progress inthe field of DNA demethylation to understand how integrin 64 as a sensor of the microenvironmentcontributes to promoter demethylation of pro-invasive and pro-metastatic genes; this work will further givetremendous insight into how specificity of demethylation at specific loci is achieved. Ultimately if our modelis proven largely correct it will uncover a new paradigm of how integrins transmit oncogenic signals that willgive us the power to target these epigenetic events therapeutically.


application_id: 10550205
project_number: 5R35GM130349-05
project_title: Functional Analysis of Programmed Genome Rearrangement
administering_ic: NIGMS
award_notice_date: 2023-01-10
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 130349
program_official: VATAKIS, DIMITRIOS NIKOLAOS
project_start_date: 2019-02-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 9381521
contact_pi: SMITH, JERAMIAH JAMES
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:
An individual's genome provides a complete set of instructions for achieving development regulatingphysiology and passing heritable information to the next generation. These instructions are encoded in thelinear sequence of DNA molecules (e.g. genes) and in the higher-order structures of chromosomes andsubchromosomal regions (e.g. regulatory elements). Alterations at any scale can severely impact anindividual's health survival and ability to reproduce. It is therefore not surprising that life has evolved a varietyof genes and molecular pathways that contribute to maintaining the integrity of information encoded in thegenome nor is it surprising that independent evolutionary lineages have evolved novel pathways or novelmodifications to their ancestral genome biology. Studying these diverse mechanisms can provide criticalcomparative perspective on the cellular molecular and evolutionary underpinnings of human genome biologyand have the potential to reveal new approaches to modulating related pathways in human. Following this philosophy my lab has sought to understand the functional and evolutionary mechanismsthat underlie the remarkable diversity of genome biologies that exist among deep vertebrate lineages. Ourrecent work has focused on dissecting the causes and consequences of programmed genome rearrangement(PGR) in the sea lamprey (Petromyzon marinus). In lampreys PGR involves changes in the physical structure(and content) of the genome that occur in a highly predictable and programmatic manner during earlydevelopment. These changes result in the reproducible loss of a specific subset of genes from all somatic celllineages. In total approximately 20% of the lamprey's genome is eliminated from somatic cells and retainedonly by germ cells. Recent progress in this line of research has shed light on the cellular/developmentalmechanisms of PGR and the functions of eliminated genes. Our analyses of PGR have demonstrated thatcanonical silencing mechanisms (DNA and histone methylation) contribute to elimination of DNA during PGRparticularly during later stages of elimination. These studies have also revealed that eliminated genescontribute to the development/maintenance of germline when normally expressed and oncogenesis whensomatically misexpressed (in other vertebrates). This proposal seeks to continue our efforts in characterizingthe mechanisms and functional outcomes of PGR and extend these toward identifying genes and molecularpathways that can impact the biology of the human genome germ/stem cells and cancer. Proposed studiesaim to address several outstanding challenges with respect to PGR: 1) Precisely defining the sequence contextof PGR-associated epigenetic changes and their interactions with other molecules 2) Identifying otherpathways that contribute to PGR especially the earliest stages that involve the targeting of sequences forelimination and the differential migration of eliminated chromatin during anaphase and 3) Characterizing thefunction of eliminated genes particularly in the contexts of genome stability/instability and reprogramming.! 1!

project_terms:
Address;Anaphase;Biology;Cell Lineage;Chromatin;Chromosome Structures;DNA;DNA Methylation;DNA Sequence;Development;Epigenetic Process;Funding;Genes;Genome;Genome Stability;Germ Cells;Health;Heritability;Higher Order Chromatin Structure;Human;Human Biology;Human Genome;Individual;Instruction;Lampreys;Life;Maintenance;Malignant Neoplasms;Mediating;Modification;Molecular;Pathway interactions;Petromyzon marinus;Philosophy;Physiology;Regulator Genes;Regulatory Element;Reproducibility;Research;Somatic Cell;Structure;Vertebrates;Work;comparative;functional outcomes;gene function;histone methylation;migration;next generation;novel;novel strategies;pluripotency;stem cells;tumorigenesis;vertebrate genome

public_health_relevance:
Lamprey is a vertebrate that undergoes developmentally programmed genome rearrangements which result inthe reproducible elimination of ~20% of the genome from nearly all somatic cell lineages (this material isretained only in the germline). Our proposed studies will allow us to unravel the mechanisms by which lampreyphysically reengineers its genome and resolve the function of genes that are eliminated from somatic celllineages. If funded these studies will contribute to our fundamental understanding of cellular mechanisms thatcontribute to stability and change in vertebrate genome structure as well as gene regulatory changes thatmediate the development of germ cells epigenetic maintenance of pluripotency and oncogenesis.! 1!


application_id: 10549006
project_number: 3R01DA044311-06S1
project_title: Dynamic Signaling of NRG3-ErbB4 in the Hippocampus Mediates Nicotine Withdrawal Phenotypes
administering_ic: NIDA
award_notice_date: 2022-02-01
opportunity_number: PA-16-160
application_type: 3
activity_code: R01
ic: DA
serial_number: 044311
suffix: S1
program_official: LOSSIE, AMY C
project_start_date: 2018-04-01
project_end_date: 2024-01-31
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10484112
contact_pi: TURNER, JILL R.
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
project_abstract:
Nearly 80% of smokers attempting to quit fail. While there is increased appreciation for geneticcontributions to this statistic the molecular mechanism(s) underlying this remain a critical gap in ourknowledge. We have previously shown that multiple single-nucleotide polymorphisms (SNPs) across theNeuregulin 3 (NRG3) gene significantly associate with smoking cessation outcomes in two independentcohorts of smokers.104 We now have new evidence that SNPs previously identified to increase NRG3expression are significantly associated with nicotine withdrawal phenotypes in smokers. Our published murineexperiments104 demonstrate that this increased NRG3 expression may be responsible for affective nicotinewithdrawal (WD) phenotypes in particular: (1) chronic nicotine and 24hWD increase mRNA and proteinexpression of NRG3 and it's receptor ErbB4 in the ventral hippocampus (2) genetic interruption of NRG3signaling blocks expression of nicotine WD anxiety-like phenotypes in the Novelty-induced Hypophagia Test amodel shown to be dependent upon ventral hippocampal function and (3) inhibition of ErbB4 the NRG3receptor by Afatinib reduced anxiety-like behaviors during WD in this same behavioral model."While this ispersuasive evidence for the role of ventral hippocampal NRG3 signaling in modulating affective nicotine WDphenotypes little is known regarding the precise mechanisms through which NRG3 and nicotine interact.Therefore the overall goal of this proposal is to systematically investigate the cell-specific role of the NRG3-ErbB4 signaling in the ventral hippocampus during nicotine treatment and withdrawal. To accomplish this weare posing three central questions: 1) Is NRG3-ErbB4 signaling between pyramidal cells and interneurons inthe hippocampus necessary for expression of nicotine WD-induced anxiety? 2) Does the location of nicotinicreceptors and NRG3/ErB4 dictate chronic nicotine and 24hWD effects on cellular cascades and glutamatergicinput? and (3) How does nicotine-mediated NRG3-ErbB4 signaling regulate the activity of CCK+ and PV+cells to influence the dynamic properties of the hippocampal circuit? Our approach is significant because itcombines collective genetic information from both human and animal studies to generate atranslational high-impact hypothesis examining the functional role of this signaling pathway within thespecific cell-types of the hippocampus during nicotine and withdrawal. Completion of these studies willexpand understanding of the complex interplay between genetics circuit function and behavior in order todevelop better more specific smoking cessation aids.

project_terms:
Accounting;Affective;Animals;Anxiety;Awareness;Behavior;Behavioral Model;Calcium;Cells;Cholecystokinin;Chronic;Complex;Data;Development;Drosophila acetylcholine receptor alpha-subunit;Electrophysiology (science);ErbB4 gene;Fluorescent in Situ Hybridization;Genes;Genetic;Glutamates;Goals;Hippocampus (Brain);Human;Image;Interneurons;Interruption;Knock-in Mouse;Knowledge;Ligands;Location;Mediating;Modeling;Molecular;Mus;NRG3 gene;Nicotine;Nicotine Dependence;Nicotine Withdrawal;Nicotinic Receptors;Outcome;Phenotype;Property;Publishing;Pyramidal Cells;Reporting;Risk;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Single Nucleotide Polymorphism;Smoker;Smoking;Surgeon;Testing;Therapeutic;Time;Tissues;Tobacco smoking behavior;United States;Western Blotting;Withdrawal;Withdrawal Symptom;anxiety-like behavior;base;behavior test;cell type;cohort;confocal imaging;density;genetic information;mRNA Expression;nicotine treatment;novel;preventable death;protein expression;receptor;receptor coupling;smoking cessation;tool;voltage sensitive dye;withdrawal-induced anxiety

public_health_relevance:
Tobacco smoking is still the leading cause of preventable death in the United States 50 years after theSurgeon General's Report on Smoking. While the majority of smokers would like to quit and are aware of the risks of smoking most are unable to do so with currently available therapeutics. This proposal aims toelucidate the roles of a novel signaling pathway (NRG3-ErbB4) during nicotine and withdrawal in hopes ofdeveloping better therapeutics for nicotine dependence by specifically targeting anxiety-related WD symptoms.


application_id: 10548540
project_number: 1R21HL166178-01
project_title: Precise in vivo gene editing of HSPC for the treatment of genetic hematologic diseases
administering_ic: NHLBI
award_notice_date: 2022-12-20
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: HL
serial_number: 166178
program_official: QASBA, PANKAJ
project_start_date: 2023-01-01
project_end_date: 2024-12-31
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 14341515
contact_pi: TONG, SHENG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryCRISPR/cas9 gene editing has shown great promise for the treatment of genetic hematologicdisorders including sickle cell disease and -thalassemia. Current therapeutic strategies areprimarily focused on ex vivo gene editing of autologous patient-derived hematopoieticstem/progenitor cells (HSPCs) which require isolation of patients HSPCs ex vivo gene editingselection and expansion of corrected HSPCs and transplantation back into the patients.Despite its initial success the clinical translation of this technique is hampered by the difficultiesin ex vivo processing of HSPCs the risks associated with myeloablation the low engraftmentefficiency and the prohibitively high cost of individualized cell therapy. Recent studies haveshown that HSPCs are sustained in specialized niches in the adult bone marrow. HSPC nichesare located near the sinusoidal blood vessels where the fenestrated endothelium is highlypermeable to nanoparticles and viral vectors. To this end we propose that the HSPCs in thebone marrow can be gene-edited by CRISPR/cas9 in situ. However in vivo CRISPR/cas9 geneediting can have substantial off-target effects due to the systemic dissemination of the deliveryvehicles and the non-specific activities of the cas9 nuclease. Recently we developed a novelgene-editing platform that combines the baculoviral vector with magnetic nanoparticles (MNP-BV). Compared with conventional viral vectors the baculoviral vector can transduce a broadrange of mammalian cells without replication. MNP-BV uses an external magnetic field and theintrinsic complement system as the on- and off-switch for site-specific transgene delivery. In thisproject we will develop an MNP-BV-based gene-editing technique for precise gene editing ofHSPCs in the bone marrow. MNP-BV will be administrated via intraosseous infusion. We willdesign a magnetic targeting method to enhance the retention of MNP-BV in the bone marrowand the extravasation of MNP-BV to the perisinusoidal niches. Furthermore the baculoviralvector has a large DNA loading capacity (>38 kb) and thus can deliver inducible cas9 or gRNAexpression cassettes targeting specific cell populations. We will design gRNAs that can only beactivated by microRNAs (miRNAs) highly expressed in HSPCs. The central hypothesis is thatby combining intraosseous infusion magnetic targeting and miRNA-mediated posttranslationalregulation the MNP-BV system can efficiently and precisely transduce HSPCs in the bonemarrow and correct hematological diseases-associated gene mutations. The success of thisproject will pave the way for developing an effective and low-cost cure for a range ofhematological diseases.

project_terms:
Adult;Allogenic;Autologous;Autologous Transplantation;Back;Basic Science;Binding Sites;Blood Vessels;Bone Marrow;Bone Marrow Cells;Bone Marrow Purging;CRISPR/Cas technology;Cell Therapy;Cells;Chromosome Mapping;Clinical Treatment;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;DNA Sequence;DNA Sequence Alteration;DNA cassette;Disease;Endothelium;Engraftment;Extravasation;Face;Femur;Future;Gene Delivery;Gene Mutation;Genes;Genetic;Guide RNA;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Hemoglobinopathies;Human;Immunologics;In Situ;Infusion procedures;Insect Viruses;Magnetic nanoparticles;Magnetism;Mammalian Cell;Mediating;Messenger RNA;Methods;MicroRNAs;Mus;Mutation;Myelogenous;Nanotechnology;Patients;Permeability;Population;Post-Translational Regulation;Regulator Genes;Regulatory Element;Risk;Sickle Cell Anemia;Site;Specificity;System;Techniques;Therapeutic;Toxic effect;Transfection;Translation Initiation;Transplantation;Untranslated RNA;Viral Vector;adaptive immunity;beta Globin;beta Thalassemia;clinical application;clinical translation;complement system;cost;curative treatments;delivery vehicle;design;gene correction;genotoxicity;in vivo;intravenous injection;lipid nanoparticle;mRNA Translation;magnetic field;mouse model;multidisciplinary;nanomedicine;nanoparticle;novel;nuclease;preclinical study;self-renewal;stem cell biology;stem cells;success;synthetic biology;targeted delivery;therapeutic target;tool;transgene delivery;translational potential;vector

public_health_relevance:
Project NarrativeCRISPR/cas9 gene editing has shown great promise for the treatment of genetic hematological diseases. Herewe propose to develop a novel gene editing platform that combines nanotechnology and synthetic biologyapproaches for precise in vivo gene editing of HSPCs in the bone marrow. The success of this project has thepotential to provide an effective and low-cost therapy for hematological diseases.


application_id: 10547764
project_number: 5R01AG061111-04
administering_ic: NIA
award_notice_date: 2024-02-21
opportunity_number: PAR-18-175
application_type: 5
activity_code: R01
ic: AG
serial_number: 061111
program_official: CLARKE, AKANNI YAO
project_start_date: 2019-02-01
project_end_date: 2025-11-30
study_section: Special Emphasis Panel[ZRG1-BBBP-Z(55)R]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-12-01
project_title:
Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging (SMArTHS)

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

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

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


application_id: 10546610
project_number: 1UT2GM148083-01
project_title: I-RED Southeast XLerator Network
administering_ic: NIGMS
award_notice_date: 2022-08-12
opportunity_number: RFA-GM-22-001
application_type: 1
activity_code: UT2
ic: GM
serial_number: 148083
program_official: ZHOU, YANG
project_start_date: 2022-08-15
project_end_date: 2023-03-14
study_section: Special Emphasis Panel[ZRG1 IMST-B (51)]
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryI-RED Southeast XLerator Network powered by XLerateHealth LLC in collaboration with the University ofKentucky as the lead academic partner institution proposes to develop a suite of experience-basedentrepreneurship education products and commercialization education tools to address the needs ofacademic institutions and their faculty researchers innovators and graduate/undergraduate students in theSoutheast IDeA states region. The ultimate aim of these entrepreneurship education and training productsis to foster the translation of promising biomedical discoveries and technologies from research laboratoriesinto the creation of commercial products which both improve human health and promote economic growth.As a result it will significantly enhance commercialization knowledge mature the entrepreneurialecosystem identify more market-ready technologies and patents see more startup entities formed increasedilutive and non-dilutive funding to these entities and accelerate the commercialization of biomedical andhealth tech innovations in the region  with the fundamental goal of positively impacting human health andpatients lives.This team has years of experience working with academic institutions innovators and healthcare startupsin the Southeast IDeA states region (including the previous NIGMS STTR IDeA Regional TechnologyTransfer Accelerator award) developing extensive entrepreneurial educational content and deliveringentrepreneurial training to biomedical innovators aspiring to become entrepreneurs. Key team memberspossess strong and diverse backgrounds that include education and training technology transfer clinicalpractice startup company creation venture capital investing building talent support systems sales andmarketing social media and program and product development among other disciplines. We will createand deploy the most impactful educational products necessary to further advance the translation ofbiomedical technologies being developed by academic researchers to the commercial marketplace.I-RED Southeast XLerator Network will leverage its teams experiences assessing building and workingwith a wide network of highly diverse partners across each state and territory in the Southeast IDeA statesregion with a governance structure to optimize communication and ensure extensive prototype testing andvalidation of unique educational programs and products that will address the needs identified through gapassessment and achieve strong engagement from our regions innovators in those educational programsand products.

project_terms:
Address;Award;Biomedical Technology;Capital;Capital Financing;Collaborations;Communication;Discipline;Economics;Ecosystem;Education;Effectiveness;Ensure;Entrepreneurship;Evaluation;Faculty;Fostering;Fund Raising;Funding;Goals;Growth;Health;Health Technology;Healthcare;Human;Institution;Kentucky;Knowledge;Laboratory Research;Lead;Legal patent;Licensing;Marketing;Monitor;National Institute of General Medical Sciences;Outcome;Participant;Patients;Phase;Pilot Projects;Positioning Attribute;Process;Program Development;Reporting;Research Personnel;Sales;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Structure;Students;Support System;Talents;Technology;Technology Transfer;Testing;Training;Training and Education;Translations;Universities;Validation;base;clinical practice;cohort;commercialization;design;experience;improved;innovation;member;new product development;product development;programs;prototype;social media;success;tool;undergraduate student

public_health_relevance:
Project NarrativeThrough this program I-RED Southeast XLerator Network will develop a suite of experience-basedentrepreneurship education products and commercialization education tools to address the needs ofacademic institutions and their faculty researchers innovators and graduate/undergraduate students in theSoutheast IDeA states region. The ultimate aim of these entrepreneurship education and training productsis to foster the translation of promising biomedical discoveries and technologies from research laboratoriesinto the creation of commercial products which both improve human health and promote economic growth.As a result it will significantly enhance commercialization knowledge mature the entrepreneurialecosystem identify more market-ready technologies and patents see more startup entities formed increasedilutive and non-dilutive funding to these entities and accelerate the commercialization of biomedical andhealth tech innovations in the region  with the fundamental goal of positively impacting human health andpatients lives.


application_id: 10545222
project_number: 1R43DD001299-01A1
project_title: A sleep biomarker test for management of ADHD
administering_ic: NCBDDD
award_notice_date: 2022-08-12
opportunity_number: PA-21-259
application_type: 1
activity_code: R43
ic: DD
serial_number: 001299
suffix: A1
program_official: OGUNFUYI, SHAKIRATU BIOLA
project_start_date: 2022-09-30
project_end_date: 2023-09-29
study_section: Special Emphasis Panel[ZRG1 ETTN-G (13)]
contact_pi_person_id: 14097488
contact_pi: BURNS, CHRISTOPHER THOMAS
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 012986391
primary_uei: ZFN5J433DCT1
duns_number: 012986391
uei: ZFN5J433DCT1
fips: US
organization_id: 10019586
organization_name: PGXL TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40206
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY PGXL Technologies is developing the Uromarker test for rapid screening of obstructive sleep apnea(OSA) and sleep disordered breathing that may contribute to attention deficit hyperactivity disorder (ADHD) inchildren. ADHD is the most common behavioral disorder in children and has significant effects on short- andlong-term outcomes including poor education performance increased risk of substance abuse and reducedoccupational success amongst others. Recent research has identified that as many as 70% of patients withADHD have mild to severe sleep problems. Daytime behavioral symptoms seen in OSA and sleep disorderedbreathing share many similarities with the clinical manifestations of ADHD including impaired attention regulationoveractivity mood lability behavior problems poor impulse control and prolonged reaction time. The associationbetween sleep problems and ADHD are likely complex and multidirectional but there is increasing evidence thatdemonstrates treatment of OSA may decrease or even eliminate ADHD symptoms. Treatment of OSA with standard approaches such as adenotonsillectomy has been associated withdecreased ADHD symptoms up to a year after treatment. Identification of patients with OSA in the context ofADHD will therefore aid in determining the more appropriate first step in the multi-modal approach to treatmentof ADHD. Unfortunately OSA and sleep disturbances in children are only diagnosed with polysomnography teststhat are expensive require overnight sleep studies and often have long wait times for patients to receive thetest. These tests are not routinely considered in ADHD work-up. The development of a rapid screening test forOSA and sleep disordered breathing will provide significant clinical value in the diagnostic clarification of ADHD. To address this need PGXL Technologies is developing the Uromarker test a rapid multiplexed test thatuses 4 biomarkers present in urine to efficiently and cost-effectively identify OSA or sleep disordered breathingin children. These biomarkers when used in combination have previously been shown to have 100% sensitivityand 96.5% specificity for detection of OSA in children compared to healthy primary snoring controls. PGXLTechnologies has the patent to these biomarkers and in this Phase I proposal PGXL will develop thesebiomarkers into a multiplexed high-throughput assay using all 4 biomarkers and will analytically characterize theassay. The stability of the biomarkers in urine will also be demonstrated to show feasibility for a mail-in urinecollection kit that will enable identification of OSA and sleep disordered breathing in children towards supportingADHD diagnosis.

public_health_relevance:
PROJECT NARRATIVEEmerging evidence strongly suggests that obstructive sleep apnea (OSA) or sleep disordered breathing mayexacerbate symptoms of attention-deficit hyperactivity disorder (ADHD) in a subset of the population andtreatment of OSA may mitigate ADHD symptoms. PGXL Technologies is developing rapid screening assays thatcan identify ADHD-related OSA or sleep disturbances to support the ADHD diagnostic process in children.Success with this technology can decrease the chance of misdiagnosing ADHD as well as enable targeted non-pharmacologic interventions such as surgery or dental procedures to be considered as alternatives to routineuse of stimulants and non-stimulants for ADHD management.


application_id: 10545018
project_number: 5F32HL149140-03
project_title: Deciphering the Relationship Between Cardiomyocyte Metabolic Configuration and Cell Cycle Re-entry
administering_ic: NHLBI
award_notice_date: 2022-12-31
opportunity_number: PA-19-188
application_type: 5
activity_code: F32
ic: HL
serial_number: 149140
program_official: WANG, WAYNE C
project_start_date: 2021-01-01
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1-F10A-K(20)L]
contact_pi_person_id: 15737705
contact_pi: ABOULEISA, RIHAM RAAFAT ELGHARIB
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:
Myocardial infarction causes irreversible loss of cardiomyocytes (CMs) and often leads to heart failure. Toreplace the lost cells we identified a combination of cell-cycle regulators that induces stable cytokinesis in adultpost-mitotic cells. Overexpression of cyclin-dependent kinase 1 (CDK1) CDK4 cyclin B1 and cyclin D1 (referredto as 4F) promotes cell division in post-mitotic mouse rat and human cardiomyocytes. The high efficiency ofthis protocol in inducing myocyte renewal provides new opportunities for understanding the mechanisms involvedin cardiomyocyte proliferation. One of the most interesting findings related to this discovery was the confirmationof a link between metabolic reprogramming and cardiomyocyte proliferation. Although in proliferating cells thereis a strong correlation between metabolic changes and cellular proliferation it remains unclear how metabolisminfluences the proliferative potential of cardiomyocytes. During the past 2 years in collaboration with Dr. Hillsgroup I have generated preliminary data which indicate that cardiomyocyte proliferation is associated withmarked reprogramming in energy metabolism. In proliferating cardiomyocytes isolated from lineage tracing(MADM) mice RNA-seq data indicate profound downregulation of fatty acid oxidation genes and upregulation ofbiosynthetic pathway enzyme expression; in human iPSC-derived cardiomyocytes (hiPSC-CMs) 4F expressiondecreases mitochondrial respiration and catabolic activities. Using stable isotope-resolved metabolomics(SIRM) we demonstrate that 4F-infected hiPS-CMs show significant elevation in 13C labeled intermediates orend products of the hexosamine biosynthetic pathway (HBP) serine biosynthesis pathway (SBP) and pentosephosphate pathway (PPP). In line with these findings our results also demonstrate that augmenting the carbonavailability for these biosynthetic pathways by overexpressing phosphoenolpyruvate carboxykinase (PCK1 orPCK2) augments the ability of cardiomyocytes to proliferate. These data suggest that higher biosyntheticpathway flux may be required for cardiomyocyte proliferation. Informed by these results we propose the generalhypothesis that activation of ancillary biosynthetic pathways of glucose metabolism are required forcardiomyocyte proliferation. We suggest that higher biosynthetic pathway flux is required for building blocksynthesis and may be important for regulating pro-proliferative gene programs. During this project we willdelineate the importance of each biosynthetic pathway in influencing cardiomyocyte proliferation. First usingpharmacological and virus-based approaches we will determine the specific contribution of the HBP SBP andPPP pathways to myocyte proliferation. In addition we will investigate the influence of increasing the carbon fluxin biosynthetic pathway through overexpression of PCK1 or PCK2 on cardiac function and repair in vivo. Theaims of this project are: Specific Aim 1: Delineate the contribution of each biosynthetic pathway on cardiomyocyteproliferation. Specific Aim 2: Investigate the functional efficacy of increasing carbon flux in biosynthetic pathwayson cardiac repair in vivo.

project_terms:
Adult;Affect;Anabolism;CDC2 gene;CDK4 gene;Carbon;Cardiac Myocytes;Cell Cycle;Cell Cycle Regulation Pathway;Cell Proliferation;Cell division;Cells;Collaborations;Cyclin D1;Cytokinesis;Data;Development;Down-Regulation;Echocardiography;Energy Metabolism;Fetus;Foundations;Gene Expression Regulation;Genes;Heart;Heart Diseases;Heart failure;Hexosamines;Hip region structure;Histology;Human;Infarction;Knowledge;Label;Link;Metabolic;Metabolism;Mitochondria;Modeling;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Pathway interactions;Patients;Pentosephosphate Pathway;Phosphoenolpyruvate Carboxylase;Proliferating;Protocols documentation;Rattus;Respiration;Salamander;Serine;Technology;Up-Regulation;Viral;Virus;Zebrafish;cardiac repair;cyclin B1;enzyme pathway;fatty acid oxidation;glucose metabolism;heart function;in vivo;induced pluripotent stem cell derived cardiomyocytes;metabolomics;mouse model;novel strategies;novel therapeutics;overexpression;pharmacologic;postmitotic;programs;stable isotope;transcriptome sequencing

public_health_relevance:
The muscle cells in the adult heart are not able to regenerate themselves which made itdifficult to treat heart disease; however in human fetuses zebrafish and salamanderthe heart muscle is able to regenerate. Here we are using cutting edge technologies tounderstand why the fetuses but not adults are able to regenerate their hearts. Thisunderstanding will allow the development of novel therapies to regenerate the deadheart muscle in heart failure patients.


application_id: 10544845
project_number: 1R43OD032088-01A1
project_title: A novel rat sperm cryopreservation and artificial insemination system
administering_ic: OD
award_notice_date: 2022-09-06
opportunity_number: PAR-21-225
application_type: 1
activity_code: R43
ic: OD
serial_number: 032088
suffix: A1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2022-09-15
project_end_date: 2024-09-14
study_section: Special Emphasis Panel[ZRG1 EMNR-K (11)]
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
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. Feasibility of the RAISwill be proven in the following Aims; 1) optimize the Cryodropper for rat sperm cryopreservation 2) manufactureand test the MED for motile sperm enrichment and recovery and 3) manufacture and test the rat NSID devicewith fresh and cryopreserved sperm. The system will provide substantial cost savings versus contractedcryopreservation services and increase the simplicity and reliability of rat sperm cryopreservation procedures.RAIS will directly benefit the welfare of laboratory animals by reducing the number of animals kept in idlecolonies improving vivarium management options and protecting rat models from catastrophic loss due tonatural disasters genetic drift disease and breeding problems. RAIS is designed to provide both a reduction inanimal numbers and a refinement to minimize animal suffering and improve welfare; meeting the requirementsof 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;Contracts;Core Facility;Cost Savings;Cryopreservation;Device or Instrument Development;Devices;Disease;Embryo Transfer;Female;Fertilization in Vitro;Freezing;Funding Opportunities;Generations;Genetic Drift;Goals;Health;Horns;Human;Insemination;Laboratory Animal Models;Laboratory Animal Production and Facilities;Laboratory Animals;Laboratory Procedures;Maintenance;Methods;Modeling;Mouse Strains;Mus;Natural Disasters;Operative Surgical Procedures;Physiology;Procedures;Process;Rat Strains;Rattus;Recovery;Research Personnel;Rodent;Sampling;Services;Sperm Motility;System;Techniques;Technology;Testing;Toxicology;United States National Institutes of Health;Uterus;animal care;assisted reproduction;assistive reproductive technique;cell motility;cohesion;cost;design;drug development;embryo culture;experience;experimental study;improved;innovation;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: 10544314
project_number: 5R01AG066724-03
administering_ic: NIA
award_notice_date: 2023-01-19
opportunity_number: PA-17-088
application_type: 5
activity_code: R01
ic: AG
serial_number: 066724
program_official: GAO, HONGWEI
project_start_date: 2021-01-01
project_end_date: 2025-11-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: KOSMAC, KATE
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-12-01
project_title:
Novel gastrocnemius muscle characteristics in peripheral artery disease patients associated with impaired functional performance

project_abstract:
Lower extremity peripheral artery disease (PAD) significantly affects aging populations and results in functionalimpairment. Although the clinical importance of finding efficacious interventions for PAD is well-recognized fewmedical therapies are currently available. PAD is diagnosed using the ankle brachial index (ABI) a measure ofblood flow to the lower extremities. Lower ABI is associated with worse function; however low ABI alonecannot fully explain functional impairments in PAD. Small studies have reported oxidative stress mitochondrialdysfunction and/or fiber damage in gastrocnemius muscle biopsies from PAD patients suggesting skeletalmuscle perturbations may contribute to functional decline. We reported highly variable fiber type compositionand fiber type grouping in a small cohort of PAD patients and observed lack of intermyofibrillar mitochondria(IMFM-) in oxidative myosin heavy chain (MyHC) type I fibers. We have provocative new preliminary datasuggesting variability in response to ongoing denervation and in fiber type and mitochondrial adaptations withPAD. The purpose of this study is to define specific characteristics of muscle in PAD associated with impairedwalking performance through detailed immunohistochemical analyses of 400 baseline gastrocnemius musclebiopsies stored in the Northwestern biorepository collected from 9 different clinical trials. This biorepository ofmuscle from PAD patients is one-of-a-kind and is associated with detailed clinical and functional characteristicsof the donors. We hypothesize that variability in fiber size fiber type and mitochondrial adaptations in responseto ischemia-reperfusion damage and denervation in individuals with PAD will have value in predicting walkingimpairment. In Aim 1 we will quantify the proportion of IMFM- areas in type I fibers with normal type I MyHCabundance or accumulation of type IIX MyHC and/or LC3 a marker of autophagy and determine associationswith fiber type composition and fiber size as well as relationships of muscle features to walking performance inPAD. We hypothesize that LC3 will co-localize with IIX MyHC in IMFM- areas suggesting both incompleteautophagic clearance of IIX MyHC and mitochondrial biogenesis during fiber transition from type IIX to type Ias a result of denervation and reinnervation. In Aim 2 we will quantify denervated NCAM+ fibers and fiberswith elevated oxidative damage markers by fiber type. We hypothesize that denervation in PAD willpreferentially affect fibers expressing IIX MyHC and that only IMFM- areas that accumulate IIX MyHC will beNCAM+. In Aim 3 we will perform predictive modeling of PAD disease severity and functional impairment usingmorphological characteristics of muscle quantified in Aims 1 and 2 as biomarkers in conjunction withsupervised classification approaches. In Aim 4 we will test the hypothesis that baseline muscle characteristicswill predict longitudinal functional outcomes at 6-month follow up. This model will provide a powerful tool toaide in identifying biologic processes for targeted interventions and to assess the mechanism of action andeffectiveness of current pharmacological and exercise interventions in ongoing PAD clinical trials.

project_terms:
Affect;Aging;Ankle;Area;Atrophic;Autophagocytosis;Biogenesis;Biological Markers;Biological Process;Biological Specimen Banks;Biopsy;Blood flow;Characteristics;Classification;Clinical;Clinical Trials;Data;Defect;Denervation;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Effectiveness;Fiber;Foundations;Future;Gastrocnemius Muscle;Goals;Grouping;Impairment;Individual;Injury;Intervention;Ischemia;Lower Extremity;Measures;Medical;Mitochondria;Modeling;Morphology;Motor Neurons;Muscle;Muscle Fibers;Myopathy;Myosin Heavy Chains;Myosin Type I;NCAM1 gene;Outcome;Oxidative Stress;Participant;Pathology;Patients;Performance;Perfusion;Peripheral arterial disease;Persons;Phase;Population;Property;Proteins;Reperfusion Injury;Reperfusion Therapy;Reporting;Sampling;Severity of illness;Skeletal Muscle;Testing;Theoretical model;Training;Walking;biobank;cohort;coping;disability;efficacious intervention;exercise intervention;follow-up;functional decline;functional disability;functional improvement;functional outcomes;improved;indexing;mitochondrial autophagy;mitochondrial dysfunction;novel;oxidative damage;pharmacologic;predictive modeling;preservation;prevent;reinnervation;response;tool

public_health_relevance:
Peripheral artery disease (PAD) significantly affects aging populations and results in functional impairment andmobility loss. Few medical therapies are currently available to treat PAD because the underlying pathology incalf muscle is not understood. The goal of this study is identify aberrant properties of muscle to aide in thedevelopment of new targeted interventions to improve walking ability in individuals with PAD.


application_id: 10544036
project_number: 5R01ES033767-02
project_title: Phthalate-Induced Dysregulation of Prostaglandin and Angiogenic Function During Ovulation in Women
administering_ic: NIEHS
award_notice_date: 2022-11-01
opportunity_number: RFA-ES-21-001
application_type: 5
activity_code: R01
ic: ES
serial_number: 033767
program_official: SCHUG, THADDEUS
project_start_date: 2022-01-01
project_end_date: 2026-10-31
study_section: ZES1-LAT-S(R1)
contact_pi_person_id: 12252020
contact_pi: HANNON, PATRICK RYAN
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThis ONES award will elucidate the mechanisms by which phthalates a class of endocrine-disrupting chemicalsdisrupt prostaglandin and angiogenic function during the critical period of ovulation. Further rescue approacheswill be investigated to alleviate phthalate-induced inhibition of ovulation and fertility which is crucial forenvironmental and reproductive health as exposure to phthalates is unavoidable. Phthalates are incorporated inseveral common consumer medical housing and personal care products leading to daily human exposure.However little is known about the effects of environmentally relevant levels and mixtures of phthalates onovulation especially in women. This is alarming because defects in ovulation are the leading cause of femaleinfertility. The abundant increase of prostaglandins in the ovary and the surge of new vasculature formation viaangiogenesis are vital for ovulation and fertility. Preliminary data for this proposal are the first to show that anenvironmentally relevant phthalate mixture decreases the levels of prostaglandins and factors that driveangiogenesis in human and mouse ovarian samples. Further the phthalate mixture decreased ovulation ratesby 96% in mouse samples. These findings suggest that environmentally relevant phthalate exposure targetsovulatory prostaglandin and angiogenic action which may cause infertility. Our compelling preliminary data alsosuggest that supplementation with cyclic adenosine monophosphate a common cell signaling molecule tohuman ovarian cells may rescue the phthalate-induced decreases in ovulatory prostaglandin and angiogenicfactor levels. A major strength of this proposal is our ability to mimic human exposure to phthalates by the useof environmentally relevant phthalate mixtures and human ovarian models. These models as well as in vivo andin vitro mouse models will be used to test the hypothesis that phthalates inhibit ovulatory prostaglandinproduction and function leading to impaired angiogenesis and ovulatory failure/infertility. Specific Aim 1 willelucidate the mechanism by which phthalates decrease ovulatory prostaglandin levels. Specific Aim 2 willdetermine the deficiencies in angiogenesis ovulation and fertility caused by phthalates. Specific Aim 3 will defineapproaches to alleviate phthalate toxicity. These findings will advance environmental health sciences byproviding mechanistic data establishing the impact of environmentally relevant phthalate mixture exposure onprostaglandin and angiogenic function which are essential mediators for fertility. Thus these findings will revealnovel actions of phthalates on infertility and reproductive dysfunction. Additionally the use of human samplesand the establishment of rescue approaches provide a translational approach to understanding and mitigatingphthalate toxicities. Infertility in women seeking to conceive leads to a decreased quality of life includingincreased levels of stress diminished social functioning and mental and physical health issues. By delineatingthe detrimental impacts of phthalate exposure on ovulation and fertility the overarching goal of this proposal isto provide a foundation to benefit womens reproductive and general healthcare.

project_terms:
Agonist;Angiogenesis Inhibition;Angiogenic Factor;Animal Model;Award;Biological Assay;Blood capillaries;Cell Proliferation;Cell model;Cells;Chemicals;Couples;Cyclic AMP;Cyclooxygenase Inhibitors;Data;Defect;Dose;Endocrine Disruptors;Endothelial Cells;Ensure;Environment;Environmental Health;Exhibits;Exposure to;FGF2 gene;Failure;Female infertility;Fertility;Fertility Rates;Foundations;Functional disorder;Goals;Healthcare;Housing;Human;Impairment;In Vitro;Infertility;Link;Literature;Mediator;Medical;Mental Health;Metabolism;Modeling;Mus;Nature;Non-Steroidal Anti-Inflammatory Agents;Oocytes;Outcome;Ovarian;Ovarian Follicle;Ovarian Granulosa Cell;Ovary;Ovulation;Ovulation Inhibition;PTGS2 gene;Parents;Pathway interactions;Pregnant Women;Prevalence;Process;Production;Proliferating;Prostaglandin Inhibition;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Public Health;Quality of life;Reproductive Health;Research;Rodent Model;Sampling;Signal Transduction;Signaling Molecule;Social Functioning;Societies;Stress;Supplementation;Testing;Time;Toxic effect;VEGFA gene;Woman;Women's Health;Work;angiogenesis;cost;critical period;exposed human population;granulosa cell;human model;in vivo;migration;mouse model;novel;personal care products;phthalates;physical conditioning;prevent;receptor;reproductive;translational approach;urinary

public_health_relevance:
PROJECT NARRATIVEExposure to phthalates a class of chemicals that humans are unavoidably exposed to on a daily basis isincreasingly being recognized as contributing to the prevalence of infertility in which defects in ovulation are theleading cause of infertility in women. The proposed research will address this public health concern by providinga more complete understanding of how phthalates inhibit prostaglandins and angiogenesis which are essentialfor ovulation and fertility in women. Because infertility in women seeking to conceive leads to impairments intheir physical and mental health the overarching goal of this proposal is to establish novel rescue approachesto alleviate phthalate-induced reproductive dysfunction and infertility.


application_id: 10543182
project_number: 5K08DK124566-03
project_title: Muscle bone interaction and its role in diabetic bone disease of Type I diabetes
administering_ic: NIDDK
award_notice_date: 2022-12-13
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: DK
serial_number: 124566
program_official: MALOZOWSKI, SAUL N
project_start_date: 2021-03-01
project_end_date: 2025-12-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 14779143
contact_pi: KALAITZOGLOU, EVANGELIA
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Summary Bone fracture incidence observed in individuals with Type 1 diabetes (T1D) is much higher compared tothe general population. The burden of diabetic bone disease is partially due to lack of evidence to supporttargeted prevention and interventions to reduce fractures in this population. Furthermore those with T1Dexhibit skeletal muscle dysfunction associated with decreased muscle strength and muscle mass. Skeletalmuscle and bone communication is a potential modifiable factor that may contribute to development of diabeticmusculoskeletal disease. More specifically the candidate proposes that a myokine called myostatin is directlyinvolved in development of diabetic bone disease and may associate with skeletal muscle dysfunction. Therole of myostatin in T1D and how it affects the musculoskeletal system in this disease are gaps in knowledgethat will be addressed with this proposal. Specifically the three aims of this proposal are: 1. Quantify therelationship between myostatin levels in serum and skeletal muscle and bone parameters of humans with andwithout T1D; 2. Quantify the relationship between myostatin levels in serum and muscle and the bonephenotype of mice with insulin-deficient diabetes; 3. Evaluate whether inhibition of myostatin is beneficial forprevention of DBD in insulin-deficient diabetes; and lastly 4: Determine the mechanism of action of myostatinon osteoblastic bone cells under normoglycemic and hyperglycemic conditions. Myostatin which is thought tonegatively affect both bone and skeletal muscle may serve both as a marker of musculoskeletal function andsurrogate for risk for fracture in those with T1D. Additionally it may offer an opportunity for targetedintervention to prevent or improve musculoskeletal dysfunction associated with T1D. The knowledge gainedfrom these studies will set the ground for future studies in musculoskeletal health in diabetes and will offer thecandidate an opportunity to transition towards an independent career in the abovementioned field. This proposal presents a five-year research career development program focused on the study ofmuscle and bone interactions in Type 1 diabetes; and specifically how muscle derived molecules calledmyokines contribute to diabetic bone disease a serious and emerging complication of Type 1 diabetes. Thecandidate currently holds a position as an Assistant Professor of Pediatrics in the Division of PediatricEndocrinology at the University of Kentucky. She has 75% protected time for research independent officespace laboratory space and access to all equipment and resources offered by the Barnstable Brown DiabetesCenter. The candidate is strongly committed to an academic career in the field of musculoskeletal research indiabetes and is supported by her mentors and her department. The proposed study and the complementarydidactic work will provide the candidate with research skills in basic translational and clinical research therebyenabling to transition to an independent clinician scientist.

project_terms:
20 year old;Activin Receptor;Address;Affect;Age;Animal Model;Antibodies;Basic Science;Biopsy;Bone Density;Bone Marrow Stem Cell;Bone Resorption;Cell Line;Cells;Childhood;Clinical;Clinical Research;Communication;Complication;Complications of Diabetes Mellitus;Data;Development;Diabetes Mellitus;Disease;Endocrine;Endocrinology;Environment;Equipment;Exhibits;FRAP1 gene;Foundations;Fracture;Functional disorder;Future;GDF8 gene;Gene Expression;Gene Proteins;General Population;Genes;Health;Hip Fractures;Hip region structure;Human;Hyperglycemia;Impairment;In Vitro;Incidence;Incidental Findings;Individual;Insulin deficiency;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Knowledge;Laboratories;Life;MAP Kinase Gene;Measures;Mechanics;Mediating;Mediator;Mentors;Mus;Muscle;Muscle function;Musculoskeletal;Musculoskeletal Diseases;Musculoskeletal System;Nurses' Health Study;Osteoblasts;Osteocalcin;Osteocytes;Osteogenesis;Outcome;Pathway interactions;Pediatrics;Phenotype;Physical Capacity;Population;Population Study;Positioning Attribute;Prevalence;Prevention;Program Development;Relative Risks;Research;Resources;Risk;Roentgen Rays;Role;Sampling;Scientist;Serum;Signal Pathway;Signal Transduction;Skeletal Muscle;Skeletal bone;Time;Trabecular Bone Score;Translational Research;Universities;Upper Extremity Fracture;Work;bone;bone cell;bone fracture repair;bone imaging;bone mass;bone turnover;career;career development;clinically significant;cost;diabetic;diabetic bone disease;diabetogenic;fracture risk;high risk;improved;in vivo;mineralization;mouse model;muscle form;negative affect;novel;osteoblast differentiation;paracrine;pharmacologic;prevent;professor;prospective;receptor;reduced muscle mass;reduced muscle strength;skills;young adult

public_health_relevance:
Project NarrativeIndividuals with Type 1 diabetes have higher fracture rates and smaller and weaker muscles compared tothose without diabetes even in young ages. With this project we will try to identify whether a molecule thatcomes from skeletal muscle called myostatin is involved in the increased risk of fractures and the poor qualityof skeletal muscle in young individuals with Type 1 diabetes.


application_id: 10543155
project_number: 5R01GM144349-02
administering_ic: NIGMS
award_notice_date: 2022-12-06
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 144349
program_official: CHO, THOMAS Y
project_start_date: 2022-01-01
project_end_date: 2026-12-31
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 15235905
contact_pi: SABO, THOMAS MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-01
project_title:
Linking the conformational landscape to enzymatic function through functional site distant mutations

project_abstract:
An ongoing debate concerns the role conformational motions often termed dynamics play in biomolceularfuntion. For enzymes it so happens that the timescales for large-scale domain motions are similar to theapparent "$$). catalytic rate (!"# This observation is where the major point of contention has developed: do "$$. In this context the proposed studiesconformational motions directly impact the true rate of catalysis (!"#) or !"#will further explore how the modulation of the conformational landscape can indeed fine-tune "$$ without!"#impacting !"# and the ground state structure. The genesis of this proposal arises from our work with humanguanylate kinase (hGMPK) a potential therapeutic target for treating cancer and perhaps even SARS-CoV-2which motivated us to solve the first structure of hGMPK with nuclear magnetic resonance (NMR) spectroscopy(PDB: 6NUI). While solving the hGMPK structure we expressed a series of seven functional site distant (FSD) "$$ when compared to the wild-non-synonymous single nucleotide variants (nsSNVs) of hGMPK that enhance !"#type (wt). Intriguingly the 2D [1H15N]-HSQC NMR spectra of the wt hGMPK and its nsSNVs suggest that the ) for GMP binding toFSD mutations minimally impact hGMPKs backbone fold yet the apparent off-rates (wt and the FSD mutant V91M differ by ~3000 s-1. We hypothesize that hGMPKs activity can be modulated withFSD mutants by reshaping the conformational landscape. Utilizing NMR spectroscopy and isothermalcalorimetry we will test this hypothesis in the following two Specific Aims. In Aim 1 we will quantify the impactof the FSD mutations on the conformational landscape from kinetic and thermodynamic perspectives. The resultsfrom this Aim will provide a comprehensive picture as to where within the hGMPK catalytic and binding schemesthe FSD mutations have the largest impact on function. For Aim 2 we will deconvolute the contribution transientstructures within the conformational landscape play in enzymatic catalysis through experimentally drivenensemble generation. Our protocol will select hGMPK structures from unbiased molecular dynamics (MD)simulations based on residual dipolar couplings and cross-correlated relaxation rates measured with NMR. Theensembles will aid in the identification of the functionally important transient conformations and an assessmentof the impact the FSD mutations have on backbone dihedral correlated motions. To our knowledge this proposalprovides the first examples 1.) of experimentally driven ensemble generation for an enzyme spanningphysiologically relevant timescales and 2.) of determining thermodynamic and kinetic parameters with ligandbinding to the same exact site on a series of enzyme variants. The impact of this proposal is the direct linkageof the conformational landscape to enzymatic function. Immediate applications for these results include drugdiscovery where targeting structures within the conformational landscape rather than the ground state structurewill lead to better outcomes and biomolecular design where FSD mutations can be implemented to adjustfunction through manipulation of the conformational landscape.

project_terms:
2019-nCoV;Active Sites;Affect;Antineoplastic Agents;Architecture;Binding;Calorimetry;Catalysis;Cyclic GMP;DNA;Data;Development;Dissociation;Distant;Enzymes;Equilibrium;Future;Generations;Grant;Guanosine Triphosphate;Guanylate kinase;Human;Kinetics;Laboratories;Ligand Binding;Ligands;Link;Malignant Neoplasms;Measurable;Measures;Methods;Molecular Conformation;Motion;Muramidase;Mutation;NMR Spectroscopy;Nuclear Magnetic Resonance;Nucleosides;Nucleotides;Outcome;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physiological;Play;Probability;Production;Proteins;Protocols documentation;RNA;Rationalization;Regulation;Relaxation;Research Personnel;Residual state;Role;SARS coronavirus;SUMO1 gene;Sampling;Scheme;Series;Shapes;Single Nucleotide Polymorphism;Site;Structural Biologist;Structure;Testing;Therapeutic;Thermodynamics;Titrations;Ubiquitin;Variant;Vertebral column;Viral;Work;cancer cell;conformational conversion;design;drug discovery;enthalpy;inhibitor;molecular dynamics;mutant;small molecule inhibitor;therapeutic target;tool

public_health_relevance:
Human guanylate kinase (hGMPK) is an essential enzyme in the production of DNA and RNA making it apotential therapeutic target for cancer and SARS-CoV-2. We have shown that active site distant mutations arisingfrom non-synonymous single nucleotide variants of hGMPK enhance enzymatic catalysis without a perceptiblechange in the kinases backbone structure an apparent contradiction to the structure-function paradigm. Thisproposal investigates what is responsible for this catalytic enhancement from a rigorous kinetic andthermodynamic perspective the results of which will impact future approaches toward drug discovery andbiomolecular regulation through the direct linkage of enzymatic function to the conformational landscape.


application_id: 10542651
project_number: 3R01AI140758-05S1
project_title: Mechanisms of actin cytoskeleton modulation by Pneumoviruses
administering_ic: NIAID
award_notice_date: 2022-06-29
opportunity_number: PA-16-160
application_type: 3
activity_code: R01
ic: AI
serial_number: 140758
suffix: S1
program_official: KIM, SONNIE
project_start_date: 2018-06-01
project_end_date: 2024-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(02)M]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: LEUNG, DAISY W
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The actin cytoskeleton controls key cellular processes including cell morphology motility and intercellularcommunication. Many viral pathogens exploit the actin cytoskeletal machinery by a variety of uniquemechanisms to facilitate viral infection replication and egress. Currently the molecular underpinnings of theseviral mechanisms remain poorly defined for a majority of viruses including members of the Pneumoviridaefamily. Human respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are non-segmentednegative strand RNA viruses that are members of the recently created Pneumoviridae family. RSV and HMPVcause significant disease including bronchiolitis and lower respiratory tract infection in the pediatric populationelderly and immunocompromised individuals. Recent studies from our groups and others have implicatedinteractions between actin or actin-interacting proteins and specific pneumovirus proteins in replication andviral spread; however the mechanisms and cellular targets required for facilitating actin rearrangementsremain unknown. Our overall hypothesis is that a cascade of specific interactions between pneumovirusproteins and the actin cytoskeleton regulates key steps in viral infection including formation of novelstructures critical for virus cell-to-cell spread. Our collaborative team with expertise in virology cellbiology biochemistry and structural biology will test our hypothesis through three specific aims. First we willdissect the interactions between RSV and HMPV matrix (M) proteins and phosphoproteins (P) that regulate theactin cytoskeleton within an infected cell. Second we will determine the biochemical and structural basis forHMPV phosphoprotein/matrix/actin complex and RSV P/M/actin complex. Finally we will determine themechanisms of intercellular extension formation stabilization and utilization in viral spread. At the completionof these studies we expect to define molecular mechanisms by which RSV and HMPV interact with andmodulate the host actin cytoskeleton during virus replication define key elements needed for this modulationand understand the molecular details of cell-to-cell spread through intercellular extensions thus providingcritical new insights that may be applicable in multiple viral systems.

project_terms:
Actins;Address;Affect;Affinity Chromatography;Bacteria;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biological Models;Biophysics;Bronchiolitis;Calorimetry;Cell physiology;Cells;Cellular Morphology;Cellular biology;Childhood;Co-Immunoprecipitations;Complex;Coupled;Cytoskeletal Proteins;Cytoskeleton;Data;Deuterium;Disease;Dyes;Elderly;Elements;Family;Fluorescent in Situ Hybridization;Human;Human Metapneumovirus;Hybrids;Hydrogen;Immunocompromised Host;In Vitro;Individual;Infection;Life Cycle Stages;Ligation;Lower Respiratory Tract Infection;Mass Spectrum Analysis;Mediating;Microscopy;Modification;Molecular;Molecular Sieve Chromatography;Mutation Analysis;NMR Spectroscopy;Nature;Nucleocapsid;Pathogenesis;Phosphoproteins;Physiological;Play;Pneumovirus;Pneumovirus Infections;Population;Process;Proteins;RNA;RNA Viruses;Respiratory Syncytial Virus Infections;Respiratory Tract Infections;Respiratory syncytial virus;Role;Structure;System;Testing;Time;Titrations;Viral;Viral Proteins;Virus;Virus Diseases;Virus Replication;X-Ray Crystallography;airway epithelium;cell motility;cellular targeting;effective therapy;human pathogen;insight;intercellular communication;light scattering;member;mutant;new therapeutic target;novel;pathogenic virus;polymerization;respiratory pathogen;structural biology;therapeutic development;therapeutic target;viral RNA;virology

public_health_relevance:
Human metanpneumovirus and respiratory syncytial virus are important human respiratorypathogens with no safe and effective treatments to date. Viral infection and spread involvecontributions from the actin cytoskeleton but the mechanisms by which the actin cytoskeletonfacilitate these processes are not well understood. Our studies will provide molecular insightsand novel therapeutic targets that will lead to new treatment options against these humanpathogens.


application_id: 10542411
project_number: 5R01DK124112-04
administering_ic: NIDDK
award_notice_date: 2023-01-20
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 124112
program_official: SADUSKY, ANNA BURKART
project_start_date: 2020-01-10
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1-DKUS-P(02)]
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
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
budget_start_date: 2023-01-01
project_title:
The role of neutral ceramidase in acute kidney injury and its progression to chronic kidney disease.

project_abstract:
Summary:The long-term goal of this proposal is to develop novel therapeutics for a serious unmet medical need namelyacute kidney injury (AKI) and its progression to chronic kidney disease (CKD) for which there are no treatmentsother than supportive care. The mechanisms of kidney injury and its progression to CKD are largely unknownand this proposal aims to fill some of these knowledge gaps. The short-term goal of this proposal is to validatea novel target for treating AKI and its progression to CKD for future drug development. This target is neutralceramidase (NCD) an enzyme involved in metabolism of the sphingolipid ceramide. The proposal is based ona strong foundation of supporting preliminary data that indicates that mice lacking NCD are protected in modelsof AKI and CKD and in vitro data indicating that deletion or inhibition of NCD increases autophagy and protectscells from a variety of cellular stresses. Thus this proposal will test the hypothesis that deletion or inhibition ofNCD confers protection from AKI and injury-induced CKD via upregulation of autophagy. We will test thishypothesis with three interrelated but independent specific aims that will (1) determine the mechanism ofprotection of kidney cells in vitro from cellular stress when NCD is deleted or inhibited; (2) determine the role ofNCD in AKI; and (3) determine the role of NCD in kidney injury progression to CKD. Data obtained in this proposalwill provide many scientific and translational advances that are essential for achieving our long-term goal ofdeveloping therapeutics for this unmet medical need.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Apoptosis;Autophagocytosis;Biochemistry;Cancer Patient;Carboplatin;Cell Cycle;Cellular Stress;Ceramidase;Ceramides;Chronic;Chronic Kidney Failure;Cisplatin;Clinic;Cytoprotection;Data;Deterioration;Development;Diabetes Mellitus;Dialysis procedure;Dose;Dose Limiting;Elderly;Electrolytes;Ensure;Enzymes;FDA approved;Fibrosis;Foundations;Future;Goals;Grant;Homeostasis;Hour;In Vitro;Inflammation;Injury;Injury to Kidney;Kidney;Knowledge;Laboratories;Lead;Lipids;Liquid substance;Long-Term Effects;Magnesium;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Medical;Metabolic;Metabolism;Methodology;Modeling;Mus;Necrosis;Oncologist;Patients;Persons;Phase;Predisposing Factor;Process;Proliferating;Publishing;Recording of previous events;Recurrent disease;Regimen;Renal Replacement Therapy;Renal function;Reproducibility;Research;Risk;Role;Sodium Chloride;Sphingolipids;Supportive care;Testing;Therapeutic;Therapeutic Uses;Toxic effect;Treatment Protocols;Up-Regulation;analog;cancer type;comorbidity;design;drug development;in vivo;innovation;kidney cell;mortality;new therapeutic target;novel;novel therapeutics;stressor;therapeutically effective;wasting

public_health_relevance:
Acute kidney injury is an unmet medical need with no FDA approved treatments other than supportive care. Inaddition a history of prior kidney injury is a major risk for development of chronic kidney disease. The overallgoal of this proposal is to determine the role of neutral ceramidase in acute kidney injury and its progressionto chronic kidney disease.


application_id: 10542291
project_number: 1R01AA030487-01
administering_ic: NIAAA
award_notice_date: 2022-08-15
opportunity_number: RFA-AA-21-016
application_type: 1
activity_code: R01
ic: AA
serial_number: 030487
program_official: FREEMAN, ROBERT
project_start_date: 2022-08-15
project_end_date: 2027-05-31
study_section: Special Emphasis Panel[ZAA1 DD (17)]
contact_pi_person_id: 12488104
contact_pi: LAUCKNER, CAROLYN
other_pis: KERSHAW, TRACE S
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-15
project_title:
Evaluation of a Combined Motivational Interviewing and Ecological Momentary Intervention to Reduce Risky Alcohol Use among Sexual Minority Males and Transgender Individuals

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

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

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


application_id: 10542284
project_number: 1R01AA030485-01
administering_ic: NIAAA
award_notice_date: 2022-09-09
opportunity_number: RFA-AA-21-016
application_type: 1
activity_code: R01
ic: AA
serial_number: 030485
program_official: WANG, JOE
project_start_date: 2022-09-10
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZAA1 DD (17)]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: HARRIS, LESLEY BETH;KERR, JELANI
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-09-10
project_terms:
AIDS prevention;Address;Adherence;Adverse event;Affect;Alcohol abuse;Alcohol consumption;Alcohols;Ambulatory Care Facilities;Behavioral;Biological;Caring;Clinic;Clinical;Clinical Research;Continuity of Patient Care;Data;Data Collection;Decision Making;Early Intervention;Early treatment;Effectiveness;Event;Exhibits;Feedback;Goals;HIV;HIV Seronegativity;Health;Healthcare;Individual;Injury to Kidney;Internal Medicine;Intervention;Interview;Intestinal permeability;Kidney Diseases;Liver diseases;Longitudinal Studies;Longitudinal cohort study;Maintenance;Movement;Nausea and Vomiting;Outcome;Participant;Pathogenicity;Pattern;Persons;Pharmaceutical Preparations;Population;Process;Public Health;Qualitative Methods;Randomized;Randomized Controlled Trials;Reaction;Regimen;Research;Research Personnel;Risk;Structure;Subgroup;Time;Treatment Effectiveness;Triage;Universities;alcohol measurement;alcohol misuse;alcohol risk;appetite loss;attenuation;dysbiosis;effectiveness testing;enteric dysbiosis;experience;gastrointestinal;gut dysbiosis;gut microbiome;gut-liver axis;inflammatory marker;intestinal homeostasis;liver function;liver injury;microbial;microbial community;pre-exposure prophylaxis;prevent;recruit;reduced alcohol use;research study;screening;screening brief intervention referral and treatment;side effect;systemic inflammatory response;transmission process;treatment as usual;treatment program;uptake


application_id: 10541154
project_number: 5K01DK116923-05
project_title: Social Network Analysis and Social Support Intervention for Rural Dwelling Older Adults with T2DM
administering_ic: NIDDK
award_notice_date: 2023-01-04
opportunity_number: PAR-18-418
application_type: 5
activity_code: K01
ic: DK
serial_number: 116923
program_official: SPAIN, LISA M
project_start_date: 2019-01-01
project_end_date: 2024-03-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
7. PROJECT SUMMARY/ABSTRACT Approximately 29.1 million (9.3%) adults in the US have type 2 diabetes (T2DM).1 T2DM is associatedwith significant complications including premature coronary artery disease kidney disease stroke andblindness.1 Estimates show that prevalence of T2DM is 17% higher in rural dwellers compared to their urbancounterparts.2 For example the prevalence of T2DM for adults in Kentucky's rural Appalachian counties is13.6%3 compared to the overall state prevalence of 10.6% 3. Appropriate self-care behaviors are necessary foroptimal clinical outcomes in T2DM 4-6 and account for 90% of the variance in glycemic control 7. Yet self-careamong T2DM is notoriously poor in general and even worse in rural-dwellers. Without attention to improvingself-care in this population we are facing an epidemic of T2DM complications in rural areas of the US. The impact of living with T2DM in rural communities is compounded in the aging population. Theprevalence of T2DM increases with age and an estimated 25% of older adults (65 years) have T2DM 8. Olderadults living with T2DM have more difficulty than younger people adhering to self-care regimens andsocial/environment factors account for up to 85% of their self-care nonadherence.69-13 Notablesocial/environment factors include competing social demands lack of social support (SS) and stress.14-17 Socialsupport plays a particularly significant role in older adults with T2DM. The extent and type of SS available inrural communities can positively or negatively impact self-care in those diagnosed with T2DM. 18-25 To better understand the effects of the social environment in communities where older rural dwellingadults reside and to lay the foundation for interventions social network analysis (SNA) will be used to determinesocial support network structures. By using SNA social support structures can be developed and relationshipsbetween individuals within a social network can be evaluated. 26 The overall objective of this study is to improveT2DM self-care regimens in older rural dwelling adults by training influential community members to becommunity health workers and provide social support strategies within an older adults' existing social networkthat promotes T2DM self-care.The proposed study seeks to: Aim 1Use social network analysis to identify key players in a rural community to serve as communityhealth workers for those living with T2DM.Aim 2Use mixed methods to evaluate the impact of social support on T2DM self-care and clinicaloutcomes and evaluate social networks in rural dwelling older adults with T2DM.Aim 3Test the feasibility and preliminary effectiveness of a 6-week intervention administered bycommunity health workers with the support of members of older adults' individual social network.

project_terms:
Address;Adherence;Adult;Affect;Age;Aging;Attention;Behavior;Blindness;Blood Pressure;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Coronary Arteriosclerosis;County;Decision Making;Diabetes Mellitus;Diagnosis;Disease;Education;Effectiveness;Elderly;Environment;Epidemic;Exposure to;Foundations;Geriatrics;Glycosylated hemoglobin A;Health Food;Health Personnel;Health behavior;High Prevalence;Individual;Influentials;Intervention;Interview;Kentucky;Kidney Diseases;Knowledge;Life Expectancy;Maps;Medical Records;Methods;Morbidity - disease rate;Neighborhoods;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway Analysis;Persons;Play;Population;Positioning Attribute;Poverty;Prevalence;Quality of life;Regimen;Research;Research Personnel;Risk;Role;Rural Appalachia;Rural Community;Self Care;Social Environment;Social Network;Social support;Source;Stress;Stroke;Structure;Surveys;Syndrome;Training;United States National Institutes of Health;aging population;blood lipid;cognitive function;diabetes management;diabetes self-management;disease transmission;empowerment;experience;fall risk;feasibility testing;frailty;glycemic control;health care service;health communication;health literacy;improved;individual patient;innovation;member;negative affect;post intervention;premature;programs;recruit;rural area;rural dwellers;rural residence;sarcopenia;social;social competition;statistics

public_health_relevance:
8. PROJECT NARRATIVEWith the high prevalence of type 2 diabetes (T2DM) and an aging population with low adherence to self-careregimens I seek to improve T2DM self-care in older rural dwelling adults. Social network analysis will be usedto identify individuals who are influential in their community who can be trained as community health workersas well as identify individuals within an older rural dwelling adult's personal network who can form a dyad withthe older adult and serve as a facilitator for adherence to T2DM self-care regimen via social support. These dyadswill participate in a 6-week T2DM self-care intervention with a booster session at 6 months post-intervention.


application_id: 10540718
project_number: 5R01NS103785-05
project_title: Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2022-11-30
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: NS
serial_number: 103785
program_official: AWWAD, HIBAH OMAR
project_start_date: 2018-12-15
project_end_date: 2024-11-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
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:
ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following atraumatic brain injury (TBI) and substantial evidence suggests therapies targeting the interleukin-1 receptor(IL-1R1) pathway may control neuroinflammation. Despite the promise there have been limited attempts tomove anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. We hold that a critical reason for the lackof progress on this promising target is the incomplete understanding of the mechanistic underpinnings of IL-1signaling after a TBI. It is well-recognized that the clinical picture of TBI is a spectrum of different primary injurymechanisms and injury severities and that it is necessary to understand the secondary injury mechanism asthey relate to the primary injury. Over 75% of TBIs are classified as mild. While not all TBIs lead toneurodegeneration a mild TBI can result in progressive brain atrophy and persistent cognitive dysfunction andis a known risk factor for the development of Alzheimers disease and related dementias. The currentknowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury.Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling and our model ofmild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge bytesting the role of IL-1R1 following a mild TBI and for the first time define a cellular mechanism for thepathological effects of IL-1R1 following a mild TBI. Importantly our exciting preliminary data has uncovered acritical role for the brain endothelium in regulating neuroinflammation which is dependent on IL-1R1. Ourpreliminary results have led us to propose the overall hypothesis: Secondary neuronal injury following amild TBI is driven by neuroinflammation and vascular dysfunction which can be reduced throughsuppression of IL-1R1. The actions of IL-1R1 following a mild TBI will require the involvement ofendothelial cells. We will test our hypothesis in the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mildTBI and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our resultswill fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotectionafter a mild TBI and potential for other disease associated with neuroinflammation (i.e. Alzheimers disease).

project_terms:
Acute;Alzheimer's Disease;Alzheimer's disease related dementia;Attenuated;Blood Vessels;Brain;Cells;Central Nervous System Diseases;Chronic;Classification;Clinical;Closed head injuries;Data;Development;Disease;Electrophysiology (science);Endothelial Cells;Endothelium;Extravasation;FDA approved;Failure;Functional disorder;Generations;Genetic;Goals;Immunosuppressive Agents;Impaired cognition;Impairment;Inflammation;Inflammatory;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Knockout Mice;Knowledge;Lead;Learning;LoxP-flanked allele;Memory;Modeling;Molecular;Mus;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neuronal Injury;Outcome;Pathologic;Pathway interactions;Patient-Focused Outcomes;Pharmaceutical Preparations;Public Health;Radial;Receptor Signaling;Regulation;Residual state;Risk Factors;Role;Severities;Signal Transduction;Synapses;Synaptic plasticity;Testing;Time;Traumatic Brain Injury;Vascular Diseases;Vascular remodeling;Vertebral column;arm;blood-brain barrier permeabilization;brain endothelial cell;cell type;central nervous system injury;cerebral atrophy;density;immune modulating agents;improved;mild traumatic brain injury;mouse model;neuroinflammation;neuroprotection;novel;response;restoration;severe injury;targeted treatment;water maze

public_health_relevance:
PROJECT NARRATIVEEmerging evidence suggests that selective modulation of neuroinflammation is a promising avenue forimproving patient outcomes following a traumatic brain injury (TBI). We have recently demonstrated thatinterleukin-1 receptor (IL-1R1) pathway may control neuroinflammation at the level of the blood vesselproviding evidence of an underappreciated mechanism of how the brain becomes inflamed after a TBI. In thisproject we propose to determine the role of endothelial IL-1R1 after experimental mild TBI with the goal ofproviding the knowledge necessary to enable the development of selective modulators of neuroinflammationfor TBI.


application_id: 10539590
project_number: 1R01DA055872-01A1
administering_ic: NIDA
award_notice_date: 2022-08-10
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: DA
serial_number: 055872
suffix: A1
program_official: GOLDSTEIN, AMY B
project_start_date: 2022-08-15
project_end_date: 2027-06-30
study_section: Health Promotion in Communities Study Section[HPC]
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Kentucky Outreach Service Kiosk (KyOSK): Reducing HIV HCV and Overdose Risk in Rural Appalachia through Harm Reduction Kiosks

project_abstract:
AbstractThe proposed project will test an innovative approach to reducing harms related to the epidemics of injectiondrug use overdoses hepatitis C (HCV) and to imminent HIV outbreaks in rural Appalachian Kentucky whichhas long been an epicenter of these intertwined crises. Our research has shown that the region has high ratesof HCV overdose injection drug use condomless sex and dense risk networks that could kindle an HIVoutbreak. Following a 2014 HIV outbreak in neighboring Indiana and a national analysis of HIV/HCV outbreakvulnerability among people who inject drugs (PWID) revealing that 54 of Kentuckys 120 counties ranked in thetop 5% nationally Kentucky passed landmark legislation permitting counties to operate syringe serviceprograms (SSPs). Despite an arduous county-level approval process Kentucky has succeeded in opening 80SSPs more than any other U.S. state. Unfortunately this robust harm reduction infrastructure remains under-utilized in rural settings. Data from our research funded by NIDAs National Rural Opioid Initiative revealed thatnearly half of PWID had never used the existing staffed SSPs and over 24 months of follow-up SSP uptakeremained low and program drop-out was not uncommon. The most frequent reason cited for having neverused an SSP was fear of stigma. Evidence suggests that PWID in the region want a range of harm reductionservice models and among those who report stigma as a reason for not using the staffed SSPs the mostdesired model is a vending machine or kiosk. Harm reduction kiosks have been operating globally for morethan 30 years and research has demonstrated that they can expand syringe access. Yet very few kiosksoperate in the U.S. and none operate in rural areas where they might be especially beneficial. Researchsuggests that kiosks might be a cost-effective way to expand syringe access when coupled with staffed SSPsbut their implementation impact and cost-effectiveness have not been rigorously evaluated. In response wepropose a type 1 hybrid effectiveness trial to test the effectiveness implementation outcomes and costeffectiveness of a community-tailored harm reduction kiosk in reducing HIV hepatitis C and overdose riskbehavior in rural Appalachia. Our kiosk or KyOSK (KY Outreach Service Kiosk) will be supplied withinjection equipment naloxone fentanyl test strips hygiene kits condoms and other supplies as well as aninnovative call-back feature for facilitated referral to needed services by trained recovery coaches. The KyOSKwill be tailored to the local context through a community-engaged process and a Kiosk Design Team involvingpeople who use drugs and local and state leaders. Interest in reduction kiosks is soaring nationwide and theproposed project would provide critical and timely data to inform scale-up of this model especially in ruralareas of the country that have been severely impacted by substance use related harms.

project_terms:
Appalachian Region;COVID-19;Callback;Communities;Country;County;Coupled;Data;Diagnosis;Disease Outbreaks;Dropout;Drug user;Effectiveness;Epidemic;Epidemiology;Equipment;Fentanyl;Fright;Funding;HIV;HIV/HCV;Harm Reduction;Health;Hepatitis C;Hepatitis C Therapy;Hepatitis C Transmission;Home;Hour;Huntington Disease;Hybrids;Hygiene;Indiana;Infrastructure;Injecting drug user;Injections;Judgment;Kentucky;Laws;Letters;Medicaid;Methods;Modeling;Naloxone;Names;National Institute of Drug Abuse;Needle-Exchange Programs;Nevada;Opioid;Overdose;Persons;Pharmaceutical Preparations;Plant Roots;Process;Puerto Rico;Qualitative Research;Recording of previous events;Recovery;Reporting;Research;Research Infrastructure;Resources;Risk;Risk Behaviors;Rural;Rural Appalachia;Science;Service delivery model;Services;Sorbus;Statutes and Laws;Surveys;Syringes;Testing;Time;Training;Transportation;Unsafe Sex;West Virginia;austin;base;cohort;condoms;cost effective;cost effectiveness;design;effectiveness testing;effectiveness trial;experience;flexibility;follow-up;implementation evaluation;implementation outcomes;improved;injection drug use;innovation;interest;lectures;outreach services;overdose death;overdose risk;programs;response;rural area;rural setting;scale up;social stigma;substance use;test strip;uptake

public_health_relevance:
NarrativeThe proposed study will test the effectiveness implementation outcomes and cost effectiveness of acommunity-tailored harm reduction kiosk in reducing HIV hepatitis C and overdose risk behavior in ruralAppalachia. The proposed project will take place in two counties in Appalachian Kentucky an epicenter for theintertwined national crises of injection drug use overdoses and hepatitis C.


application_id: 10539150
project_number: 1R13HL165800-01
project_title: The Don S. Fredrickson Lipid Research Conference
administering_ic: NHLBI
award_notice_date: 2022-07-27
opportunity_number: PA-21-151
application_type: 1
activity_code: R13
ic: HL
serial_number: 165800
program_official: LIU, LIJUAN
project_start_date: 2022-08-01
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZHL1 CSR-B (M2)]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
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 Don S. Fredrickson Lipid Research Conference (FLRC) brings together scientists andtrainees investigating the impact of lipid and lipoprotein metabolism on the development andtreatment of Cardiometabolic Disease. The FLRC is named after the late Don S. Fredricks whoas the director of the National Heart Institute (now the NHLBI) from 1966  1974 and later theNIH developed the clinical classification for dyslipidemias (Type I-V) described TangiersDisease and made seminal discoveries in lipoprotein metabolism. Most importantly he trainedboth basic and clinical scientists and practitioners who have had a tremendous impact on thefield of lipoprotein metabolism.Since 2016 the FLRC has employed a rotating institutional host model the first of which washeld at the University of Kentucky in conjunction with the Saha Cardiovascular Research CenterResearch Day. The FLRC has since been hosted by Vanderbilt University the University ofCincinnati. The 2022 conference will be hosted by Duke University and the University of NorthCarolina in conjunction with the North Carolina Diabetes Research Day. The FLRC will behosted by Vanderbilt University in 2023 and the Medical College of Wisconsin in 2024.Keynote Lectures at the 2022 Fredrickson conference include Karen Mohlke University of NorthCarolina and Deborah Muoio Duke University on Days 1 and 3 of the conference. The scientificsessions include Novel Models in Lipid Metabolism Adipose Tissue Lipoprotein Metabolismand Lipids and Body Composition. Day 2 of the conference will be sponsored by the NorthCarolina Diabetes Research Center. The agenda includes additional scientific sessions; multiplePoster Pitch sessions (5-7 90-second presentations by trainees) and two judged postersessions. The FLRC places a strong emphasis students and fellows early career faculty andunderrepresented groups. The combined agenda affords every trainee in attendance theopportunity to present their research on stage network with leaders in the field and broadentheir scope and understanding of research in lipid metabolism and Cardiometabolic Diseases.Our format encourages informal interactions between scientists at all levels providing aninnovative approach to the exchange of ideas and synthesis that will move the field of lipidresearch forward. The conference will have high impact as the program spans basic sciencediscovery to clinical significance. It is therefore expected that the meeting will provide newinsights not only into basic aspects of lipid metabolism but also how to treat and ultimatelycure a wide variety of Cardiometabolic Disease states.

project_terms:
Address;Adipose tissue;Apolipoproteins;Basic Science;Biological Models;Body Composition;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Ceramides;Classification;Clinical;Clinical Investigator;Collaborations;Development;Diabetes Mellitus;Disease Progression;Dyslipidemias;Ensure;Faculty;Fostering;Goals;Heart;Hypertension;Hypertriglyceridemia;Institutes;Institution;Insulin Resistance;Kentucky;Lipids;Lipoproteins;Metabolic Diseases;Metabolic syndrome;Metabolism;Midwestern United States;Mitochondria;Modeling;Molecular Genetics;Names;National Heart Lung and Blood Institute;North Carolina;Obesity;Oral;Participant;Research;Research Activity;Research Personnel;Research Project Grants;Role;Science;Scientist;Seminal;Senior Scientist;Students;Talents;Tangier Disease;Technology;Thinking;Training;Underrepresented Populations;United States National Institutes of Health;Universities;Wisconsin;cardiovascular risk factor;career;career development;clinically significant;early-career faculty;experience;innovation;insight;lectures;lipid metabolism;medical schools;meetings;new technology;novel;posters;programs;relative cost;social;social engagement;symposium;translational scientist

public_health_relevance:
Project NarrativeThe Don S. Fredrickson Lipid Research Conference is an annual meeting held since 1992 that bringstogether scientists in the field of lipid and lipoprotein metabolism and their impact on cardiovascularand metabolic disease. Its goal is to provide a venue for senior scientists early career investigatorsand trainees to share cutting-edge science; encourage new lines of thinking experimentation andcollaboration; and the opportunity for host institutions to showcase their research activity to have agreater impact in the advancement of our understanding and treatment of cardiometabolic disease.


application_id: 10538928
project_number: 1R01AG079525-01
project_title: The impact of insulin sensitivity on the potential of metformin to delay age-related inflammation
administering_ic: NIA
award_notice_date: 2022-08-08
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 079525
program_official: JOSEPH, LYNDON
project_start_date: 2022-08-15
project_end_date: 2026-04-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Age;Age of Onset;Aging;Ancillary Study;Anti-Inflammatory Agents;Autophagocytosis;Bioenergetics;Bioinformatics;Biological Markers;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;Longevity;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;aged;arm;base;clinical practice;comorbidity;cytokine;glycemic control;healthspan;improved;inflammatory marker;insight;insulin sensitivity;predictive modeling;primary endpoint;recruit;repaired;response;success;systemic inflammatory response;trait


application_id: 10538925
project_number: 1R01DK131786-01A1
project_title: Role of SMPDL3B in obesity-associated non-alcoholic fatty liver disease
administering_ic: NIDDK
award_notice_date: 2022-06-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 131786
suffix: A1
program_official: LOH, KATRINA SHUEH WEN
project_start_date: 2022-07-01
project_end_date: 2027-04-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
3-Dimensional;Acids;Affect;Animal Model;Animals;Attenuated;Back;Binding;CD36 Antigens;CD36 gene;Cell membrane;Ceramides;Data;Development;Diet;Disease;Disease Progression;Down-Regulation;Epidemic;Fatty Liver;Feedback;Feeds;Fibrosis;GPI Membrane Anchors;Human;In Vitro;Inflammation;Inflammatory;Knock-out;Knowledge;Kupffer Cells;Lead;Lipids;Liver;Liver Fibrosis;Liver diseases;Macrophage Activation;Mediating;Membrane Lipids;Membrane Microdomains;Membrane Proteins;Metabolic Diseases;Modeling;Modification;Obesity;Organoids;Pathogenesis;Pathway interactions;Patients;Peptides;Phenotype;Process;Production;Proteins;Reducing diet;Risk Factors;Rodent;Role;Signal Transduction;Sphingomyelinase;TLR4 gene;Testing;Therapeutic;Thrombospondin 1;Western World;base;chronic liver disease;cytokine;in vitro Model;in vivo;knock-down;macrophage;monocyte;mouse model;nanoparticle;new therapeutic target;non-alcoholic fatty liver;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutic intervention;novel therapeutics;obesity treatment;overexpression;peripheral blood;receptor;recruit;targeted treatment;therapy development


application_id: 10536667
project_number: 5R01AG070830-03
project_title: Contributions of astrocyte RelA signaling in aging-related neurodegenerative sequelae following TBI
administering_ic: NIA
award_notice_date: 2023-01-18
opportunity_number: PAR-19-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 070830
program_official: OPANASHUK, LISA A
project_start_date: 2021-01-15
project_end_date: 2025-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG-R]
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
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:
ABSTRACTTraumatic brain injury (TBI) is significantly correlated with increased risk for developing severalneurodegenerative disorders including Alzheimers Disease (AD) and AD-related dementia (ADRD)representing one of the most powerful environmental risk factors for AD/ADRD. Compounding these correlatesis that aging is a substantial factor in the incidence and vulnerability to TBI. Owing to the complexities surroundingTBI as a progressive neurodegenerative disorder leading to AD/ADRD the cellular mechanisms potentiallyunderlying the aging brains susceptibility to acquire degenerative responses remains elusive. To date the bulkof published findings related to TBI-related Alzheimers-like impairments have been examined using young adultand predominantly male rodents which does not accurately model the greatest at-risk population in humans.However our aging TBI model recapitulates several correlates of Alzheimers like impairments including chronicmemory impairment exacerbated neuroinflammation gliosis phosphorylated tau as well as microglialphenotypes previously documented in both humans and mouse models of Alzheimers disease. Guided bypreliminary findings our overarching hypothesis is that in the aging brain following TBI RelA drives exacerbatedastrocyte responses underlying the aging brains susceptibility for persistent decremental outcomes related tohomeostatic astrocyte susceptibility neuroinflammation and neural network dysfunction. We believe thesealtered responses initiated by TBI in the aging brain ultimately manifest in correlates characteristic of progressiveneurodegeneration associated with AD/ADRD. We will pursue three aims to test this hypothesis using novelgenetic models for targeting astrocytes in young and aged mice to determine 1.) The susceptibility of agedastrocytes to lose critical homeostatic features following TBI 2.) The ability of astrocytes to regulate theconversion of microglia towards decremental AD-associated inflammatory phenotypes following TBI and 3.) Therole of astrocytes in the vulnerability of synaptic circuitry and impaired memory a critical hallmark associatedwith TBI/ADRD. Cumulatively these studies will help to elucidate both the cellular and molecular substratesthrough which the aging brains response to TBI facilitates progressive neurodegenerative sequelae that caneventually lead to AD/ADRD. Our salient findings will ultimately determine the extent to which RelA is a criticalmediator in these AD-associated sequelae with the potential to elucidate new therapeutic targets toward theirprevention.

project_terms:
Acute;Affect;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Alzheimer's disease risk;Animal Model;Astrocytes;Automobile Driving;Behavioral;Brain;Calcium;Cells;Characteristics;Chronic;Complement;Complex;Data;Development;Disease;Environmental Risk Factor;Excision;Feedback;Functional disorder;Genetic Models;Gliosis;Heterogeneity;Human;Impaired cognition;Impairment;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Ischemia;Knockout Mice;Lead;Link;Mediator;Memory impairment;Methods;Microglia;Modality;Modeling;Molecular;Multiple Sclerosis;Mus;NF-kappa B;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurons;Neurophysiology - biologic function;Outcome;Pathway interactions;Persons;Phenotype;Physiology;Populations at Risk;Predisposition;Prevention;Publishing;Risk;Rodent;Role;Signal Pathway;Signal Transduction;Slice;Spinal cord injury;Synapses;Synaptic plasticity;Testing;Time;Tissues;Transcriptional Activation;Trauma;Traumatic Brain Injury;age related;aged;aging brain;astrogliosis;cerebrovascular;conditional knockout;knockout animal;knowledgebase;loss of function;male;mouse model;network dysfunction;neural;neural circuit;neural network;neuroinflammation;new therapeutic target;novel;progressive neurodegeneration;protein profiling;response;response to injury;restoration;single-cell RNA sequencing;tau-1;transcription factor;transcriptome sequencing;transcriptomics;young adult

public_health_relevance:
Project NarrativeTraumatic brain injury (TBI) is a complex and progressive neurodegenerative disorder affectingmillions of people each year in the US as well as being a known environmental risk factor forthe development of Alzheimers disease-related dementia. However the mechanisms underlyingthe increased risk to develop Alzheimers disease-related dementia following TBI remainunclear. The salient findings from this project will significantly contribute to fundamentalknowledge-base of the role of inflammatory response of astrocytes in the aging brain asdeterminants of outcome following TBI.


application_id: 10536651
project_number: 5K23DK128562-02
administering_ic: NIDDK
award_notice_date: 2022-12-16
opportunity_number: PA-20-205
application_type: 5
activity_code: K23
ic: DK
serial_number: 128562
program_official: GREER, RAQUEL CHARLES
project_start_date: 2022-01-01
project_end_date: 2026-11-30
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 16335091
contact_pi: FLANNERY, ALEXANDER H
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: 2022-12-01
project_title:
Classical and Alternative Renin-Angiotensin System Dysregulation in Sepsis-Associated AKI: A Reverse Translation Approach

project_abstract:
PROJECT SUMMARY/ABSTRACTThis proposal includes a five-year research career development program to study classical and alternativerenin-angiotensin system (RAS) dysregulation in sepsis-associated acute kidney injury (SA-AKI). Thecandidate is currently an Assistant Professor at the University of Kentucky College of Pharmacy. The proposalbuilds on the candidates strong background in clinical research on AKI and integrates mentorship fromestablished investigators in sepsis AKI RAS therapeutics and murine models of SA-AKI. The proposedcareer development activities will equip the candidate with the skills necessary to become established as anindependent clinical and translational scientist conducting patient-oriented research on SA-AKI. Over 4 millionpatients are hospitalized annually with AKI and sepsis is estimated to contribute to 26-50% of all cases.Current therapy is limited to supportive care and kidney replacement therapy. Recent evidence suggestssepsis causes a disruption in angiotensin converting enzyme (ACE) and ACE2 that could severely dysregulatethe RAS. This disruption may ultimately result in local excess of the proinflammatory classical RAS anddeficiencies in the counter-regulatory anti-inflammatory alternative RAS (Alt-RAS). An intra-renal RASoperating independently from the circulatory RAS may drive pathophysiology and urinary RAS biomarkershave been proposed as surrogate markers of intra-renal RAS activation. Using a bedside-to-bench approachour overall objective is to quantify the classical and Alt-RAS disturbances present at the circulatory and tissuelevel in SA-AKI and evaluate the relationship between the extent of this disturbance and major adverse kidneyevents. Our central hypothesis is that a deficiency of the regenerative RAS or Alt-RAS exists relative to theclassical RAS in SA-AKI at the circulatory and tissue level and that the degree of this imbalance differentiallyassociates with outcomes in patients with SA-AKI. We propose three specific aims to accomplish this: (1) Todetermine the relationship between RAS dysregulation kidney biomarkers of tubular injury and function andmajor adverse kidney events within 30 days (MAKE-30) in SA-AKI (2) To assess the relationship betweenurinary biomarkers of intra-renal RAS activation and MAKE outcomes out to one year in critically ill patientswith SA-AKI and heterogenous AKI and (3) To test the hypothesis that the kidney RAS peptide metabolomeand receptor expression profile shift to a regenerative or Alt-RAS deficiency in a murine model of SA-AKI andthat the degree of Alt-RAS deficiency (relative to classical RAS) corresponds to the degree of kidney injury andintra-renal RAS activation. Career development activities that align with this research include: training inapplication of laboratory assays including mass spectrometry advancement of statistical analysis skills withlongitudinal data and introductory machine learning and learning pre-clinical models of SA-AKI. This proposalsupports the mission of NIDDK by furthering the understanding of SA- AKI a leading cause of AKI and kidneycomplications impacting the publics health and quality of life.

project_terms:
ACE2;Acute;Acute Renal Failure with Renal Papillary Necrosis;Angiotensin II;Angiotensinogen;Angiotensins;Anti-Inflammatory Agents;Biological Assay;Biological Markers;Chronic;Chronic Disease;Classification;Clinical;Clinical Research;Critical Illness;Data;Development;End stage renal failure;Etiology;Event;Evolution;Frequencies;Functional disorder;Future;Health;Hospitalization;Infection;Inflammatory;Injury;Injury to Kidney;Kentucky;Kidney;Laboratories;Learning;Machine Learning;Mass Spectrum Analysis;Measurement;Measures;Mentorship;Mission;Modeling;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Outcome;Patient-Focused Outcomes;Patients;Peptides;Peptidyl-Dipeptidase A;Pharmacy facility;Pre-Clinical Model;Program Development;Prospective cohort;Proteins;Public Health;Quality of life;Recovery;Renal Replacement Therapy;Renin;Renin-Angiotensin System;Research;Research Personnel;Risk;Risk Marker;Role;Sepsis;Septic Shock;Statistical Data Interpretation;Supportive care;Surrogate Markers;Testing;Therapeutic;Tissues;Training;Translational Research;Tubular formation;Universities;Up-Regulation;Urine;bench to bedside;biobank;career development;clinical care;clinical translation;cohort;college;complex biological systems;improved;metabolome;metabolomics;molecular marker;mortality;mouse model;patient oriented research;patient subsets;professor;receptor;receptor expression;regenerative;renal damage;response;skills;translational approach;translational model;translational scientist;urinary

public_health_relevance:
PROJECT NARRATIVESepsis a dysregulated response to infection is the leading cause of acute kidney injury impacting millions ofpatients every year and has no proven therapy aside from supportive care. The proposed research willinvestigate the role of a complex biologic system the renin-angiotensin system and its relationship with kidneyinjury in sepsis. By increasing our understanding future therapies may be developed that help treat patientswith this condition and improve meaningful short- and long-term patient outcomes.


application_id: 10536470
project_number: 2R01DK112034-06A1
project_title: Mechanisms Regulating Neurotensin Secretion and Function
administering_ic: NIDDK
award_notice_date: 2022-06-22
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: DK
serial_number: 112034
suffix: A1
program_official: SERRANO, JOSE
project_start_date: 2017-02-01
project_end_date: 2026-06-30
study_section: Nutrition and Metabolism in Health and Disease Study Section[NMHD]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
5'-AMP-activated protein kinase;Adipocytes;Adipose tissue;Affinity;Amino Acids;Assimilations;Attenuated;Biochemistry;Biological Models;Biometry;Body Weight decreased;Body mass index;Breast Cancer Risk Factor;Cells;Clinical;Computational Biology;Consumption;Development;Diabetes Mellitus;Dietary Fats;Digestion;Disease;Disease Resistance;Distant;Drosophila genus;Endocrinology;Enteroendocrine Cell;Epidemiology;Epigenetic Process;Fasting;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Future;Gastrointestinal Hormones;Gastrointestinal Physiology;Genes;Genetic;Goals;Grant;Growth;Hepatic;High Fat Diet;Homeostasis;Hormones;Human;Ingestion;Innovative Therapy;Insulin Resistance;Interdisciplinary Study;Intestinal Hormones;Intestinal Mucosa;Intestines;Knockout Mice;Knowledge;Laboratories;Lead;Length;Link;Lipase;Lipids;Lipolysis;Liver;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Metabolic Diseases;Metabolism;Molecular;Morbidity - disease rate;Mus;Neurotensin;Neurotensin Receptors;Nutrient;Obesity;Organ;Overnutrition;Physiological;Physiology;Play;Prevention;Process;Prognostic Marker;Protein Kinase;Publishing;Regulation;Reporting;Research;Role;Signal Pathway;Signal Transduction;Small Intestines;Stimulus;System;Technology;Time;Transgenic Organisms;Triglycerides;Weight Gain;Woman;absorption;base;blood glucose regulation;cardiovascular disorder risk;diet-induced obesity;drug development;experimental study;fatty acid oxidation;insight;lipid biosynthesis;lipid metabolism;metabolomics;mortality;mouse model;multidisciplinary;non-alcoholic fatty liver disease;novel;obesity prevention;obesity treatment;receptor;response;sortilin;sterol esterase;uptake


application_id: 10536039
project_number: 1F31HL165826-01
project_title: Role of Pck2 in cardiac fibrosis
administering_ic: NHLBI
award_notice_date: 2022-08-09
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: HL
serial_number: 165826
program_official: HUANG, LI-SHIN
project_start_date: 2022-09-01
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 F10A-K (20)]
contact_pi_person_id: 77801946
contact_pi: WELLS, COLLIN
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_terms:
Address;Affect;Amino Acids;Anabolism;Biology;Carbon;Cardiac;Cardiovascular system;Cell division;Chronic;Citric Acid Cycle;Collagen;Data;Deposition;Development;Enzymes;Extracellular Matrix;Fibroblasts;Fibrosis;Foundations;Genetic Transcription;Gluconeogenesis;Glucose;Glutaminase;Glutamine;Glycolysis;Heart;Heart Injuries;Infarction;Knowledge;Ligands;Metabolic;Metabolic Pathway;Metabolism;Myocardial Infarction;Myofibroblast;Nucleotides;Output;Pathology;Pathway interactions;Phase;Phenotype;Phosphoenolpyruvate Carboxylase;Phospholipids;Positioning Attribute;Process;Production;Proteins;Role;Serine;Source;Stimulus;Suggestion;Testing;Transcript;Transforming Growth Factor beta;coronary fibrosis;diminished oxidative phosphorylation;extracellular;glucose metabolism;in vivo;meetings;mouse model;programs;response;therapeutic target;transcriptome sequencing;transdifferentiation;virtual


application_id: 10535630
project_number: 1F30NS129251-01
project_title: The Role of Perilipin 2 in Macrophages after Experimental Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2022-08-09
opportunity_number: PA-21-050
application_type: 1
activity_code: F30
ic: NS
serial_number: 129251
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2022-08-09
project_end_date: 2026-08-08
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 12283385
contact_pi: GLASER, ETHAN PHARES
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/ABSTRACT Spinal cord injury (SCI) leads to permanent motor and sensory loss that isexacerbated by persistent inflammation months after the injury. After SCI monocyte-derived macrophages(MDMs) infiltrate the lesion to aid in cellular debris clearance. However this response is emerging as a double-edged sword. Lingering debris inhibits repair and plasticity while clearance of the debris by infiltrating MDMsinduces a proinflammatory and damaging phenotype. Clearance of cholesterol-rich myelin debris causesMDMs to resemble proinflammatory foam cells both phenotypically and morphologically. Foam cells are lipid-laden macrophages with numerous lipid droplets (LDs) that form when excessive cholesterol uptakeoverwhelms cholesterol metabolism. Foam cells also drive chronic inflammation in atherosclerosis and non-alcoholic steatohepatitis (NASH). Foam cells persist chronically in the injured cord and may contribute to thesustained proinflammatory lesion environment. However their role in the chronic inflammatory state is poorlyunderstood. Therefore elucidating the effect of foam cell formation after SCI is integral to understanding thecontribution of MDMs to injury pathology. Preliminary and published data identify Perilipin 2 (Plin2) as a keydifferentially upregulated gene in both infiltrating MDMs after SCI and foam cells in atherosclerosis. Plin2 isessential in regulating the formation and storage of cholesterol (i.e. lipid droplets (LDs)) in macrophages aslipid metabolites are either exported from these cells or stored in LDs. Plin2 coats LDs sequesters them in thecytosol and prevents lipolytic enzymes from accessing their cargo. Reducing Plin2 may therefore reduce LDaccumulation and mitigate foam cell formation after SCI. In models of atherosclerosis and NASH Plin2deficient mice produced fewer foam cells and were protected from atherosclerotic plaque formation andcirrhosis respectively. To understand the effects of Plin2 upregulation in MDMs after SCI a novel targeteddeletion of Plin2 using a LysMCre/lox system will be employed. Using this mouse model this project willdetermine (1) the role of Plin2 in myelin-induced foam cell formation using an in vitro approach and (2) theeffects of targeted Plin2 deletion in MDMs on foam cell formation inflammation and locomotor recovery afterexperimental. These experiments will test the hypothesis that cell-specific Plin2 ablation in MDMs suppressesfoam cell formation after SCI inhibits inflammation and promotes functional recovery. If successful this projectwill provide novel insight into how CNS macrophages metabolize myelin and may provide new therapeutictargets to improve SCI recovery by resolving chronic intraspinal inflammation. Through the completion of thistraining grant the PI will receive ample training regarding the implementation of project managementresponsible conduct of research and the dissemination of findings. This training will provide the PI with theskillset necessary to carry out the specific aims and lay the foundation for the PI to become an independentphysician-scientist with an extramurally supported research portfolio in the field of neurotrauma.

project_terms:
Ablation;Acute;Alzheimer's Disease;Arterial Fatty Streak;Atherosclerosis;Bone Marrow;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Cirrhosis;Code;Custom;Cytosol;Data;Disease;Environment;Enzyme-Linked Immunosorbent Assay;Enzymes;Extramural Activities;Family;Fluorescent in Situ Hybridization;Foam Cells;Foundations;Functional disorder;Gene Expression;Genes;Genetic;Grant;Health Care Costs;Immunofluorescence Immunologic;In Vitro;Individual;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Interleukin-6;Lesion;Leukocytes;Lipid-Laden Macrophage;Lipids;Locomotor Recovery;Mediating;Metabolism;Microscopy;Modeling;Morphology;Motor;Mus;Myelin;Myeloid Cells;Nervous System Trauma;Paralysed;Pathology;Pathway interactions;Phagocytosis;Phenotype;Physicians;Process;Production;Publishing;Quantitative Reverse Transcriptase PCR;Recovery;Recovery of Function;Research Support;Role;Scientist;Sensory;Site;Sorting - Cell Movement;Spinal Cord;Spinal cord injury;Stains;Stimulus;System;Testing;Time;Tissues;Training;Transgenic Model;Up-Regulation;Western Blotting;Work;collected works;cytokine;design;experimental study;histological stains;improved;in vitro Model;injured;injury recovery;insight;lipid metabolism;macrophage;molecular sequence database;monocyte;mouse model;nano-string;neuroinflammation;new therapeutic target;non-alcoholic;nonalcoholic steatohepatitis;novel;perilipin;prevent;repaired;research data dissemination;response;responsible research conduct;single-cell RNA sequencing;therapeutic target;uptake

public_health_relevance:
PROJECT NARRATIVESpinal cord injury (SCI) often results in permanent paralysis and expensive health care costs for individualsand their families. After SCI normal repair processes are limited by ineffective clearance of lipid-rich cellulardebris caused by white blood cells (monocyte-derived macrophages) transforming into inflammatory cellsthereby limiting recovery. Using a novel transgenic model this study will examine the role of a potentialtherapeutic target (Plin2) that may dramatically improve this debris clearance process which will limitinflammation and improve recovery after SCI.


application_id: 10535090
project_number: 1F31DC020639-01
project_title: Mechanisms of Tip Link Tensioning in Mammalian Auditory Hair Cells
administering_ic: NIDCD
award_notice_date: 2022-05-05
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: DC
serial_number: 020639
program_official: SCHURMAN, JACLYN REBECCA
project_start_date: 2022-07-31
project_end_date: 2025-07-30
study_section: Special Emphasis Panel[ZDC1 SRB-Y (56)]
contact_pi_person_id: 78133926
contact_pi: DRAGICH, ABIGAIL
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;Auditory;Biochemical;CDH23 gene;Cell Survival;Cells;Cellular biology;Clinical Treatment;Cochlea;Confocal Microscopy;Data;Detection;Development;Electron Microscopy;Electrophysiology (science);Ensure;Environment;Future;Genes;Hair;Hair Cells;Hearing;Height;Human;Image;Immobilization;In Vitro;Knock-out;Laboratories;Link;Liquid substance;MYO7A gene;Maintenance;Mechanics;Methods;Microscopy;Modeling;Molecular;Motor;Mouse Strains;Mus;Mutation;Myosin ATPase;Outer Hair Cells;Patients;Phenotype;Physiological;Play;Preparation;Principal Investigator;Proteins;Research;Rest;Role;Shapes;Slide;Speed;Structure;Techniques;base;career;deaf;deafness;density;experimental study;extracellular;hearing impairment;inhibitor;mechanotransduction;mutant;myosin VI;patch clamp;protein function;response;skills;sound


application_id: 10534915
project_number: 2R01AI142841-05
project_title: Maternal obesity and neonatal innate immunity
administering_ic: NIAID
award_notice_date: 2022-07-26
opportunity_number: PAR-20-298
application_type: 2
activity_code: R01
ic: AI
serial_number: 142841
program_official: PRABHUDAS, MERCY R
project_start_date: 2018-09-24
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1 EMNR-V (56)]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: VARLAMOV, OLEG
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The developing fetal immune system is exquisitely sensitive to signals from the maternalenvironment. Maternal pre-pregnancy (pregravid) obesity has emerged as one of the mostconsequential regulators of fetal health. Data from clinical and animal model studiesdemonstrated increased susceptibility to microbial infection as well as a higher incidence ofinflammatory disorders and auto-immune diseases with maternal obesity. This dichotomy isillustrated by splenocytes generating dampened inflammatory responses to LPS stimulation whilegut resident immune cells generate exaggerated ones. Similarly pregravid obesity resulted inlower expression of inflammatory genes in umbilical cord blood monocytes at rest but followingdifferentiation into macrophages expression of inflammatory genes was significantly increased.These observations strongly suggest that pregravid obesity disrupts the development andmaturation of the fetal immune system and differentially impacts circulating monocytesand tissue resident macrophages (TRMs). However the molecular underpinnings of thisdysregulation by maternal obesity remain poorly understood due to the difficulty of obtaining termfetal tissues and of controlling for multiple maternal variables that modulate fetal immunity. Thusin this application we will leverage the rhesus macaque model to interrogate multiple fetalcompartments within the same subject to address this knowledge gap. Immune ontogeny occursvia 3 different waves starting with yolk sac transitioning to fetal liver and finally the bone marrow.TRMs are derived primarily from yolk sac and fetal liver while circulating monocytes are derivedfrom bone marrow. We recently reported that pregravid obesity is associated with low gradeinflammation that is further compounded by pregnancy. Thus we postulate that exposure to lowgrade maternal inflammation leads to training of TRMs while heightened maternal inflammatoryenvironment in late gestation leads to tolerance of bone marrow derived monocytes. Thereforethis application will test the central hypothesis that pregravid obesity results in differentialrewiring of TRMs and circulating monocytes wherein TRMs are poised to generate aheightened inflammatory response while circulating monocytes display a stuntedresponse. The novelty of this application lies in the systems biology approach integratingmaternal clinical metadata with genomic and functional readouts obtained in multiple immunecompartments in the same animal. Completion of the proposed experiments will reveal themolecular mechanisms that result in altered fetal macrophage and monocyte functions thusinforming the potential development of early interventions.

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

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


application_id: 10534346
project_number: 1F31DA057050-01
project_title: Calcium Imaging of Central Amygdala Activity after Fentanyl Escalation
administering_ic: NIDA
award_notice_date: 2022-07-28
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: DA
serial_number: 057050
program_official: BABECKI, BETH
project_start_date: 2022-07-03
project_end_date: 2024-07-02
study_section: Special Emphasis Panel[ZRG1 F02A-K (20)]
contact_pi_person_id: 16596090
contact_pi: MALONE, SAMANTHA
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Evidence suggests that rats given long access (LgA) sessions to self-administer (SA) opioids escalate theirintake while also showing greater withdrawal severity and drug-induced reinstatement compared to ratsmaintained on short access (ShA) daily SA sessions. Little is known about the neural changes that occur duringcontingent opioid escalation that may impact withdrawal and relapse. Past work examining opioid SA using ShAsessions in rodents has identified the central amygdala (CeA) as an area of interest that becomes hyperactivein acute withdrawal and may be involved in the incubation of craving that occurs after protracted withdrawal.However these studies have not examined the impact of escalated opioid intake using LgA sessions on CeAactivity during acute withdrawal when individuals experience heightened craving and negative emotionality orfollowing protracted withdrawal during extended abstinence when individuals experience an increasedsusceptibility to relapse. Furthermore no study has determined if changes in CeA activity depend on theescalation of fentanyl intake that is self-administered contingently or merely from exposure to fentanyl per seeven if it were administered non-contingently. The specific aims of this research are to determine if contingentfentanyl escalation alters basal ex vivo CeA activity following either acute withdrawal (Aim 1) or protractedwithdrawal (Aim 2). The effect of ex vivo application of fentanyl on the activity of CeA slices obtained followingacute or protracted withdrawal will also be determined. Male and female Sprague Dawley rats will be dividedinto three groups: (1) contingent fentanyl (2) yoked fentanyl or (3) yoked saline. Rats in the contingent fentanylgroup will undergo 7 days of fentanyl (2.5 ug/kg/inf) acquisition and 21 days of 6 h SA. Yoked rats will receivenon-contingent infusions of fentanyl or saline dependent upon responding emitted by the contingent fentanyl rat.In preparation for calcium (Ca2+ ) imaging rats will be euthanized either 17 h into withdrawal or after 30 days offorced abstinence. Ca2+ imaging will be conducted at baseline and in the presence of fentanyl (0.1 uM or 1 uM)to determine differences in CeA Ca2+ fluorescence a measure of neural activity. We hypothesize that at bothstages of abstinence fentanyl rats will demonstrate greater Ca2+ transients than yoked saline rats; contingentfentanyl rats may also display a greater effect than yoked fentanyl rats. We also hypothesize that at both stagesof abstinence all rats will demonstrate a fentanyl dose-dependent decrease in Ca2+ transients an effect that willbe greater in saline rats than fentanyl rats. Finally we predict that greater basal CeA activity will be observedafter protracted withdrawal compared to acute withdrawal particularly for contingent fentanyl rats. Studying themechanisms underlying differences in withdrawal and relapse after opioid escalation using Ca2+ imaging is highlynovel and will elucidate the role of the CeA in driving withdrawal and relapse in OUD. The long-term goal of thiswork is to inform the development of novel treatments for OUD particularly those that may target the CeA toreduce the negative emotionality and craving that occurs during acute withdrawal and throughout abstinence.

project_terms:
Abstinence;Acute;Amygdaloid structure;Area;Automobile Driving;Behavior;Behavioral;Brain;Calcium;Cell Nucleus;Centers for Disease Control and Prevention (U.S.);Characteristics;Development;Dose;Emotional;Exposure to;Female;Fentanyl;Fluorescence;Frequencies;Future;Goals;Home;Hyperactivity;Image;Individual;Infusion procedures;Intake;Measures;Opioid;Oxycodone;Pattern;Pharmaceutical Preparations;Phase;Predisposition;Preparation;Rattus;Recording of previous events;Recovery;Relapse;Research;Rodent;Role;Saline;Self Administration;Severities;Slice;Sprague-Dawley Rats;Structure;Time;Withdrawal;Work;addiction;behavior influence;craving;experience;interest;male;neuromechanism;novel;novel therapeutic intervention;opioid use;opioid use disorder;overdose death;pre-clinical;relating to nervous system;response;treatment group;trend

public_health_relevance:
Evidence suggests that rats with a history of escalated opioid intake express greater withdrawal severity anddrug-induced reinstatement compared to non-escalated rats; however the neural mechanisms driving theseheightened responses are unknown. The proposed study seeks to elucidate the neural activity and structuralchanges in the central amygdala (CeA) associated with contingent fentanyl escalation following either acute orprotracted withdrawal. This work will inform us about the impact of fentanyl on CeA activity related to opioid usedisorder (OUD) phases vital for recovery.


application_id: 10533795
project_number: 5F31NS116935-03
project_title: The effects of activity on propriospinal neuron morphology and connectivity
administering_ic: NINDS
award_notice_date: 2022-12-19
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: NS
serial_number: 116935
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-12-01
project_end_date: 2023-09-30
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 16080666
contact_pi: BROWN, BRANDON LEE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary. The majority of human spinal cord injuries (SCI) are anatomically incomplete potentiallyleaving propriospinal pathways which may relay information past the injury epicenter intact. Following SCI inrodents descending motor tracts sprout and increasingly contact descending propriospinal neurons (DPNs)forming detour circuits to relay signals caudal to the injury. However no studies have evaluated the potentialfor ascending PNs to form bottom-up detour circuits post-SCI. We previously found that silencing longascending PNs (LAPNs) which directly connect the lumbar and cervical spinal enlargements disruptedcoordination at each limb girdle. Surprisingly silencing this anatomically intact pathway post-SCI improvedlocomotor function. Thus it is critical to evaluate LAPN plasticity and determine how this plasticity might berefined by therapeutic interventions. To do so LAPN somatic and dendritic morphology will be characterizedusing a dual-viral system to specifically label LAPNs. We will also use a multi-viral system with a highlymodified rabies virus to identify the sources of direct synaptic input to LAPNs. Increased physical activity andrehabilitative training are known to improve locomotor function and anatomical outcomes post-SCI. To evaluatethe impact of physical activity and rehabilitative training on LAPN plasticity and locomotor function post-SCIwe will alter activity levels by housing animals in tiny cages or in large cages to restrict or facilitate activity.Animals in large cages will also receive rehabilitative training which mimics clinical rehabilitation. Furtherunderstanding SCI-induced neuroplasticity and how physical activity and rehabilitative training impact thisplasticity will further our understanding of SCI pathology and provide new therapeutic targets. Working closelywith my mentors we have developed a training plan that will broaden my scientific skills facilitate independentscientific thought and cultivate skills needed to be a productive postdoctoral fellow. The Kentucky Spinal CordInjury Research Center provides clinical and scientific expertise in SCI and related fields and has a history ofsuccessfully preparing trainees for current and next stages in their careers.Hypothesis. Pre-SCI we hypothesize that DPNs reticulospinals and sensory afferents will provide input toLAPNs. Post-SCI we anticipate 1) LAPN dendrite orientation change 2) LAPNs will be increasingly contactedby sensory afferents to form bottom-up detour circuits and 3) increased activity plus rehabilitative training post-SCI will improve locomotor function impact dendrite reorganization and refine detour circuits.Aim 1. Characterize the somatic and dendritic morphology of LAPNs and identify the sources of directsynaptic input onto LAPNs.Aim 2. Evaluate the effects of activity and rehabilitative training on locomotor function LAPN morphology andthe sources of direct synaptic inputs to LAPNs after T10 contusive spinal cord injury.

project_terms:
Anatomy;Animal Housing;Animal Model;Animals;Area;Axon;Behavior;Behavioral;Behavioral Assay;Breathing;Cells;Central Nervous System;Cervical;Cervical spine;Chest;Clinical;Data;Dendrites;Dependovirus;Ensure;Enterobacteria phage P1 Cre recombinase;Forelimb;GTP-Binding Proteins;Gait;Genes;Genetic Transcription;Growth and Development function;Hindlimb;Human;Injections;Injury;Kentucky;Label;Lateral;Lentivirus;Limb structure;Locomotion;Locomotor Recovery;Mentors;Messenger RNA;Morphology;Motor;Muscle;Nervous System;Neuronal Plasticity;Neurons;Ontology;Outcome;Output;Pathology;Pathway interactions;Pattern;Periodicity;Physical activity;Positioning Attribute;Postdoctoral Fellow;Presynaptic Terminals;Productivity;Rabies;Rabies virus;Recording of previous events;Recovery of Function;Regulation;Rehabilitation therapy;Research;Rodent;Role;Sensory;Signal Transduction;Source;Specificity;Spinal;Spinal Ganglia;Spinal cord injury;Stereotyping;Synapses;System;Therapeutic Intervention;Training;Transcriptional Regulation;Vertebral column;Vertebrates;Viral;career;central pattern generator;improved;kinematics;neuronal excitability;neuroregulation;new therapeutic target;receptor;reconstruction;skills;transcriptome sequencing;white matter

public_health_relevance:
This project aims to evaluate spinal cord injury (SCI)-induced neuroplasticity and how rehabilitative trainingalters this plasticity. By characterizing the morphology of and inputs to long ascending propriospinal neurons(LAPNs) before SCI we will be able to assess SCI induced changes to LAPN morphology determine the roleof LAPNs in forming de novo spinal circuits post-SCI and determine the potential for rehabilitative training torefine these newly formed spinal circuits. Elucidating this will enhance our understanding of SCI pathology andprovide new targets for neuromodulatory and rehabilitative therapies.


application_id: 10533745
project_number: 5R01CA175105-09
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2022-12-07
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 175105
program_official: AULT, GRACE S
project_start_date: 2013-04-01
project_end_date: 2024-11-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
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 SUMMARYMetastatic colorectal cancer (CRC) is an aggressive disease impacting about 50000 deaths annually in theUSA. Patients with metastatic CRC are predominantly unresponsive to existing therapies. The metastaticprocess is mediated in part by dysregulated translation of oncogenic mRNAs leading to overproduction of theirencoded proteins. Previous findings established dysregulation of cap-dependent mRNA translation downstreamof mTOR at the level of 4E-BP1/eIF4E as a key to tumor formation and metastatic progression in CRC. Whiletargeting mTOR is thought to be a promising strategy for CRC therapy limited therapeutic efficacy of mTORinhibitor drugs correlates largely with loss of the translation repressive function of 4E-BP1. More recent findingsindicate that Snail acts as a strong repressor of 4E-BP1 transcription and cooperates with mTOR-mediatedphosphorylation (inactivation) of 4E-BP1 to significantly increase eIF4E-initiated cap-dependent mRNAtranslation. These processes support tumor growth and decrease the efficacy of the mTOR kinase (ATP-competitive) inhibitors (mTORkis) in CRC therapy. Although mTORkis effectively inhibit phosphorylation of 4E-BP1 and restore its repressive effects on cap-dependent translation and tumor growth treatment with mTORkisin CRC cells can promote the active translation and expression of the immunosuppressive protein PD-L1 viainitiation at an internal ribosome entry site (IRES) in a cap-independent manner. In addition the RNA helicaseeIF4A is a key PD-L1 IRES binding protein that regulates its translation and expression. Importantly elevatedPD-L1 levels induced by mTORkis result in evasion of anti-CRC immunity. Further targeted inhibition of PD-L1can restore T-cell immunity and enhance the efficacy of mTORkis. Based on these findings the centralhypothesis of the proposed study is that CRC cells usurp the regulatory mechanisms underlying both cap-dependent translation through co-activation of Snail and mTOR and IRES-mediated translation of PD-L1 toescape immune surveillance in mTOR kinase-targeted therapy thereby causing CRC resistance to mTORkisand promoting CRC progression. To test this hypothesis the following specific aims are proposed: 1) to identifyhow Snail cooperates with mTOR in translational control of CRC progression and modulation of mTOR kinase-targeted therapy; 2) to determine the cap-independent mechanism of PD-L1 mRNA translation upon mTORkinase inhibition; and 3) to define the in vivo utility of co-targeting PD-L1 and mTOR to enhance CRC therapy.The focus of this study is the innovative concept that both Snail and PD-L1 promote CRC progression bycooperating with mTOR to modulate therapeutic response to mTORkis through dysregulation of 4E-BP1-mediated translation initiation processes. This research will not only define the novel mechanistic roles of bothSnail and PD-L1 in the modulation of mTOR/4E-BP1-mediated translational control of CRC progression andresistance to mTORkis but also facilitate rational approaches for the development of new translatabletherapeutic strategies for patients with advanced CRC.

project_terms:
Binding Proteins;Biological Markers;Biology;Cancer Etiology;Cell Line;Cessation of life;Clinical;Colorectal Cancer;Dependence;Development;Disease;Down-Regulation;EIF4EBP1 gene;Environment;Epigenetic Process;FRAP1 gene;Fostering;Foundations;Funding;Genes;Genetic Transcription;Goals;Immune Evasion;Immunity;Immunologic Surveillance;Immunologist;Immunotherapy;Internal Ribosome Entry Site;Knowledge;Left;Malignant Neoplasms;Mediating;Messenger RNA;Molecular;Monoclonal Antibodies;Neoplasm Metastasis;Oncogenic;Oncologist;Outcome Study;Pathogenesis;Pathologist;Patients;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Polyribosomes;Positioning Attribute;Process;Production;Property;Protein Biosynthesis;Proteins;Public Health;RNA;RNA Helicase;Reporting;Research;Resistance;Role;Signal Pathway;Signal Transduction;Snails;T-Lymphocyte;Testing;Therapeutic;Transact;Translating;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Tumor Immunity;Tumor-Infiltrating Lymphocytes;United States;Woman;Work;anti-PD-1;cancer cell;clinically relevant;colon cancer patients;colorectal cancer progression;colorectal cancer treatment;effective therapy;effectiveness evaluation;experience;genetic corepressor;improved;in vivo;inhibitor;inhibitor therapy;innovation;insight;kinase inhibitor;mRNA Translation;mTOR Inhibitor;men;metastatic colorectal;metastatic process;mouse model;novel;novel strategies;novel therapeutics;patient derived xenograft model;polysome profiling;programmed cell death ligand 1;protein complex;recruit;response;silvestrol;targeted treatment;therapeutic target;treatment response;tumor;tumor growth

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the second most common cause of cancer deaths in the United States for men and womencombined and approximately 40% of patients with this disease will eventually die of tumor metastasis. Thisproposal aims to deepen our understanding of signaling pathways and immune evasion mechanisms inmetastatic colorectal cancer by taking a novel approach for investigating mTOR signaling biology and itsderegulation in the molecular pathogenesis of this invasive disease with the goal of identifying selectivetranslational regulators as novel cancer therapeutic targets. This knowledge is expected to lay a foundation forthe development of novel therapies for metastatic colorectal cancer a goal with clear and significant implicationsfor public health.


application_id: 10533743
project_number: 5R01HL149351-04
project_title: Atherogenic Mechanisms of Electronic Nicotine Delivery Systems
administering_ic: NHLBI
award_notice_date: 2022-12-12
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 149351
program_official: CHEN, JUE
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1-VH-J(02)]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Nicotine is an abundant toxicant in various tobacco products including cigarette smokesmokeless tobacco cigars cigarillos and hookah. The use of tobacco products increase the riskfor atherosclerosis. Although usage of conventional cigarette has steadily declined over the lastthree decades usage of new and emerging tobacco products and electronic nicotine deliverysystems (ENDS) such as electronic cigarettes (e-cig) e-hookah and e-cigars has increasedexponentially. ENDS aerosolize a solution known as an e-liquid (typically a combination ofpropylene glycol PG and vegetable glycerol VG) that contains a small percentage of nicotine.Although several combustion products and toxins such as CO and tobacco-specific nitrosaminesare non-detectable in ENDS carbonyls including short-chain toxic aldehydes (acroleinformaldehyde acetaldehyde etc.) have been detected in e-cig-derived aerosols up to levelsfound in tobacco smoke. Our preliminary data suggest that exposure to e-cig or its componentssuch as acrolein and nicotine (oral exposure) induce macrophage activation (cytokine formationMMP activation and apoptosis) and exacerbate atherosclerosis. Conversely quenching ofendogenous aldehydes by feeding with the endogenous dipeptide - carnosine (-ala-his) oroverexpressing carnosine synthase in macrophages prevents atherosclerosis. Our preliminarystudies also show that chronic exposure to e-cig nicotine and acrolein increase the expressionof micro RNA-21 (miR-21) in the aortae of atherogenic mice; and acrolein and nicotine inducemiR-21 in macrophages in culture presumable as an adaptive response to macrophageactivation. Based on these observations we hypothesize that miR-21 decreases ENDS-inducedatherogenesis by preventing macrophage activation by ENDS-derived aldehydes and nicotine.To test this hypothesis we will 1) Examine the effect of e-cig on atherogenesis. In LDL receptor-null mice exposed to filtered air varying proportions of propylene glycol (PG):vegetable glycerin(VG) PG:VG + nicotine and JUUL-specific e-liquids we will quantify the time- dose- and sex-dependent changes in atherosclerotic lesion formation. We will examine how ENDS and theircomponents affect the plaque composition the nature and the stability; 2) Delineate theatherogenic contribution of ENDS-derived aldehydes. We will examine whether quenching of e-liquid and ENDS-derived aldehydes by oral feeding with carnosine or macrophage-specificoverexpression of carnosine synthase prevents macrophage activation and atherogenesis andhow are these processes regulated by miR-21; 3) Elucidate the atherogenicity of ENDSderivednicotine. We will probe how ENDS activate macrophage 7nAChR and how macrophage-specificdeficiency of 7nAChR affects ENDS-induced macrophage activation and atherogenesis. We willalso examine how miR-21 regulates these processes. Overall the proposed studies will establishnovel animal models of ENDS-induced atherosclerosis and delineate the underling chemicalcellular and molecular mechanisms of toxicity.

project_terms:
Acetaldehyde;Acrolein;Aerosols;Affect;Aldehydes;Animal Experiments;Animal Model;Aorta;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Carnosine;Cells;Cessation of life;Characteristics;Chemicals;Chronic;Chronic Disease;Cigar;Collagen;Data;Devices;Dipeptides;Disease;Dose;Electronic Nicotine Delivery Systems;Electronic cigarette;Electronics;Emerging Tobacco Products;Endothelium;Excision;Exposure to;Fatty acid glycerol esters;Formaldehyde;Glycerol;Human;In Vitro;Inflammation;Inflammatory;JUUL;Knockout Mice;Lesion;Life;Low Density Lipoprotein Receptor;Macrophage;Macrophage Activation;Matrix Metalloproteinases;Measures;Mediating;MicroRNAs;Molecular;Mus;Myeloid Cells;Myocardial Infarction;Nature;Necrosis;Nicotine;Nitrosamines;Oral;Pathway interactions;Persons;Play;Process;Propylene Glycols;Proteins;Risk;Role;Signal Transduction;Smoke;Smokeless Tobacco;Smoker;Smoking;Smooth Muscle Myocytes;Stroke;Supplementation;Testing;Thromboplastin;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Toxin;Trees;Untranslated RNA;Urine;Vegetables;adduct;aerosolized;air filter;alpha-bungarotoxin receptor;atherogenesis;atherosclerosis risk;chronic inflammatory disease;cigarette smoke;cigarette smoking;cigarillos;combustible cigarette;combustion product;cytokine;electronic hookah;electronic liquid;feeding;heart disease risk;hookah;insight;mortality risk;nicotine vapor;novel;overexpression;premature;prevent;recruit;response;sex;tobacco products;toxicant;vegetable glycerin

public_health_relevance:
Nicotine is an abundant toxicant in various tobacco products including cigarette smokesmokeless tobacco cigars cigarillos and hookah. While combustible cigarette smoking has beenshown to increase the risk for heart disease little is known about the effect of electronic nicotinedelivery systems (ENDS) on cardiovascular disease. In this project we will examine the effect ofchronic usage of ENDS-derived nicotine on the accumulation of fat and inflammatory cells in theblood vessels which can eventually cause heart attack and stroke.


application_id: 10533348
project_number: 5R01NS110169-05
project_title: Regulation of swallow and the effects of high cervical spinal cord injury
administering_ic: NINDS
award_notice_date: 2022-12-19
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: NS
serial_number: 110169
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2018-12-15
project_end_date: 2024-11-30
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 10816268
contact_pi: PITTS, TERESA G
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
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. Swallow is a basic critical behavior necessary for the movement of liquids and food from themouth through the esophagus to the stomach. When swallow is abnormal (dysphagia) liquid and food mayenter the larynx and trachea (aspiration) causing subsequent pneumonia. While the collective literature reportsa large variance in the incidence of dysphagia a 2017 prospective study shows disordered swallow productionin 76% of cSCI patients. Our long-term goal is to understand the mechanism(s) of dysphagia following cSCIand to develop novel therapies which have a high likelihood of clinical utility. Our central hypothesis is thatspinal circuits are critical for the successful execution of swallow. Specifically the central pattern generator(CPG) in the brainstem controlling this vital airway protective behavior is connected to circuitry in the cervicalspinal cord. Our preliminary data demonstrates that acute C2 and C3 hemisections depress diaphragm activitywhich results in positive intra-thoracic pressure during swallow. These lesions also increased upper airwaymuscle recruitment considerably (~200-800%) with a total loss of sequential muscle recruitment during thepharyngeal phase of swallow. Additionally a high dose of a 5-HT1A agonist increased diaphragm activity duringswallow which was accompanied by restoration of upper airway sequential activation. Guided by strongpreliminary data our central hypothesis will be tested with the following aims: Aim 1: Identify the effects ofcervical spinal cord disruption on the swallow motor pattern; and Aim 2: Determine the therapeutic efficacy of8-OH-DPAT (5-HT1A agonist) on recovery of swallow function after acute spinal hemisection. We will useelectrophysiology techniques to determine the effects of C2 C3 and C4 hemisection on execution of swallow.We will also determine changes in swallow function with a combined protocol of C2 hemisection and medialmyelotomy. The therapeutic effectiveness of 8-OH-DPAT on swallow function will be tested in intact animals aswell as with C2 C3 and C4 hemisections. To ensure the treatment effects are related to 5-HT1A receptoractivation a series of experiments will also be performed with the 5-HT1A antagonist WAY-100635. Thesestudies will be the first to show in an animal model that loss of cervical spinal pathways has a deleteriouseffect on swallow. Additionally we will provide pre-clinical evidence that a 5-HT1A receptor agonist can be usedto treat swallow impairments which will be the first of its kind for dysphagia. This information will educate theclinical community about risk of dysphagia after cSCI and provide options for novel interventions.

project_terms:
Acute;Address;Agonist;Animal Model;Animals;Autoreceptors;Behavior;Brain Stem;Bypass;Cause of Death;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Cervical spine;Clinical;Clinical Treatment;Communities;Coughing;Data;Deglutition;Deglutition Disorders;Depressed mood;Dose;Electrophysiology (science);Ensure;Enteral Feeding;Esophagus;Felis catus;Fiber;Food;Goals;Health;Impairment;Incidence;Individual;Infusion procedures;Injury;Intervention;Larynx;Lesion;Liquid substance;Literature;Longterm Follow-up;Medial;Mental Depression;Motor;Movement;Muscle;Oral;Oral cavity;Patient Selection;Patients;Pattern;Performance;Pharyngeal structure;Phase;Pneumonia;Population;Prevalence;Production;Prospective Studies;Protocols documentation;Quality of life;Receptor Activation;Recovery;Regulation;Reporting;Respiratory Diaphragm;Retrospective Studies;Risk;Series;Serotonin;Serotonin Receptor 5-HT1A;Spinal;Spinal cord injury patients;Stomach;Techniques;Testing;Therapeutic;Trachea;Treatment Efficacy;Tube;Vertebral column;Work;airway muscle;antagonist;artery infusion;aspirate;central pattern generator;experimental study;forgetting;improved;insight;novel;novel therapeutics;nutrition;pre-clinical;preservation;pressure;prevent;protective behavior;recruit;rehabilitation strategy;response;restoration;spinal pathway;therapeutic effectiveness;treatment effect

public_health_relevance:
PROJECT NARRATIVEThis study focuses on the importance of spinal circuitry for swallow production the effects of disrupting thiscircuitry and a potential swallow therapeutic. Dysphagia (abnormal swallow) is a critical health problem thatcan cause pneumonia which is a primary cause of death in patients with cervical spinal cord injury.


application_id: 10533341
project_number: 5R01NS116068-03
project_title: Macrophage Depletion Therapy for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2023-02-01
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 116068
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2025-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: ALILAIN, WARREN JOSEPH
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. Spinal cord injury (SCI) is a devastating lifelong affliction that impairs anumber of functions including locomotion breathing autonomic regulation and sensation/pain. Unfortunatelythere is no current FDA approved therapy for SCI. Therefore there is a critical need to translate basic sciencediscoveries developed in the laboratory with promising effects after experimental SCI towards humanapplication. SCI elicits an intraspinal inflammatory response comprised of resident glia and infiltrating bloodleukocytes. Although subsets of resident and recruited immune cells have been implicated in CNS repair morethan 20 years of experimental data in different animal models of SCI indicate that acute monocyte depletion(MD) is consistently neuroprotective. Further there are clinically viable drugs such as clodronate that caneffectively deplete monocytes after SCI. However a number of fundamental questions must be answeredbefore successful translation including understanding the extent to which injury level impacts therapeuticefficacy as well as understanding the long-term consequences of MD on functional recovery and monocyterepopulation and fate. Therefore the goals of this proposal are to examine chronic and level-specific functionalchanges after acute MD using clinically relevant outcomes including pain autonomic dysreflexia respirationand forelimb/hand function. We will study the effects of acute liposome encapsulated clodronate treatment forup to one year in rodent models of cervical and thoracic SCI. Specifically this grant seeks to: Aim 1: evaluatethe dose-response effects of acute MD on myelopoiesis biodistribution and toxicity; Aim 2: determine theefficacy of acute MD on recovery of locomotor sensory and autonomic function in chronic SCI rats. Aim 3:determine the effects of acute MD on recovery of respiratory motor and forelimb function after cervical SCI.The combined approach of examining the effects of MD after both cervical and thoracic SCI will provideunprecedented preclinical data regarding the effects of monocyte function on sensory autonomic pain andrespiratory outcomes. The feasibility of clodronate (aka disodium dichloromethylene diphosphonate) treatmentin SCI individuals was reported almost 40 years ago therefore our proposal is significant as data from ourstudies could be adapted to treat human SCI and is expected to be of critical translational impact.

project_terms:
Acute;Affect;American;Animal Model;Animals;Anti-Inflammatory Agents;Applications Grants;Autonomic Dysreflexia;Basic Science;Biodistribution;Biological Assay;Bone Marrow;Breathing;Caring;Cell Death;Cells;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chronic;Clinical;Clinical Trials;Congresses;Contusions;Data;Dichloromethylene Diphosphonate;Distal;Dose;Encapsulated;Esthesia;FDA approved;Flow Cytometry;Forelimb;Frustration;Funding;Goals;Grant;Hand functions;Hindlimb;Hour;Human;Immune;Immune Targeting;Immunologic Deficiency Syndromes;Impairment;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Laboratories;Lesion;Leukocytes;Liposomes;Liver;Locomotion;Locomotor Recovery;Macrophage;Mediating;Minocycline;Modeling;Modification;Motor;Multiple Trauma;Myelopoiesis;Neuroglia;Organ;Outcome;Outcome Measure;Output;Pain;Pathology;Persons;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Population;Production;Publishing;Quality of life;Rattus;Recovery;Recovery of Function;Regulation;Reporting;Research;Research Personnel;Respiration;Rodent;Rodent Model;Sensory;Site;Spinal Cord;Spinal Cord Contusions;Spinal Cord Plasticity;Spinal Injuries;Spinal cord injury;Spleen;Steroids;Testing;Therapeutic;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Translating;Translations;Treatment Efficacy;United States;United States National Institutes of Health;Voice;arm;axonal sprouting;central pattern generator;clinically relevant;efficacy evaluation;functional disability;functional outcomes;improved;improved outcome;indexing;innovation;meetings;monocyte;neuroprotection;novel therapeutic intervention;pre-clinical;preclinical evaluation;recruit;repaired;respiratory;response;side effect;synaptogenesis;tissue repair;translational impact;translational therapeutics

public_health_relevance:
PROJECT NARRATIVE. There are near 290000 people in the United States of America that have a spinalcord injury (SCI) (with at least 18000 new cases each year) many with functional impairment. The mainobjective of this grant proposal is to investigate a novel therapeutic strategy which modifies the inflammatoryresponse and can potentially lead to protection of the spinal cord after injury as well as functional recovery.This dose-response experimental approach will be studied in multiple injury levels and functional outcomes aswell as tracked over time and collectively these studies will lead to better understanding of the impact ofinflammatory modification after injury and can potentially lead to improvement in human care and outcomes.


application_id: 10532229
project_number: 5R01DK128033-02
project_title: Mirabegron and tadalafil effectiveness for treatment of prediabetes
administering_ic: NIDDK
award_notice_date: 2022-11-30
opportunity_number: PAS-20-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 128033
program_official: GOROSPE, RAFAEL
project_start_date: 2021-12-01
project_end_date: 2024-11-30
study_section: Human Studies of Diabetes and Obesity Study Section[HSDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Approximately 84 million Americans have prediabetes and progression to type 2 diabetes occurs at a rateof 5% to 10% per year and is a risk factor for heart disease. Although lifestyle change is effective mostprediabetic individuals cannot achieve the changes necessary to reverse prediabetes or prevent diabetes. In recent studies we treated obese insulin-resistant humans with the -adrenergic receptor (3AR) agonistmirabegron and this resulted in improved oral glucose tolerance lower HbA1c and increased insulinsensitivity and -cell function. These changes occurred in the absence of weight loss. Although brownadipose tissue did not increase mirabegron treatment increased beige fat reduced adipose inflammation andincreased type 1 fibers and capillary density in skeletal muscle. Beige adipocytes have beneficial effects onglucose metabolism and are postulated to act as a glucose sink. Mirabegron stimulates the 3AR which stimulates the cAMP-mediated activation of PKA and the activationof p38 map kinase which induces UCP1 and adipose beiging. Recent studies showed that cGMP activation ofprotein kinase G (PKG) acted in a similar fashion to improve glucose metabolism and increase white adiposebeiging. Indeed cGMP is stimulated by natural ligands (ANP BNP nitric oxide); the phosphodiesterase 5(PDE5) inhibitor drugs sildenafil and tadalafil prevent breakdown of cGMP activating PKG and this results inincreased UCP1 in adipocytes. Therefore we hypothesize that treatment of prediabetic subjects withmirabegron or tadalafil will improve glucose metabolism. We further hypothesize that the combined treatmentwith mirabegron and tadalafil will have additive improvements in glucose metabolism likely due to their parallelactions of stimulating the cyclic nucleotides cAMP and cGMP and inducing adipose beiging. Specific Aim 1. We hypothesize that a 4 month treatment with the 3 agonist mirabegron will result inimproved glucose metabolism in obese prediabetic human research participants and this improvement inglucose metabolism will be further improved by combination therapy with mirabegron plus tadalafil. Specific Aim 2. We will identify underlying mechanisms of the improved glucose homeostasis in responseto mirabegron and tadalafil by characterizing insulin sensitivity insulin secretion adipose tissue beigingmuscle fiber type and muscle capillaries.Clinical relevance: Other than weight loss we have only limited methods for improving prediabetes. Drugsthat target white adipose beiging improve glucose metabolism in both rodents and humans and we proposethat this can be exploited to attenuate prediabetes. This application addresses the effectiveness of two drugsthat are widely prescribed well tolerated but which have not been extensively studied for their metaboliceffectiveness in subjects with prediabetes and have never been studied in combination. Results from thisstudy could lead to a larger trial which could considerably alter our approach to the treatment of prediabetes.

project_terms:
Address;Adipocytes;Adipose tissue;Adrenergic Agonists;Adrenergic beta-Agonists;Agonist;American;Attenuated;Beta Cell;Bladder;Blood capillaries;Body Weight decreased;Brown Fat;Cell physiology;Clinical Trials;Combined Modality Therapy;Consumption;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cyclic GMP;Cyclic GMP-Dependent Protein Kinases;Cyclic Nucleotides;Data;Diabetes Mellitus;Disease;Drug Combinations;Drug Targeting;Effectiveness;Exercise;FDA approved;Fatty acid glycerol esters;Fiber;Glucose;Glycosylated hemoglobin A;Goals;Heart Diseases;Human;Individual;Inflammation;Insulin Resistance;Life Style;Ligands;Link;Lipids;Lipolysis;Mediating;Metabolic;Methods;Mission;Multicenter Trials;Muscle;Muscle Fibers;National Institute of Diabetes and Digestive and Kidney Diseases;Nitric Oxide;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oral;Overactive Bladder;Participant;Pathway interactions;Pharmaceutical Preparations;Prediabetes syndrome;Recommendation;Research;Research Project Grants;Risk Factors;Rodent;Skeletal Muscle;Smooth Muscle;Thinness;Treatment Effectiveness;Woman;beta-adrenergic receptor;blood glucose regulation;clinical efficacy;clinically relevant;comorbidity;density;design;diabetes prevention program;effectiveness evaluation;glucose metabolism;glucose tolerance;heart disease risk;improved;inhibitor;inhibitor therapy;insulin secretion;insulin sensitivity;oral glucose tolerance;p38 Mitogen Activated Protein Kinase;phosphodiesterase V;placebo controlled trial;prevent;protein activation;response;side effect;sildenafil;subcutaneous;tadalafil;uncoupling protein 1

public_health_relevance:
This research grant is designed to examine the importance of repurposing two drugs that holdpromise for improving glucose metabolism. Mirabegron and tadalafil augment levels of cAMPand cGMP respectively and we will determine whether mirabegron tadalafil or a combinationof these drugs improve glucose homeostasis. These drugs both cause induction of beigeadipose and this study will also explore mechanisms for their effects.


application_id: 10531750
project_number: 3R01AA028735-04S1
administering_ic: NIAAA
award_notice_date: 2022-07-13
opportunity_number: PA-17-297
application_type: 3
activity_code: R01
ic: AA
serial_number: 028735
suffix: S1
program_official: LIN, LI
project_start_date: 2021-11-01
project_end_date: 2025-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ATAC-seq;Abstinence;Address;Adverse event;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Animals;Area;Bacterial Infections;Biological Assay;Biological Response Modifiers;Biology;Blood;Blood specimen;Bone Marrow;Cardiovascular Diseases;Cell Line;Cells;Chromatin;Chronic;Chronic Disease;Communicable Diseases;Complex;Data;Defect;Development;Dose;Environment;Epigenetic Process;Ethanol;Etiology;Event;Failure;Female;Gene Expression;Genetic Transcription;Goals;Health;Heavy Drinking;Hematopoietic;Hematopoietic stem cells;Heterogeneity;Homeostasis;Host Defense;Housing;Human;Immune;Immune Tolerance;Immunity;Immunocompetence;Immunologics;Immunology procedure;Impaired wound healing;In Vitro;Individual;Infection;Inflammation Mediators;Inflammatory;Inflammatory Response;Intercistronic Region;Intervention;Knowledge;Link;Macaca;Macaca mulatta;Mediating;Metabolic;Metabolism;Modeling;Myelogenous;Myeloid Cells;Myelopoiesis;Natural Immunity;Outcome;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phenotype;Physiology;Postoperative Period;Predisposition;Promoter Regions;Reporting;Research;Risk;Sampling;Self Administration;Testing;Tissues;Viral Respiratory Tract Infection;Virus Diseases;alcohol availability;alcohol effect;antimicrobial;cancer type;chronic alcohol ingestion;cytokine;drinking behavior;epigenome;experimental study;fitness;histone modification;immune activation;improved;in vivo;in vivo Model;insight;macrophage;male;migration;monocyte;next generation sequencing;nonhuman primate;novel;pathogen;peripheral blood;progenitor;programs;response;single cell analysis;single-cell RNA sequencing;stem cells;therapy design;tissue repair;transcriptome;transcriptomics;wound healing


application_id: 10531712
project_number: 1R01AA030424-01
project_title: Intestine FXR activation by LGG-derived nanoparticles in alcohol-associated liver disease
administering_ic: NIAAA
award_notice_date: 2022-08-15
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AA
serial_number: 030424
program_official: WANG, JOE
project_start_date: 2022-08-15
project_end_date: 2022-12-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
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:
Numerous studies have reported the efficacy of probiotics for alcohol associated liver disease (ALD). Thisreflects a strong interest among the scientific and medical communities in identifying alternative or adjunctiveapproaches for ALD for which there is no current effective or widely accepted therapeutic option. However indepth molecular knowledge on how probiotics render their effects is lacking. Patients with ALD often exhibitmanifestations of cholestasis a liver pathology defined by accumulation of hepatic bile acids (BAs) which aretoxic and are an important causative factor in hepatocyte death and liver injury in ALD. Excess hepatic BAconcentration is partially a result of increased BA de novo synthesis. We have identified a miRNA (miR194) thatis overexpressed in the intestinal epithelial cells in mice fed alcohol. MmiR194 suppresses a nuclear receptorFXR that is activated by BAs and regulates intestine-derived hormone FGF15 expression which plays a majorrole in maintaining hepatic BA homeostasis by suppressing BA synthesis via down-regulation of Cyp7A1. Whilethe BA activation of FXR is well-studied how FXR is regulated transcriptionally is less clear. Our preliminarydata showed that probiotic Lactobacillus rhamnosus GG-derived nanoparticles (LDNPs) administration reducedintestinal miR194 and increased FXR and FGF15 expression and decreased hepatic BAs and fatty liver in micewith ALD. We hypothesize that alcohol suppresses both the transcriptional expression and ligand-mediatedactivation of FXR in the intestine through upregulating miR194 and disturbing gut-microbiome-BA transformationrespectively which lead to the increases in hepatic de novo BA synthesis lipogenesis and ALD and that LDNPsupplementation can diminish alcohol-induced increases in BA synthesis and lipogenesis and attenuate ALDthrough suppressing intestinal miR194 expression and regulating gut microbiome BA transformation. Thefollowing specific aims will be pursued to test this hypothesis: Aim 1. Determine the role of intestinal miR194 inthe alcohol-induced dysregulation of liver BA synthesis and lipogenesis. Aim 2. Determine the role of LDNPs inthe regulation of intestinal miR194-FXR-FGF15 signaling in ALD. AIM 3. Determine whether LDNP treatmentalters gut microbiota and BA profile that contribute to FXR activation in ALD. Aim 4. Evaluate the intestinalmiR194 and FXR activity in patients with AH. In summary the proposed study represents the first molecularstudy on how intestinal miRNA regulates liver BA homeostasis and how a probiotic product targets intestinalmiRNA194-FXR-FGF15 singling in ALD. The results obtained from this study may lead to improved managementof ALD.

project_terms:
Alcohols;Animal Model;Attenuated;Bile Acid Biosynthesis Pathway;Bile Acids;Binding;Biological Markers;Biological Process;Cessation of life;Cholestasis;Clinical Research;Clinical Trials;Communities;Data;Detergents;Development;Down-Regulation;Enzymes;Epithelial Cells;Evaluation;Exhibits;FDA approved;FGF19 gene;Fatty Liver;Fatty acid glycerol esters;Feces;Fibroblast Growth Factor;Fibroblast Growth Factor Receptors;Genetic Transcription;Goals;Hepatic;Hepatitis;Hepatocyte;Homeostasis;Hormones;Human;Intestines;Knock-out;Knowledge;Lactobacillus casei rhamnosus;Lead;Ligands;Lipids;Liver;Liver diseases;Mediating;Medical;MicroRNAs;Molecular;Mus;Nuclear Receptors;Pathology;Pathway interactions;Patients;Pharmacology;Play;Prevention strategy;Probiotics;Property;Receptor Activation;Regulation;Reporting;Role;Sampling;Serum;Signal Transduction;Signaling Molecule;Supplementation;Testing;Therapeutic;Transcriptional Activation;Translating;Treatment Efficacy;Urine;absorption;alcohol abuse therapy;base;exosome;feeding;gut microbiome;gut microbiota;improved;interest;intestinal epithelium;lipid biosynthesis;liver injury;mRNA Expression;mouse model;nanoparticle;novel therapeutic intervention;overexpression;probiotic supplementation;protective effect;receptor

public_health_relevance:
The goals of this project are to investigate the mechanisms of gut-derived microRNA in liver bile acid andlipid synthesis. This study will have a major impact on the development of a probiotics-based new therapeuticstrategy for the prevention and treatment of alcohol-associated liver disease.


application_id: 10531677
project_number: 3RF1AG027297-11A1S1
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2022-01-27
opportunity_number: PA-20-272
application_type: 3
activity_code: RF1
ic: AG
serial_number: 027297
suffix: A1S1
program_official: OPANASHUK, LISA A
project_start_date: 2006-09-01
project_end_date: 2023-08-31
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract (FROM ORIGINAL FUNDED PROPOSAL)Mounting evidence suggests that comorbid vascular contributions to cognitive impairment anddementia (VCID) may complicate the treatment of Alzheimers disease (AD)-related dementia. Ouroverarching hypothesis is that AD and VCID pathological sequelae converge at the level of activatedastrocytes providing a common druggable target for a wide range of dementias (i.e. AD alone VCID aloneand mixed dementia). Central to this hypothesis is the Ca2+ -dependent phosphatase calcineurin (CN) whichappears at high levels in activated astrocytes and positively regulates multiple components of theactivated astrocyte phenotype through direct interactions with NFAT transcription factors. We and othershave shown that hyperactivation of CN/NFAT occurs in astrocytes during early stages of cognitive declinein humans and mice with AD-like pathology and is linked to glutamate-dependent hyperexcitability.However little is known about astrocytic CN/NFAT in VCID presenting a critical knowledge gap in ourunderstanding of mixed dementia. New preliminary data obtained from human cerebrovascular pathology cases and from an establisheddiet-based VCID mouse model suggest that hyperactive CN/NFAT signaling also arises with cerebrovascularpathology. Based on these observations we predict that combined AD and VCID pathology willexacerbate aberrant CN/NFAT signaling leading to a neurotoxic astrocyte phenotype characterized bythe loss of EAAT2/Glt-1 glutamate transporters and impaired glutamate uptake. We further predict thatnormalization of the CN/NFAT/Glt-1 axis using cell-type specific AAV vectors and novel pharmacologicagents will alleviate neuronal and cerebrovascular abnormalities in AD VCID and mixed AD/VCIDmodels. Our overarching hypothesis and corollary predictions will be tested using human biospecimensand relevant mouse models including the hyperhomocysteinemia (HHcy) model of VCID and the 5xFADmodel of A pathology. Aim 1 will test the hypothesis that mixed AD and VCID pathologies in both humansand mice converge to exacerbate CN/NFAT hyperactivity in astrocytes leading to a neurotoxic astrocytemolecular phenotype. Aim 2 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis drivescerebrovascular dysfunction in AD VCID and mixed VCID/AD models. And Aim 3 will test thehypothesis that the astrocytic CN/NFAT/Glt-1 axis drives hyperexcitability synapse dysfunction andcognitive loss in AD VCID and mixed VCID/AD models. These aims will be pursued using novelreagents and cutting-edge multidisciplinary approaches. This work is essential for assessing the role ofastrocytic CN/NFATs in VCID and mixed pathology and may help stimulate the development of astrocyte-targeted approaches for treating a broad range of dementia cases.

project_terms:
Address;Administrative Supplement;Aging;Air;Alzheimer like pathology;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Animal Model;Area;Astrocytes;Autopsy;Blood - brain barrier anatomy;Blood Flow Velocity;Blood capillaries;Brain;Budgets;COVID-19 pandemic;Calcineurin;Caliber;Cells;Cephalic;Cerebrovascular Circulation;Cerebrovascular Disorders;Contralateral;Data;Dementia;Development;Diet;Dyes;Electrophysiology (science);Ensure;Equipment;Extravasation;Functional disorder;Funding;Glass;Glutamate Transporter;Glutamates;Hour;Human;Human Resources;Hyperactivity;Hyperhomocysteinemia;Image;Impaired cognition;Impairment;Inflammatory;Investigation;Kentucky;Knowledge;Lasers;Lead;Link;Maintenance;Methods;Microscope;Modeling;Molecular;Molecular Profiling;Mus;NFAT Pathway;Neurons;Optics;Parents;Pathologic;Pathology;Performance;Pharmacology;Phenotype;Phosphoric Monoester Hydrolases;Physiological;Procedures;Process;Reagent;Research;Research Personnel;Resources;Role;Running;Scanning;Schedule;Signal Transduction;Specimen;Synapses;System;Techniques;Testing;Time;Transgenic Animals;Universities;Vascular Cognitive Impairment;Vibrissae;Work;adeno-associated viral vector;arteriole;awake;barrel cortex;base;cell type;cerebrovascular;cerebrovascular pathology;comorbidity;coronavirus disease;druggable target;experimental study;imaging facilities;improved;innovation;insight;interdisciplinary approach;mixed dementia;molecular phenotype;mouse model;multidisciplinary;neurotoxic;neurovascular coupling;novel;patch clamp;post-COVID-19;rhodamine dextran;transcription factor;two photon microscopy;two-photon;uptake;vascular cognitive impairment and dementia;vector

public_health_relevance:
Project Narrative (FROM ORIGINAL FUNDED PROPOSAL)Project will investigate the role of astrocyte activation in vascular cognitive impairment usingpostmortem human brain specimens transgenic animal models and multidisciplinarytechniques. This work could lead to nonconventional cell-directed strategies for combatingdementia.


application_id: 10531550
project_number: 5R01AI143690-04
project_title: Biogenesis and Function of Streptococcus Pyogenes Cell Wall
administering_ic: NIAID
award_notice_date: 2022-10-18
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 143690
program_official: GU, XIN-XING
project_start_date: 2019-11-25
project_end_date: 2024-10-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
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:
Group A streptococcus (GAS Streptococcus pyogenes) is a leading bacterial pathogen of thehuman pharynx and skin. In recent years a striking resurgence in severe invasive GASinfections has been observed worldwide. GAS infections account for more than 650000 casesof severe invasive disease annually. The invasive GAS infections necrotizing fasciitis cellulitisand erysipelas with concomitant scarlet fever and streptococcal toxic syndrome are difficult totreat with antibiotics and a GAS vaccine is urgently needed to combat this neglected disease. Amajor component of the GAS cell wall is the Group A Carbohydrate (GAC) covalently linked topeptidoglycan consisting of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc)side-chains. GAC is an attractive vaccine candidate due to its conserved expression in all GASserotypes and the absence of its constitutive component rhamnose in humans. Our geneticbiochemical and structural studies identified two novel modifications of GAC glycans: glycerolphosphate modification of GAC and de-N-acetylation of the GAC linkage unit. The goal of thisproposal is to characterize the mechanisms of GAC biosynthesis and modification andelucidate the roles of cell wall modifications in antimicrobial resistance mechanisms and GASpathogenesis. To help answer these questions we will employ a variety of genetic biochemicalanalytical and structural approaches. The function of cell wall modifications in GASpathogenesis will be studied in ex vivo and in vivo models of GAS infection. The proposedstudies provide a platform for design of a safe and effective vaccine against this importanthuman pathogen and should have broad application to other streptococci which express similarcell wall polysaccharides. Since the enzymes of the GAC biosynthesis pathway are attractivedrug targets the proposed studies will have important implications for drug design.

project_terms:
Acetylation;Anabolism;Analytical Chemistry;Antibiotic Therapy;Antibiotics;Antimicrobial Cationic Peptides;Antimicrobial Resistance;Bacterial Physiology;Binding;Biochemical;Biogenesis;Biological;Biological Assay;Carbohydrates;Cations;Cell Wall;Cell membrane;Cell physiology;Cells;Cellulitis;Charge;Chemicals;Communicable Diseases;Control Groups;Data;Deacetylase;Dental;Development;Diagnostic;Disease;Drug Design;Drug Targeting;Electrostatics;Enzymatic Biochemistry;Enzymes;Epitopes;Erysipelas;Freeze Substitution;Gene Cluster;Genetic;Glycerol;Goals;Histones;Homologous Gene;Human;Infection;Knowledge;Link;Mass Spectrum Analysis;Methods;Modeling;Modification;Molecular;Molecular Genetics;Molecular Structure;Muramidase;Necrotizing fasciitis;Outcome;Outcome Study;Outcomes Research;Pathogenesis;Pathway interactions;Peptidoglycan;Permeability;Pharyngeal structure;Phospholipase A2;Polymers;Polysaccharides;Predisposition;Proteins;Publishing;Rhamnose;Role;Scarlet Fever;Serotyping;Serum;Skin;Streptococcal Infections;Streptococcal Vaccines;Streptococcus;Streptococcus mutans;Streptococcus pyogenes;Structure;Surface;Syndrome;Techniques;Testing;Therapeutic Intervention;Thick;Vaccine Antigen;Vaccine Design;Vaccines;Vertebral column;Work;analog;antimicrobial;antimicrobial peptide;carbohydrate biosynthesis;cell envelope;combat;density;design;drug development;extracellular;human pathogen;improved;in vivo;in vivo Model;inorganic phosphate;insight;molecular size;mortality;mouse model;mutant;neglect;neutrophil;novel;pathogen;pathogenic bacteria;resistance mechanism;targeted treatment;vaccine candidate

public_health_relevance:
The proposed studies investigate structure biosynthesis pathway and function of cellwall in the important human pathogen Streptococcus pyogenes. The outcomes of this researchare expected to have a positive impact on the development of highly targeted therapeutics tocontrol S. pyogenes infections.!


application_id: 10531210
project_number: 5R01DK124626-03
project_title: Mechanisms for activation of beige adipose tissue in humans
administering_ic: NIDDK
award_notice_date: 2022-11-29
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 124626
program_official: GOROSPE, RAFAEL
project_start_date: 2020-12-01
project_end_date: 2025-11-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have been studying subcutaneous white adipose tissue (SC WAT) beiging in response to mirabegronwhich is a 3 adrenergic receptor (3AR) agonist. 3ARs are found in adipocytes and smooth muscle andmirabegron is an FDA approved drug for overactive bladder. Treatment of obese insulin resistant humans fortwelve weeks with mirabegron consistently induced SC WAT beiging and this led to improved oral glucosetolerance and a lower HbA1c. The mechanism for improved glucose homeostasis involved both a smallimprovement in insulin sensitivity and a significant improvement in -cell function (insulin secretion) along withan increase in muscle oxidative type 1 fibers; however there was no weight loss or induction of brown fat.Since pancreatic -cells and muscle do not express the 3AR the beneficial effects of mirabegron in thesecells likely occurred by an indirect mechanism. The physiological effects of mirabegron are likely mediated in part by the induction of beige adipose whichrepresents a metabolic sink for glucose and lipids and which may alter adipose remodeling. In addition thechanges in adipose tissue and other organs may result in secondary effects that target other tissues. Specific Aim 1. To examine the effects of the 3 agonist mirabegron on glucose metabolism we willcomprehensively analyze glucose tolerance insulin sensitivity and -cell function in prediabetic subjects in a4-month placebo-controlled randomized trial. We will assess changes in adipose tissue including beiginginflammation fibrosis and insulin-stimulated glucose uptake by adipocytes. We will also fully characterizegene expression in SC WAT by RNA-seq to identify potential mechanisms such as altered adipokine profiles. Specific Aim 2. We hypothesize that mirabegron causes cells that express the 3AR to change the levelsof secreted factors that affect peripheral cell types such as -cells and muscle. We will use biochemical andpharmacological approaches to identify the mechanism by which conditioned medium from mirabegron-treatedadipocytes increases PGC1 expression in muscle in vitro. We will utilize unbiased approaches to identifychanges in lipids metabolites and exosome miRNA composition in the adipocyte conditioned media. We willuse these approaches to identify molecules altered in plasma by mirabegron treatment that are responsible forthe improvement in -cell and muscle function. Clinical relevance: Mirabegron treatment has positive effects on glucose tolerance due to improvementsin insulin sensitivity and -cell function. This may be exploited to prevent conversion of prediabetes todiabetes or used as a therapeutic in diabetics. This application will also increase our understanding of themechanism(s) by which mirabegron acts which may reveal new therapeutic targets

project_terms:
Adipocytes;Adipose tissue;Adrenergic Agonists;Adrenergic Receptor;Affect;Agonist;Antidiabetic Drugs;Beta Cell;Biochemical;Body Weight decreased;Brown Fat;Cell physiology;Cells;Chronic;Conditioned Culture Media;Consumption;Development;Diabetes Mellitus;Elderly;Epidemic;FDA approved;Fatty acid glycerol esters;Fiber;Fibrosis;Gene Expression;Glucose;Glycosylated hemoglobin A;Health;Homeostasis;Human;In Vitro;Inflammation;Insulin;Insulin Resistance;Lipids;Lipolysis;Mammals;Measures;Mediating;Metabolic;Metabolic syndrome;Methods;MicroRNAs;Mus;Muscle;Muscle Cells;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Overactive Bladder;Participant;Peripheral;Pharmaceutical Preparations;Physiological;Plasma;Play;Prediabetes syndrome;Property;Proteins;Research;Research Project Grants;Rodent;Role;Skeletal Muscle;Smooth Muscle;Structure of beta Cell of islet;Therapeutic;Thinness;Tissues;Volatile Fatty Acids;adipokines;adult obesity;bile acid metabolism;blood glucose regulation;cell type;clinically relevant;combat;design;diabetic;exosome;fighting;functional improvement;glucose metabolism;glucose tolerance;glucose uptake;human study;improved;insulin secretion;insulin sensitivity;interest;mRNA Expression;new therapeutic target;novel strategies;obesity treatment;oral glucose tolerance;pharmacologic;prevent;randomized placebo controlled trial;response;subcutaneous;transcriptome sequencing;uncoupling protein 1

public_health_relevance:
This research grant is designed to determine whether chronic treatment with mirabegron a 3adrenergic receptor agonist approved for treatment of over active bladder improves metabolichomeostasis in prediabetic obese research participants. We will also investigate theunderlying mechanisms for improved -cell function and insulin sensitivity by mirabegrontreatment which we recently demonstrated. There is a tremendous need for new approachesto fight the obesity and type 2 diabetes epidemic and this research is thus highly relevant tohuman health.


