# projects

application_id: 10354691
project_number: 2P42ES023716-06
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5055
contact_pi_person_id: 9972311
contact_pi: NANTZ, MICHAEL H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-20
project_abstract:
PROJECT SUMMARY (Project 3)This proposed work is to advance airborne volatile organic compound (VOC) detection and quantificationtechnologies and to robustly characterize indoor/outdoor contrast and in-home determinants for exposures totarget Superfund-relevant VOCs. This research will continue to grow and expand two VOC real-time in situmeasurement platforms developed by the University of Louisville Superfund Research Center established in2017. One platform comprises small low-cost sensors that can be deployed alone or in networks. Novel gassensors and sensor arrays are being developed to measure target Superfund-relevant VOCs including acroleintrichloroethene (TCE) benzene toluene ethylbenzene and xylene (BTEX). The devices use novel surfacechemistries to address the common challenges of selectivity and sensitivity and are fabricated usingmicroelectromechanical systems (MEMS) technology. Another platform addresses the need for flexiblydesigned field-deployable instruments that can measure with high sensitivity a large range of compounds tointerrogate microenvironments with complex VOC mixtures. The Multichannel Organics In-situ enviRonmentalAnalyzer (MOIRA) instrument developed in the first cycle of Center funding for mobile monitoring will beexpanded and optimized for indoor/outdoor VOC monitoring studies. MOIRA is a gas chromatographymassspectrometry (GC-MS) instrument with high time resolution (e.g. ten minutes). Its capabilities will be expandedto measure both higher and lower volatility compounds than can be achieved with the current design. Theseinnovative high time resolution in situ measurements will be coupled with conventional time-integrated VOCpassive sampling to measure target Superfund-relevant VOCs at homes of some participants in the allied clinicalstudy. These data will be used to build spatiotemporal models to estimate ambient VOCs at the homes of allclinical study participants and to gain new insights into VOC levels and their determinants in the homemicroenvironment. In addition to exposure assessment the two measurement platforms are responsive toongoing Superfund program advancements; these innovative developments will expand future capacities tomonitor VOC indoor vapor intrusion monitor outdoor VOC levels during site remediation and monitor bothindoors and outdoors during post-remediation surveillance.

project_terms:
Acrolein;Address;Air;Automobile Driving;Benzene;Cardiometabolic Disease;Chemistry;Clinical Research;Collection;Complex;Coupled;Custom;Data;Detection;Development;Devices;Electrodes;Environmental Exposure;Exhibits;Exposure to;Funding;Future;Gases;Goals;Gold;Home;Hour;In Situ;Indoor environment;Industrialization;Infiltration;Investigation;Mass Fragmentography;Measurement;Measures;Modeling;Modification;Monitor;Participant;Pattern;Process;Protons;Reaction;Research;Residual state;Resolution;Sampling;Signal Transduction;Site;Small-Area Variations;Source;Sulfhydryl Compounds;Superfund;Surface;System;Technology;Temperature;Testing;Time;Toluene;Trichloroethylene;Universities;Work;Xylene;base;cost;design;ethylbenzene;exposed human population;flexibility;gas analyzer;innovation;insight;instrument;mass spectrometer;metal oxide;miniaturize;nanoGold;new technology;novel;programs;remediation;residence;sensor;spatiotemporal;superfund chemical;superfund site;time use;tool;urban setting;vapor intrusion;volatile organic compound

public_health_relevance:
RELEVANCEThis proposed work is to support continued research within the University of Louisville Superfund ResearchCenter on novel technologies to detect and quantify Superfund-relevant volatile organic compounds (VOCs) inair. These technology platforms will be used to better understand VOC sources and human exposures.


application_id: 10354690
project_number: 2P42ES023716-06
project_title: Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5054
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
13-Butadiene;2-butenal;ATF6 gene;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Animal Model;Apoptosis;Apoptotic;Atherosclerosis;Benzene;Biological;Biological Markers;Blood Vessels;Body Burden;Butadiene;Cardiometabolic Disease;Cardiovascular Physiology;Cardiovascular system;Carnosine;Cell physiology;Chemical Exposure;Chemical-Induced Change;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Disease Resistance;Dose;Endoplasmic Reticulum;Endothelial Cells;Endothelium;Environmental Exposure;Environmental Impact;Exposure to;Fatty acid glycerol esters;Formaldehyde;Functional disorder;Funding;Glutathione;Goals;Hazardous Chemicals;Hazardous Substances;Health;Heart Diseases;Heart failure;Heat shock proteins;Hepatic;High Prevalence;Human;Hypertension;Individual;Inflammatory;Inhalation;Injury;Insulin Resistance;Investigation;Lead;Link;Lipid Peroxidation;Lipids;Measures;Mediating;Mediator of activation protein;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Obesity;Oxidative Stress;Parents;Pathway interactions;Pharmacology;Plasma;Platelet Activation;Poison;Process;Production;Property;Proteins;Protocols documentation;Reporting;Risk;Role;Signal Recognition Particle;Signal Transduction;Source;Stress Tests;Stroke;Structure;Superfund;Surveys;Testing;Therapeutic;Tobacco smoke;Toxic effect;Trichloroethylene;Vinyl Chloride;Work;ambient air pollution;base;cardiometabolic risk;cardiometabolism;cardiovascular health;cardiovascular injury;design;diet-induced obesity;disorder risk;endoplasmic reticulum stress;endothelial dysfunction;fatty liver disease;heart function;indexing;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;preclinical study;prevent;protein folding;protein misfolding;response;superfund site;systemic inflammatory response;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;vascular injury;volatile organic compound;western diet


application_id: 10354689
project_number: 2P42ES023716-06
project_title: Project 1 - Cardiometabolic Injury due to VOCs
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5053
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acrolein;Affect;Air;Animals;Area;Atherosclerosis;Benzene;Bile Acids;Biological Markers;Blood Platelets;Blood Pressure;Blood Vessels;Butadiene;Carcinogens;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Chronic;Collaborations;Communities;County;Data;Data Analyses;Development;Diabetes Mellitus;Disease Progression;Dose;Environmental Exposure;Enzymes;Event;Exposure to;Farm;Formaldehyde;Functional disorder;Goals;Hazardous Chemicals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Hospital Mortality;Hospitalization;Human;Individual;Injury;Insulin Resistance;Kentucky;Keratin;Lipids;Liquid substance;Liver;Liver diseases;Location;Measurement;Measures;Metabolic Diseases;Metabolism;MicroRNAs;Modeling;Monitor;Neighborhoods;Participant;Plasma;Population;Process;Risk;Serology;Serum;Steatohepatitis;Superfund;Target Populations;Testing;Time;Toluene;Trichloroethylene;Variant;Vascular Diseases;Water;Work;Xylene;arterial stiffness;blood glucose regulation;blood pressure elevation;carcinogenicity;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;circulating biomarkers;cohort;data management;diabetes risk;disorder risk;exposed human population;fatty liver disease;indexing;land use;landfill;liver biopsy;monocyte;mortality;primary endpoint;response;stem cells;superfund site;toxicant;urinary;vascular injury;volatile organic compound;wastewater monitoring


application_id: 10354688
project_number: 2P42ES023716-06
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (Overall)This proposal is to continue to grow and expand the University of Louisville Superfund Center established in2017. Currently the Center supports research on the cardiometabolic effects of volatile organic chemicals(VOCs) that are of high relevance to the Superfund Program. Center investigators conduct mode-of-actionresearch to unravel critical pathways of toxicity and to identify toxicological end-points (cardiometabolic changes)of chemicals (VOCs) found at Superfund and related sites. Using high throughput mass spectrometry and aninnovative suite of mechanism-based biomarkers animal experiments and human population studies Centerinvestigations have contributed to the discovery and validation of novel biomarkers of both exposure andcardiometabolic injury that would lay the foundation for future remediation strategies. These studies employstate-of-the-art tools to develop pollutant atmospheres for animal exposure and to measure unique and sensitivebiological endpoints reflective of cardiometabolic injury. In addition work supported by the Center is leading tothe development of new methods and devices for quantifying atmospheric levels of VOCs that employ advancedtechnologies and offer precise but low-cost measurements of hazardous waste sites. As before the majorobjectives of the Center are to conduct state-of-the-art research on the cardiometabolic toxicity of VOCs and todetermine how they affect cardiometabolic disease (CMD) prevalence and severity in exposed populations.These studies will be complemented by mode-of-action mechanistic studies in animals to identify the molecularand cellular mechanisms that contribute to VOC toxicity. The findings of these studies will continue to contributeto both the discovery and the validation of sensitive and robust biomarkers that could be used to assess theextent of exposure metabolism and toxicity. Center investigators are creating new technologies for detectingVOCs at low environmental levels to enable future exposure assessment activities. Senior Center memberseducate and train junior investigators graduate students and post-doctoral Fellows in the field of environmentalscience and promote relevant community awareness and participation to enhance mutual bidirectionalunderstanding of exposure risk and the health effects of exposure. The findings and discoveries of the Centerwill be transferred to affected communities end users in public and private sectors and other stakeholders. Forfuture use and analysis all samples of human and animal tissues and all data collected during Centerinvestigations will be stored in a computer-coded biorepository. Collectively expansion and growth of the Centeractivities will enhance its contribution and lead to rigorous evaluation and better understanding of the effects ofthese hazardous chemicals on obesity diabetes and cardiovascular disease.

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

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


application_id: 10353383
project_number: 5F30CA232550-04
project_title: The role of MIF in mitochondrial metabolism and M2-TAM polarization
administering_ic: NCI
award_notice_date: 2022-02-23
opportunity_number: PA-18-673
application_type: 5
activity_code: F30
ic: CA
serial_number: 232550
program_official: ODEH, HANA M
project_start_date: 2019-03-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-F09C-Q(20)L]
contact_pi_person_id: 15053134
contact_pi: NOE, JORDAN T
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/ABSTRACTThe role of MIF in mitochondrial metabolism and M2-TAM polarization. Tumor-associated macrophages (TAMs) promote intratumoral microvessel density increase tumorstromal matrix remodeling and potently suppress anti-tumor immunity in late-stage cancer patients. Althoughsubstantial research has identified how M2 TAM polarization promotes tumor progression much less is knownabout how TAMs obtain this M2 phenotype within tumor microenvironments. Metabolic reprogramming is acritical determinant of macrophage polarization as recent studies demonstrate that M2 TAMs adopt an oxidativephosphorylation/mitochondrial metabolic phenotype and uniquely respond to metabolites within the tumormicroenvironment. This proposals long-term objective is to investigate the mechanisms by which macrophagemigration inhibitory factor (MIF) dictates lactate-enhanced M2 polarization. Our preliminary studies demonstratethat M2 macrophages metabolize extracellular lactate to pyruvate which in turn is oxidized in the mitochondriaand is both necessary and sufficient to significantly enhancing Th2 cytokine-dependent M2 TAM polarization.Our data further indicates that MIF promotes mitochondrial metabolism which is required for maximallactate/pyruvate-enhanced M2 polarization and acquisition of pro-tumorigenic phenotypes. Two aims areproposed to test our hypotheses: Specific Aim 1: Delineate the mechanistic effectors of lactate/pyruvate toHIF1-dependent M2-macrophage polarization. Objective: To use a combination of metabolic flux analysesmetabolomics gene expression assays transgenic mice and mechanistic studies to answer three primaryquestions: 1) Whether M2 macrophages actively metabolize lactate; 2) Which metabolic pathways are utilizedto accomplish this and; 3) How is lactate metabolism mechanistically linked to M2 polarization Specific Aim 2:Determine the mechanistic contributions of MIF in lactate/pyruvate-mediated M2 TAM polarization.Objective: Use mutant MIF protein re-expression small-molecule rescue studies flow cytometry and geneexpression assays to make three determinations: 1) Whether MIF dictates mitochondrial biogenesis andmetabolism in M2 macrophages; 2) Whether and how MIF influence mitochondrial metabolism by binding toCSN5 and regulating NRF2 stability and; 3) If MIF is functionally linked to lactate-amplified HIF1 stability andensuing M2 polarization.

project_terms:
Adopted;Anaerobic Bacteria;Binding;Biogenesis;Biological Assay;COPS5 gene;Cancer Patient;Cell Proliferation;Citric Acid Cycle;Clinical;Complex;Data;Development;Diagnosis;Electron Transport;Exhibits;Flow Cytometry;Fumarates;GA-binding protein transcription factor;Gene Expression Profiling;Genetic;Hypoxia Inducible Factor;IL4 gene;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Incidence;Interleukin-4;Laboratories;Lead;Link;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metastatic Melanoma;Migration Inhibitory Factor;Mitochondria;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Oxidative Phosphorylation;Oxides;Oxygen Consumption;Pathway interactions;Patients;Phenotype;Process;Production;Proteins;Pyruvate;Pyruvate Metabolism Pathway;Reporter;Research;Resistance;Role;Solid;Solid Neoplasm;Stimulus;Stromal Neoplasm;Succinate Dehydrogenase;Survival Rate;Testing;Transgenic Mice;Tumor Immunity;Tumor-Derived;Tumor-associated macrophages;Unresectable;Warburg Effect;adenoviral-mediated;angiogenesis;anti-tumor immune response;cancer cell;cancer type;cytokine;density;expression vector;extracellular;gene product;glucose metabolism;improved;macrophage;melanoma;metabolic phenotype;metabolomics;mitochondrial metabolism;mortality;mutant;neoplasm immunotherapy;novel therapeutics;response;small molecule;transcription factor;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenic;uptake

public_health_relevance:
Project NarrativeThe role of MIF in mitochondrial metabolism and M2-TAM polarization. Patients diagnosed with unresectable stage IV melanoma have a median survival rate of 6-10 months.Despite encouraging improvements in overall survival in patients receiving immunotherapies for melanomamany patients are unresponsive to these therapies. As tumor-associated macrophages (TAMs) polarized to anM2 phenotype promote both tumor progression and resistance to the latest immunotherapies investigatinghow TAMs acquire an M2 polarization phenotype may lead to the identification of molecular targets for thedevelopment of new and highly improved tumor immunotherapies.


application_id: 10352620
project_number: 1R21OD031964-01
project_title: Development of long-term preservation and revival protocols for Drosophila
administering_ic: OD
award_notice_date: 2021-08-13
opportunity_number: PAR-19-176
application_type: 1
activity_code: R21
ic: OD
serial_number: 031964
program_official: ZOU, SIGE
project_start_date: 2021-08-15
project_end_date: 2023-07-31
study_section: Development - 2 Study Section[DEV2]
contact_pi_person_id: 16031718
contact_pi: TEETS, NICHOLAS
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary: This project will improve methods for cryopreserving the model organismDrosophila melanogaster thereby reducing the time and resources needed to maintain diversegenetic stocks. Two of the primary challenges for successful cryopreservation in Drosophila arepromoting uptake of cryoprotectants through embryonic membranes and overcoming the toxicityof these cryoprotective compounds. To address these challenges we will use a two-prongedapproach. First we will use dietary additives to increase cryoprotectants in fly embryos. Secondwe will optimize methods for using sonoporation to further augment cryoprotective moleculesand load embryos with LATE EMBRYOGENESIS ABUNDANT PROTEIN(s) (LEAPs) a class ofproteins that protect against osmotic stress and promote freeze tolerance. After optimizingloading of cryoprotectants and LEAPs we will vary freezing and thawing rates to identifyconditions that can successfully recover live flies from ultralow temperatures.Specific aims and research design: Specific Aim 1: Improving the efficacy ofsonoporation to introduce cryoprotectants into embryos. We have devised a modified dietthat increases trehalose and proline in embryos and here will optimize sonoporation methods tofurther augment cryoprotectant levels. Sonoporation uses ultrasonic frequencies in conjunctionwith lipid microbubbles to generate small pores in cells and drive uptake of solutes. We will usefluorescent molecules to optimize sonoporation methods and these optimized methods will thenbe used to load augment cryoprotectants and load LEAPs into embryos. LEAPs have previouslybeen shown to increase stress tolerance of D. melanogaster cell lines.Specific Aim 2: Investigate freezing and thawing strategies to improve cryopreservation.We will test the ability of cryoprotectant-loaded fly embryos to survive various freezing/thawingrates. Three different strategies to freeze (and subsequently thaw) fly embryos will be exploredusing established methods for insect cryopreservation.Significance: This project will significantly improve the efficiency by which cryoprotectivemolecules can be introduced into D. melanogaster embryos. Current cryopreservation methodsare technically challenging and inaccessible to most labs. The methods developed here willprovide routine inexpensive strategies for overcoming the impermeability of embryos to manycryoprotectants. Successful strategies will be tested in multiple commonly used geneticbackgrounds and mutant strains to test the extent to which these preservation strategies areeffective in different genotypes.

project_terms:
Address;Animal Model;Animals;Arthropods;Biological;Cell Line;Cells;Collaborations;Communities;Cost Savings;Cryopreservation;Data;Desiccation;Development;Devices;Diet;Disease;Drosophila genus;Drosophila melanogaster;Embryo;Embryonic Development;Engineering;Erythrocytes;Freeze Drying;Freezing;Frequencies;Genes;Genetic;Genetic Research;Genetic Transformation;Genotype;Goals;Homo sapiens;Human;Insecta;Interdisciplinary Study;Lipids;Measures;Membrane;Methods;Microbubbles;Microfluidics;Molecular;Molecular Weight;Mutation;Nature;Organism;Postdoctoral Fellow;Preparation;Process;Production;Proline;Proteins;Protocols documentation;Research;Research Design;Resources;Seeds;Stress;Technology;Temperature;Testing;Time;Toxic effect;Trehalose;Ultrasonics;Water;authority;cold temperature;cost;dietary;dietary manipulation;dietary supplements;experience;fly;improved;mutant;novel strategies;nucleic acid delivery;preservation;prevent;solute;sonoporation;stress tolerance;success;training opportunity;undergraduate student;uptake

public_health_relevance:
The fruit fly (Drosophila melanogaster) is an outstanding model organism that possesses similargenes to nearly 75% of those causing disease in humans (Homo sapiens) but labs working withflies have no means to store them for prolonged periods. Thus fly labs invest substantialresources into continuous rearing of fly strains. In this project we will develop strategies forintroducing protective molecules into fly embryos that will facilitate routine storage of flies at lowtemperature.


application_id: 10352301
project_number: 5R01NS102196-05
project_title: RIT1-mediated Protection following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2022-01-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 102196
program_official: AWWAD, HIBAH OMAR
project_start_date: 2018-02-15
project_end_date: 2025-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
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:
Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affectingmore than 1.7 million individuals each year. TBI not only results in tissue damage and cell death but canperturb surviving neuronal function leading to alterations in neural connectivity abnormal plasticity andnetwork dysfunction. Due to the inherent diversity in post-TBI dysfunction a critical need exists for therapeuticinterventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approachescould have enormous clinical social and economic benefit. However implementation of this strategy requiresthe identification of endogenous molecular cascades capable of regulating multiple protective/restorativepathways. The discovery that the Rit GTPase (RIT1) is dramatically down-regulated following corticalcontusion injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functionalrecovery following TBI. Drawing upon a collection of RIT1 transgenic mice exciting preliminary datademonstrate that Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunctionfollowing CCI. Additional data suggest that Rit is critical for post-TBI neurogenesis and promotes synapticintegrity by reducing post-contusion synaptic loss. Collectively these data are the first to demonstrate asignificant role for Rit in directing neuroprotection and neuroplasticity following TBI and suggest that Ritfunctions as a linchpin regulator of multiple injury response mechanisms following CCI. The overall hypothesisis that: (1) Rit plays a key role in cellular and functional recovery from brain trauma and (2) that activation ofRit signaling therefore has broad therapeutic potential in the setting of TBI. Three complementary aims guideour studies. Aim 1 will test the hypothesis that contusion-dependent Rit loss disrupts gene expressionprograms that promote neural survival and neurogenesis. In Aim 2 we will evaluate the extent to which Ritsignaling controls neuronal survival after contusive brain injury. The efficacy of Rit-targeted therapies will beevaluated using an inducible knock-in mouse model to permit Rit activation over a clinically relevant period ofhours to days after the onset of brain injury. Aim 3 will test the hypothesis that Rit signaling preserves synapticfunction following traumatic brain injury using transgenic mice electrophysiology and biochemical assays.Overall these studies are expected to identify Rit as a crucial signal integration hub in the setting of brain injury orchestrating diverse endogenous pathways that regulate neuronal survival promote neuronal regenerationand control neuroplasticity mechanisms.

project_terms:
Acute;Affect;Area;Attenuated;Behavioral;Biochemical;Biological Assay;Brain Contusions;Brain Injuries;CREB1 gene;Cause of Death;Cell Death;Cells;Chronic;Clinical;Collection;Contusions;Cortical Contusions;Data;Development;Economics;Electrophysiology (science);Emotional;Experimental Models;Functional disorder;Gene Expression;Genetic Transcription;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);Hour;Impaired cognition;Individual;Injury;Knock-in Mouse;Language;Learning;Leg;Link;Mediating;Memory impairment;Modeling;Molecular;Multiple Trauma;Nerve Degeneration;Neuronal Dysfunction;Neuronal Injury;Neuronal Plasticity;Neurons;Pathway interactions;Play;Proteins;Recovery;Recovery of Function;Role;Signal Transduction;Speech;Suggestion;Survivors;Synapses;Testing;Therapeutic;Therapeutic Intervention;Thinking;Tissues;Transgenic Mice;Traumatic Brain Injury;United States;adult neurogenesis;arm;bioinformatics tool;brain repair;clinically relevant;dentate gyrus;disability;experience;experimental study;in vivo;injured;injury-related death;insight;loss of function;mouse model;network dysfunction;neurogenesis;neuron regeneration;neuronal survival;neuroprotection;preservation;programs;relating to nervous system;response to injury;social;synaptic function;targeted treatment;transcriptome sequencing

public_health_relevance:
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States and survivors mayhave persistent loss of function in arms or legs abnormal speech or language loss of thinking ability oremotional problems. The wide range of injuries suggests that the development of multi-prong therapeuticapproaches to TBI could have enormous clinical social and economic benefit. This project will investigate theRIT1 protein as a linchpin capable of counterbalancing diverse injury mechanisms providing a unique avenuefor therapeutic intervention by allowing a combined approach of protecting neurons and promoting brain repairin a single target.


application_id: 10350707
project_number: 5R01CA251663-02
project_title: Targeting Mitochondrial Redox Capacity to Overcome Cancer Subtype that Regrowth After Radiation
administering_ic: NCI
award_notice_date: 2022-04-01
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 251663
program_official: ESPEY, MICHAEL G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animal Model;Antibiotics;Azithromycin;Biochemical;Biogenesis;Cell Death;Cell Survival;Cells;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Computer software;Coupled;Data;Dose;Electron Transport;Enzymes;Event;Exhibits;External Beam Radiation Therapy;FDA approved;Failure;Homeostasis;Hydrogen Peroxide;Image;Impairment;In Vitro;Macrolides;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolism;Microscopy;Mitochondria;Mitochondrial Proteins;Molecular;Mus;Normal Cell;Oxidation-Reduction;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Property;Prostate;Protein Array;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrence;Regulation;Research Design;Resistance;Resistance development;Resolution;Site;Testing;Therapeutic;Time;Translating;Translations;Treatment Efficacy;Xenograft Model;bioluminescence imaging;cancer cell;cancer heterogeneity;cancer recurrence;cancer subtypes;cancer survival;catalase;factor A;fractionated radiation;high risk;improved;in vivo;inhibitor;insight;knock-down;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;mortality;novel;novel therapeutics;overexpression;patient derived xenograft model;prevent;prostate cancer cell;prostate cancer model;prototype;radiation delivery;radiation resistance;radioresistant;response;stable isotope;success;transcription factor;tumor;tumor growth;tumor heterogeneity


application_id: 10349569
project_number: 5P20GM125504-05
project_title: Novel synthetic analogue of microbial metabolite Urolithin A mitigates inflammatory bowel diseases
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
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8243
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract  Inflammatory Bowel Diseases (IBDs) which include f ulcerative colitis and Crohns disease affect as many as 1.4 million people in the USA. Chronic inflammation and microbial dysbiosis are major features of IBDs. Beneficial effects rendered by healthy dietary practices are not uniform among individuals and are attributed to variations in gut microbiota and their active metabolites. To overcome the challenge of inter-individual differences in gut microbiota their metabolites and poor bioavailability here we propose direct usage of microbial metabolites to maintain gut immune homeostasis to mitigate IBDs. Urolithin A (UroA) is one of such beneficial microbial metabolite derived from ellagic acid and ellagitannins major polyphenolic components of berries and pomegranate. Based on UroA structure we developed novel potent structural analogue UAS03 which exhibited increased anti-inflammatory and gut barrier functional activities compared to parent UroA compound. The current proposal investigates the molecular and cellular mechanisms of UAS03 and its therapeutic efficacies in IBD pre-clinical models.  Our preliminary results showed that the oral administration of UAS03 mitigated colitis in dextran sodium sulphate (DSS)- or 246-Trinitrobenzenesulfonic acid (TNBS) induced murine colitis even at 10 fold lower dose compared to UroA. UAS03 significantly inhibited lipopolysaccharide (LPS)-induced increase in inflammatory mediators in immune cells and epithelial cells with 10 fold higher efficacy than UroA. Further treatment with UAS03 reduced intestinal permeability by up-regulating junctional proteins through activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-hemoxygenase (HO1) pathways in epithelial cells. Based on these results we propose two-pronged beneficial activities of UAS03 and UroA where these compounds protect the host from external challenges by protecting gut barrier function and dampening inflammatory activities. In this proposal we will test the hypothesis that treatment with UAS03 an effective analogue of a microbial metabolite protects from IBD development by reducing barrier dysfunction and inflammation. In Aim 1 we will investigate how USA03/UroA increase gut barrier function in a Nrf2-dependent manner by upregulating junctional proteins as well as molecular events involved anti-inflammatory activities of UAS03. In Aim 2 therapeutic efficacies of UAS03 and UroA will be examined in acute chronic and spontaneous IBD pre-clinical models. In Aim 3 we propose to identify the bacteria responsible for UroA production and test their pro-biotic activities in colitis models. The successful completion of proposed studies will allow understanding of UAS03 and UroA mechanisms of actions and establishes the basis for therapeutic usage in IBDs.

project_terms:
Acids;Acute;Affect;Anti-Inflammatory Agents;Bacteria;Benzopyrans;Berry;Biological;Biological Availability;Cells;Chemopreventive Agent;Chronic;Clinical;Colitis;Crohn's disease;Data;Development;Diet;Dietary Intervention;Dietary Practices;Disease;Disease model;Dose;Down-Regulation;Ellagi-Tannins;Ellagic Acid;Epithelial Attachment;Epithelial Cells;Erythroid;Event;Exhibits;Functional disorder;Glycols;Goals;Heme;Homeostasis;Human;Ileitis;Immune;In Vitro;Indigenous;Individual;Individual Differences;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Bowel Diseases;Interleukin-1;Interleukin-6;Intestinal permeability;Lipopolysaccharides;Measures;Mediating;Modeling;Molecular;Mus;Nuclear;Oral Administration;Oxygenases;Parents;Pathogenicity;Pathway interactions;Persons;Phenotype;Phytochemical;Pilot Projects;Pomegranate;Pre-Clinical Model;Probiotics;Production;Proteins;Risk;Role;Sampling;Sodium Dextran Sulfate;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic;Therapeutic Uses;Tight Junctions;Time;Treatment Efficacy;Trinitrobenzenesulfonic Acid;Ulcerative Colitis;Variant;Wild Type Mouse;analog;bacterial metabolism;base;chemokine;comparative efficacy;dysbiosis;efficacy evaluation;gastrointestinal epithelium;gut bacteria;gut microbiota;in vivo;in vivo Model;inter-individual variation;macrophage;microbial;microbiome research;microbiota metabolites;molecular targeted therapies;murine colitis;novel;preservation;protective effect;translational potential


application_id: 10349568
project_number: 5P20GM125504-05
project_title: Functional Microbiomics Core-Bodduluri
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
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8242
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Biomedical research areas including the study of metagenomics inflammation and pathogenesis are resource and technology intense. All COBRE-supported investigators require state of-the-art resources to successfully compete with investigators from other resource-rich institutions for NIH support. The primary goal of the Functional Microbiomics Core (FMC) is to establish an integrated service center that functions as a critical resource for all Microbiome Inflammation and Pathogenicity COBRE investigators. Since all the COBRE projects utilize mouse models to explore the inter-relationships between inflammation and pathogenesis and the contribution of microbiota to this process the development of a facility to house and maintain germ-free and gnotobiotic mice is crucial to the FMC. An anaerobic culture facility will support research on gnotobiotic mice that requires specific colonization with fecal transplants or defined anaerobic bacteria. Further in Aim 2 we propose to establish an integrated metagenomics center for microbiota. This facility will prepare genomic DNA following unified protocols and generate 16S rRNA gene amplicon sequences and provide bioinformatics support for all microbiota analysis. The FMC will also support all COBRE projects with analysis of their biological samples for inflammatory markers as well as histopathological examination of tissue sections. Education and training of junior investigators and the university wide research community in microbiota research is an important goal of the FMC. Towards this goal the FMC will organize seminars as well as informal meetings that will serve as a forum for highlighting the scientific and technical advances in the field. Finally the FMC plans to become an independent service center at UofL to support the needs of all researchers in this area of research

project_terms:
Address;Adopted;Anaerobic Bacteria;Area;Attention;Award;Bioinformatics;Biological;Biomedical Research;Centers of Research Excellence;Clinical;Communities;Continuing Education;Core Facility;Data Analyses;Development;Dietary Intervention;Disease;Equipment;Extramural Activities;Fee-for-Service Plans;Fostering;Funding;Generations;Genomic DNA;Genomics;Germ-Free;Gnotobiotic;Goals;Health;Housing;Human Resources;Incubators;Individual;Infection;Inflammation;Inflammation Mediators;Institution;Kentucky;Laboratories;Mentors;Metagenomics;Methodology;Mission;Mus;Outcome;Pathogenesis;Pathogenicity;Phase;Pilot Projects;Process;Protocols documentation;Research;Research Personnel;Research Support;Resources;Ribosomal RNA;Sampling;Services;Sterility;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;animal facility;base;biosafety level 3 facility;experimental study;fecal transplantation;histopathological examination;inflammatory marker;innovation;interest;investigator training;meetings;member;metabolomics;microbial;microbiome;microbiome research;microbiota;mouse model;pathogen;programs;protocol development;rRNA Genes;social health determinants;social relationships;success;tool


application_id: 10349567
project_number: 5P20GM125504-05
project_title: COBRE-Administrative Core
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
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3
subproject_number: 8241
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville (UofL) COBRE in Functional Microbiomics Inflammation and Pathogenicity comprises a multidisciplinary group of investigators addressing thematic aspects of microbiome inflammation and pathogenicity studies. The UofL is uniquely poised to investigate these problems in a coordinated and efficient fashion and the COBRE is horizontally integrated with a number of UofL funded initiatives and grant applications in related areas. The departments of Oral Immunology and Infectious Diseases Microbiology and Immunology and Bioengineering all contribute to the cross-disciplinary nature of the center. These units have established records of federal funding mentoring junior faculty graduate student training and collaborative interactions across campus. This application is led by well-qualified and well-funded Center Directors. There are five outstanding PI-mentees with senior established funded mentoring teams. Our proposed COBRE will have a major positive impact on research throughout UofL and will help recruit and retain faculty. The germ free animal facility to be established will be one of only a few in the country. Many of the projects address chronic inflammatory diseases that occur at disproportionately high incidence in minority communities. Other projects involving plague and melioidosis have national and international significance. The Administrative Core will provide overall governance and will ensure that the COBRE projects and cores work together in a cohesive and coordinated manner. All projects and cores will utilize the Administrative Core. The Specific Aims are: to provide a formal governance structure to allow coordination direction and prioritization of activities including budget issues ensuring the quality of all functions; to evaluate progress; to resolve any conflicts as they arise; to provide a formalized process for mentoring junior faculty; to provide a mechanism to replace mentees as they become independent; to provide a mechanism to replace any key individuals who may leave; to provide pilot funding for junior faculty to ensure a pipeline of investigators; to provide biostatistical and bioimaging support; and to disseminate pertinent information resulting from the COBRE activities.

project_terms:
Acute;Address;Applications Grants;Area;Biological Warfare;Biomedical Engineering;Biometry;Bubonic Plague;Budgets;Burkholderia pseudomallei;Centers of Research Excellence;Communicable Diseases;Conflict (Psychology);Country;Disease;Disease Outcome;Ensure;Faculty;Funding;Germ-Free;Goals;Guidelines;Health;Human;Human Microbiome;Immunology;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Interdisciplinary Study;International;Location;Melioidosis;Mentors;Microbiology;Modality;Natural Immunity;Pathogenicity;Plague;Play;Population;Process;Records;Regulation;Research;Research Personnel;Role;Structure;Universities;Work;Yersinia pestis;animal facility;bioimaging;chronic inflammatory disease;cohesion;graduate student;host-microbe interactions;immune system function;microbiome;microbiome research;microbiota;minority communities;multidisciplinary;nature center;new technology;new therapeutic target;oral immunology;oral infection;pathogen;recruit;student training;underserved community


application_id: 10349566
project_number: 5P20GM125504-05
project_title: Functional Microbiomics Inflammation and Pathogenicity
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: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: ZGM1-RCB-3(C1)
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
In the past few decades the fields of microbiology and immunology have undergone a renaissance driven inpart by technological advances which have shaped our understanding of microbes as components of complexpolymicrobial interactive communities. This microbiome can play a role in a number of fundamental aspects ofhuman health and disease in many instances through the interface with host innate immunity. The immunesystem functions to restrict the potential for damage caused by the microbiota while simultaneously minimizingdestructive inflammatory responses. Disruption of the intensity duration or physical location of inflammationhowever can contribute to disease. Advances in our understanding of the microbiome along with a realizationthat inflammatory processes are at the core of a number of common diseases necessitates a cross-disciplinaryperspective that accommodates the host-microbe interaction in toto. The major goal of this COBRE is toestablish a thematic multidisciplinary research center for the study of the interface between the microbiomeinflammation and pathogenicity. We have assembled a team of junior investigators with complementaryexpertise and outstanding potential and have partnered these project leaders with well-qualified and dedicatedmentors. An integrated set of complementary projects will make novel connections between inflammatoryprocesses and bacterial pathogenicity and establish the basis for the development of novel therapeutics anddelivery methods. We will create a multidisciplinary program in research education mentoring and careerdevelopment that will facilitate and accelerate the transition of junior faculty to independent extramural fundedstatus. Research will be support by a Functional Microbiomics Core that will provide germ free animal facilitiesanaerobic culture capability microbiome sequencing and bioinformatics assay of inflammatory markers andpathology services. An Administrative Core will co-ordinate activities and provide additional biostatistical andbioimaging support along with a Pilot Project program to ensure a pipeline of investigators. Institutionalcommitment will also help ensure long term sustainability of the thematic research program.

project_terms:
Anaerobic Bacteria;Anti-Inflammatory Agents;Area;Autoimmune Diseases;Basic Science;Bioinformatics;Biological Assay;Biometry;Centers of Research Excellence;Chronic;Colorectal Cancer;Communities;Complex;Dentistry;Development;Disease;Distant;Education;Engineering;Ensure;Environment;Environmental Science;Equilibrium;Evaluation;Extramural Activities;Faculty;Funding;Germ-Free;Goals;Health;Health Sciences;Homeostasis;Human;Human Microbiome;Immune response;Immune system;Immunologist;Immunology;Indigenous;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Lead;Location;Mentors;Methods;Microbe;Microbiology;Monitor;Mucous Membrane;Natural Immunity;Normal tissue morphology;Outcomes Research;Parkinson Disease;Pathogenicity;Pathology;Pathway interactions;Periodontitis;Physiology;Pilot Projects;Play;Positioning Attribute;Postdoctoral Fellow;Process;Recovery;Renaissance;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resources;Rheumatoid Arthritis;Role;Scientist;Services;Shapes;Site;Specificity;Structure;Surface;System;Talents;Teacher Professional Development;Therapeutic Agents;Time;Tissues;Training;Universities;animal facility;autism spectrum disorder;bioimaging;career development;chronic infection;dysbiosis;graduate student;host-microbe interactions;immune system function;inflammatory marker;intercellular communication;medical schools;microbial;microbial community;microbiome;microbiome research;microbiome sequencing;microbiota;multidisciplinary;nervous system disorder;novel;novel therapeutics;pathogen;programs;recruit;response;tool

public_health_relevance:
The University of Louisville COBRE in Functional Microbiomics Inflammation and Pathogenicity is a uniquethematic research center. COBRE scientists comprise a multidisciplinary group of senior mentors and juniorinvestigators on a pathway to independence who are focusing on diseases that involve complex interactionsbetween microbial challenge and host inflammatory responses. Outcomes of this research may lead to thedevelopment of novel therapeutic agents and delivery systems to protect against a number of chronic and difficultto treat conditions.


application_id: 10349438
project_number: 5R01AG038651-09
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2022-02-16
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AG
serial_number: 038651
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2024-01-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: ABNER, ERIN ;YU, LEI
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractPopulation demographic trends suggest an expected dramatic increase in age-associateddementias and a looming public health crisis. Current emphasis is on disease prevention with afocus on older adults who express early cognitive impairment. The SMART (Statistical Modelingof Aging and Risk of Transitions) has successfully harmonized data from nine differentlongitudinal studies on aging involving records on 5032 subjects with 1657 having autopsyinformation. We propose to identify authoritatively the roles of diabetes and hypertension on theoccurrence and duration of pre-dementia states as well as mixed pathology. The project hasshown that self-reported diabetes is not a risk for Alzheimer pathology but is a risk forcerebrovascular pathology that subjective memory complaints are a risk for a future cognitiveimpairment and that transitioning to a subjective complaint or even to mild cognitive impairmentis no guarantee of future dementia. The SMART renewal proposes to obtain Medicare claimsdata on its participants to determine the severity of diabetes hypertension and othercomorbidities that have not been investigated such as renal disease with a focus on improvingthe prediction of who is at risk for a transition to an impaired cognitive state and mixed dementiapathology. This will be accomplished through the following specific aims:Aim 1. Update and extensively revise the existing SMART project database with additionalparticipant data; obtain and integrate linked Medicare claims data; assess agreement betweenself-reported medical history and claims data. Aim 2. Investigate the relationship of HTN T2DMand multimorbidity in advanced old age with AD and non-AD neuropathologies. Aim 3. Investigatethe relationship of HTN T2DM and multimorbidity in advanced old age with cognitive statesincluding subjective memory complaints mild cognitive impairment and dementia.

project_terms:
Academic Medical Centers;Adult;Affect;Age;Age of Onset;Aging;Agreement;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease pathology;Alzheimer's disease risk;Americas;Area;Autoimmune Diseases;Autopsy;Brain;Cerebrovascular Disorders;Cessation of life;Chronic Disease;Clinical;Cognitive;Conflict (Psychology);Data;Databases;Dementia;Diabetes Mellitus;Diagnosis;Elderly;Factor Analysis;Female;Funding;Future;Goals;Grant;Health Sciences;Hypertension;Impaired cognition;Impairment;Individual;Infarction;Investments;Kentucky;Kidney Diseases;Knowledge;Life;Link;Longitudinal Studies;Medical Genetics;Medical History;Medicare;Medicare claim;Memory;Microvascular Dysfunction;National Institute on Aging;Non-Insulin-Dependent Diabetes Mellitus;Oregon;Paper;Participant;Pathology;Patient Self-Report;Population;Primary Prevention;Probability;Public Health;Records;Research;Research Personnel;Respiratory Disease;Risk;Risk Factors;Role;Sample Size;Secondary Prevention;Severities;Statistical Models;Universities;Update;Washington;age related;care costs;cerebrovascular pathology;clinical diagnosis;cognitive testing;comorbidity;data harmonization;data integration;dementia risk;disorder prevention;follow-up;human old age (65+);improved;mild cognitive impairment;mixed dementia;multiple chronic conditions;neuropathology;sex;trend

public_health_relevance:
Project NarrativeWith the graying of America the cost of caring for older adults with dementia will risesubstantially over the next few decades. Current emphasis in the field is on primary andsecondary prevention. This project will study diabetes and hypertension as risk factors forvarious forms of dementia inducing pathology as well as the impaired clinical states thatprecede diagnosed dementia.


application_id: 10348268
project_number: 1R21EB032515-01
administering_ic: NIBIB
award_notice_date: 2022-07-15
opportunity_number: PAR-20-084
application_type: 1
activity_code: R21
ic: EB
serial_number: 032515
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2022-08-01
project_end_date: 2025-04-30
study_section: Emerging Imaging Technologies and Applications Study Section[EITA]
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-01
project_title:
Non-destructive optical spectroscopic assay for high-throughput metabolic characterization of in vitro cell models  and patient-derived organoids

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

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

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


application_id: 10347759
project_number: 1R34MH128213-01
administering_ic: NIMH
award_notice_date: 2021-12-17
opportunity_number: RFA-MH-18-706
application_type: 1
activity_code: R34
ic: MH
serial_number: 128213
program_official: VILLATTE, JENNIFER L
project_start_date: 2021-12-17
project_end_date: 2024-11-30
study_section: Special Emphasis Panel[ZMH1 ERB-N (08)]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-12-17
project_terms:
Address;Adult;Aftercare;Anorexia Nervosa;Behavior Disorders;Binge Eating;Binge eating disorder;Body mass index;Bulimia;Caring;Cellular Phone;Cessation of life;Clinical;Cognitive Therapy;Complex;Data;Development;Diagnosis;Diagnostic;Dropout;Eating Disorders;Evidence based treatment;Fright;Goals;Gold;Heterogeneity;Impairment;Individual;Intervention;Investigation;Judgment;Lead;Left;Mental disorders;Methodology;Methods;Modeling;Outcome;Participant;Pathology;Pathway Analysis;Pattern;Population;Precision therapeutics;Psychiatry;Psychotherapy;Quality of life;Randomized;Recovery;Research;Specific qualifier value;Structure;Symptoms;Testing;Time;Translating;United States National Institutes of Health;Weight Gain;Work;acceptability and feasibility;base;clinical efficacy;cognitive enhancement;comorbidity;economic cost;evidence base;feeding;follow-up;improved;individualized medicine;innovation;mobile computing;mortality;novel;personalized medicine;prevent;public health relevance;response;severe mental illness;smartphone based assessment;societal costs;standard care;therapy development;treatment optimization;treatment planning;treatment response;user friendly software;virtual


application_id: 10345905
project_number: 1R01AG075583-01
project_title: Blood-Brain Barrier Repair in Alzheimers Disease with Epilepsy
administering_ic: NIA
award_notice_date: 2022-04-26
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 075583
program_official: NEWMAN, ELIZABETH
project_start_date: 2022-05-01
project_end_date: 2027-04-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
other_pis: BAUER, BJOERN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid beta-Protein;Attenuated;Blood - brain barrier anatomy;Brain;Characteristics;Clinical;Clinical Data;Cognition;Cyclooxygenase Inhibitors;Data;Disease Progression;Epilepsy;Extravasation;Feedback;Functional disorder;Glutamates;Health;Impaired cognition;Inflammation;Intervention;Knowledge;LOX gene;Lead;Life Expectancy;Link;Matrix Metalloproteinases;Mediating;Mission;Modeling;Molecular Target;Mus;National Institute of Neurological Disorders and Stroke;Outcome;Oxidative Stress;Pathway interactions;Patients;Personal Satisfaction;Pharmaceutical Preparations;Process;Public Health;Research;Rodent;Seizures;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;Work;base;brain tissue;cerebral capillary;comorbidity;design;glutamatergic signaling;improved;in vivo;innovation;nervous system disorder;neurovascular;novel therapeutic intervention;pre-clinical;prevent;repaired;success;therapy design;translational potential;vascular inflammation


application_id: 10345684
project_number: 1R01AA029798-01
project_title: Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
administering_ic: NIAAA
award_notice_date: 2021-09-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AA
serial_number: 029798
program_official: RADAEVA, SVETLANA
project_start_date: 2021-09-22
project_end_date: 2026-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: 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:
Affect;Alcoholic Liver Diseases;Alcohols;Animal Model;Apoptosis;Attenuated;Automobile Driving;CYP2E1 gene;Cell model;Cell physiology;Cessation of life;Complex;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cytochrome P450;Data;Development;Disease;Enzymes;Ethanol;FDA approved;Fatty Acids;Fatty Liver;Genes;Goals;H19 gene;HIF1A gene;Heavy Drinking;Hepatic;Hepatitis;Hepatocyte;Hydrolysis;Impairment;In Vitro;Inflammatory;Injury;Knockout Mice;Liver;Liver diseases;MAPK phosphatase;MAPK8 gene;Mediating;Metabolic;Mitogen-Activated Protein Kinases;PDE4B;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Population;Process;Regulation;Role;Second Messenger Systems;Signal Transduction;Specificity;Toxic effect;Transcriptional Regulation;United States;Untranslated RNA;Up-Regulation;Work;alcohol effect;base;cell injury;genetic manipulation;hypoxia inducible factor 1;in vitro Model;in vivo;inhibitor/antagonist;lipid biosynthesis;lipid metabolism;liver injury;member;mortality;new therapeutic target;novel;oxidation;phosphatase-1 kinase;phosphodiesterase IV;phosphoric diester hydrolase;preclinical study;response;transcription factor


application_id: 10345440
project_number: 1R01HL160927-01
project_title: Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2021-11-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 160927
program_official: LIU, LIJUAN
project_start_date: 2021-12-01
project_end_date: 2026-11-30
study_section: Special Emphasis Panel[ZRG1 TDPS-R (01)]
contact_pi_person_id: 12101586
contact_pi: TAN, YI
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adipose tissue;Agonist;Animal Model;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherosclerosis;Attenuated;Biliary;Binding Sites;Blood;Cardiovascular Diseases;Cell Proliferation;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Clinical;Clinical Research;Coagulation Process;Data;Development;Diabetes Mellitus;Dose;Dyslipidemias;Engineering;Enterocytes;FGF1 gene;Feces;Fluorescein;Future;Genetic Transcription;Heparin Binding;Hepatic;Hepatocyte;Human;Hyperlipidemia;Intestinal Absorption;Intestines;Knockout Mice;LDL Cholesterol Lipoproteins;Label;Lead;Life Style;Lipids;Liver;Mediating;Mediator of activation protein;Metabolic;Metabolic syndrome;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Translocation;Operative Surgical Procedures;Organ;Organoids;Pathogenesis;Pathologic;Patients;Phenotype;Play;Prevention approach;Radioisotopes;Recombinants;Regulation;Risk;Risk Factors;Role;Site;Testing;Therapeutic;Up-Regulation;Variant;angiogenesis;atherogenesis;blood glucose regulation;cholesterol absorption;cholesterol biosynthesis;clinical practice;db/db mouse;dietary;insight;macrophage;neovascularization;non-alcoholic fatty liver disease;novel;novel strategies;novel therapeutic intervention;overexpression;prevent;side effect;transcription factor;translational potential;tumorigenic


application_id: 10339720
project_number: 1R01HL160910-01
project_title: Platelet Metabolism in Diabetes Mellitus
administering_ic: NHLBI
award_notice_date: 2022-09-15
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 160910
program_official: GOLDBERG, ILANA GRACE
project_start_date: 2022-09-20
project_end_date: 2026-06-30
study_section: Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT]
contact_pi_person_id: 8688832
contact_pi: WANG, QINGJUN
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Address;Affect;Animal Model;Arterial Injury;Biological Assay;Biology;Blood Glucose;Blood Platelets;Blood Vessels;Blood coagulation;Buffers;Calcium;Carbon;Cardiovascular system;Cause of Death;Chelating Agents;Citric Acid Cycle;Clot retraction;Coagulation Process;Consumption;Data;Development;Diabetes Mellitus;Doctor of Philosophy;Enzymes;Event;Fibrin;Fructose;G6PD gene;Genetic;Gluconeogenesis;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glycogen;Glycogen Phosphorylase;Glycolysis;Heart Diseases;Hemostatic function;Homeostasis;Human;Hyperactivity;Hyperglycemia;Impairment;In Vitro;Incidence;Insulin-Dependent Diabetes Mellitus;Kentucky;Kinetics;Knowledge;Lead;Learning;Literature;Mediating;Metabolic;Metabolic Pathway;Metabolism;Middle Cerebral Artery Occlusion;Modeling;Morbidity - disease rate;Mus;Myocardial Infarction;NADP;Obstruction;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Pathogenicity;Patients;Pentosephosphate Pathway;Pharmacology;Phosphoric Monoester Hydrolases;Platelet Activation;Positioning Attribute;Production;Pulmonary Embolism;Reactive Oxygen Species;Reduced Glutathione;Regulation;Reporting;Rest;Risk;Rodent;Role;Source;Streptozocin;Stroke;Testing;Thrombin;Thrombosis;Thrombus;Time;Universities;base;chelation;diabetic patient;first responder;glucose metabolism;glucose uptake;glycemic control;glycogen metabolism;in vivo;inhibitor;metabolomics;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;platelet function;stable isotope;stroke risk;thrombotic;tool


application_id: 10338842
project_number: 7R21AG055996-03
project_title: Understanding the Role GPRC6a During Tau Metabolism
administering_ic: NIA
award_notice_date: 2021-04-27
opportunity_number: PA-16-161
application_type: 7
activity_code: R21
ic: AG
serial_number: 055996
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2018-07-01
project_end_date: 2024-03-31
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 9300523
contact_pi: LEE, DANIEL CARL
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Tauopathies including Alzheimer's disease (AD) consist of age-associated neurodegenerative diseases forwhich no disease-modifying treatments exist. Our group has uncovered a unique interaction between thearginine metabolism and tauopathies. Arginine metabolism affects multiple biological processes that showconsiderable influence upon tau biology. We hypothesize that L-arginine acts as a sensor for amino acidabundance and that the depletion of arginine initiates autophagy to replenish amino acid levels. Arginase 1(Arg1) remains one of several different enzymes capable of metabolizing the semi-essential amino acid L-arginine. In fact numerous isoforms exist for Arg and nitric oxide synthases (NOS). We demonstrate in cellsand animal models of tauopathy the benefits of increasing Arg1 in reducing many aspects of the tau phenotype(hallmarks comprised of tau effects). Several seminal findings show lysosomal and cytoplasmic argininesensors that modulate mechanistic target of rapamycin complex 1 (mTORC1). GPRC6a is a G-protein coupledreceptor that binds L- amino acids including L-arginine and may serve as an extracellular arginine sensor formTORC1. Our preliminary data indicates increased activation of the arginine-sensing mTORC1 pathway in ADbrains and animal models of tauopathies. We show that arginine producing and metabolizing enzymesarginine sensors and mTORC1 complexes increase in the hippocampus of AD patients compared to controlaged matched brains. We also find that tau increased total arginine levels in the brain by 35% increased basallevels of extracellular arginine and arginine release following neuronal stimulation in the brain. Furthermorenovel allosteric antagonist to GPRC6a clears various forms of tau in cell lines primary neurons and mice.Genetic reduction of GPRC6a also reduced tau expression and seemingly regulates several intracellulararginine sensors. We posit that tauopathies (including AD) cause impaired arginine metabolism and uncouplingof arginine-sensing mTORC1 signaling which lead to hyper-mTORC1 activation creating a positive feed-forward loop to augment the tau phenotype. We will test the hypothesis that decreased GPRC6a signaling fromallosteric antagonists or shRNA to GPRC6a modulate arginine-sensing mTORC1 signaling induces autophagyand increases tau clearance in vitro and in vivo. We will use tetracycline inducible tau cell lines with a photo-switchable fluorescent tracer to measure tau metabolism split tau-GFP constructs that measure tauoligomerization and primary neurons to determine the role of GPRC6a and tau fate. We will determine ifgenetic knockdown and pharmacological inhibition of GPRC6a impacts tau biology in vitro and in vivo. Successin this application would provide a new receptor target that may impact arginine-sensing mTORC1 signaling.Furthermore we aim to identify an entirely new class of drugs that targets GPCR6a to mitigate the tauphenotype provide new strategies for tauopathies and AD.

public_health_relevance:
Tauopathies consist of a group of neurodegenerative diseases including Alzheimer's disease (AD) and currently no therapeutic treatments exist for tauopathies. This study will test how modulation of GPRC6a impact taubiology in vitro and in vivo. We aim to identify novel targets through GPRC6a that increase tau clearance andhopefully identify a new class of drugs that treat tauopathies and AD.


application_id: 10338492
project_number: 1R01GM144349-01
administering_ic: NIGMS
award_notice_date: 2021-12-21
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: GM
serial_number: 144349
program_official: SHEWMAKER, FRANK PAUL
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: 2022-01-01
project_terms:
2019-nCoV;Active Sites;Affect;Antineoplastic Agents;Architecture;Binding;Calorimetry;Catalysis;DNA;Data;Development;Dissociation;Distant;Enzymes;Equilibrium;Future;Generations;Grant;Guanylate kinase;Human;Kinetics;Laboratories;Ligand Binding;Ligands;Link;Malignant Neoplasms;Measurable;Measures;Methods;Mind;Molecular Conformation;Motion;Muramidase;Mutation;NMR Spectroscopy;Nuclear Magnetic Resonance;Nucleosides;Nucleotides;Outcome;Phosphorylation;Phosphotransferases;Physiological;Play;Production;Proteins;Protocols documentation;RNA;Regulation;Relaxation;Research Personnel;Residual state;Role;SARS coronavirus;Sampling;Scheme;Series;Single Nucleotide Polymorphism;Site;Structural Biologist;Structure;Testing;Therapeutic;Thermodynamics;Time;Titrations;Ubiquitin;Variant;Vertebral column;Viral;Work;base;cancer cell;conformational conversion;design;drug discovery;enthalpy;inhibitor;knowledge of results;molecular dynamics;mutant;small molecule inhibitor;therapeutic target;tool


application_id: 10337059
project_number: 5R01NS112693-03
project_title: Mitochondrial Uncoupling Prodrug as a Translational Therapy for TBI
administering_ic: NINDS
award_notice_date: 2022-02-04
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: 2026-01-31
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;Aftercare;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;Spinal cord injury;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;Work;behavior measurement;behavioral outcome;biosignature;clinically relevant;cognitive testing;cohort;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;porcine model;pre-clinical;preclinical efficacy;primary endpoint;repaired;residence;response;restoration;severe injury;sex;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: 10335967
project_number: 5P42ES007380-24
project_title: Fate and Transport of Contaminants in Aging Piping Systems
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5743
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY 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 SUMMARYMillions of miles of water and sewer piping systems are currently buried across the United States. Near sitescontaminated with hazardous wastes pipe deterioration provides pathways for contaminant entry and transportto surrounding communities. One challenge of leaking sewer pipes near Superfund sites involves volatilizationof contaminants that enter subsurface pipes posing indoor inhalation exposure risks. In drinking water pipingsystems pipe fractures coupled with pressure transients within the piping system allow subsurfacecontaminants to enter the systemespecially at contaminated sites where such breaks become conduitsimpacting water quality. This project provides strategies to reduce and prevent exposure risks to environmentalcontaminants especially chlorinated ethenes and per- and polyfluoroalkyl substances (PFAS) that result fromleaking and damaged subsurface piping networks. The overarching project goal is to combine pipinginfrastructure science with fate and transport science to identify and reduce exposure risks associated withtrichloroethene (TCE) tetrachloroethene (PCE) and PFAS. To achieve this goal we propose three specificaims: 1) To measure mass flux of contaminants at field sites where TCE and PCE exposure risks are impactedby piping networks; evaluate flow and pressure field data from drinking water systems; and determine theeffect of broken or failed piping components and joints in lab settings 2) To develop models that: a) predictmass flux of contaminants to indoor air and evaluate exposure risks; b) predict mass flux of contaminantsthrough piping networks; and 3) To use stakeholder input and stochastic analyses to characterize modeluncertainty and sensitivity in an effort to develop stakeholder-relevant solutions that reduce and preventexposure risks. The specific aims integrate advanced computational modeling approaches with fieldmeasurements collected from piping systems in Eastern Kentucky and at a start-of-the-art vapor intrusionresearch facility near a Superfund site. Comparing data from different measurement techniques including anovel sensor technology provides information about temporal variability of sewer gas mass flux which iscritical due to the high level of uncertainty that surrounds environmental exposure risks. The research teamaims to bolster a paradigm shift in the way uncertain exposure risks are managed and develop solutions toreduce exposure risks in ways that are acceptable to communities. Risk communication science will informstrategies to evaluate uncertainty using stakeholder perspectives and evidence-based practices as aframework to promote solution-oriented research and environmental health literacy.

project_terms:
Address;Aging;Air;Analytical Chemistry;Biological Monitoring;Biomedical Research;California;Communication;Communities;Computer Models;Coupled;Data;Data Analyses;Deterioration;Ensure;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Hazards;Environmental Health;Environmental Pollution;Environmental Science;Equation;Ethylenes;Evidence based practice;Foundations;Fracture;Gases;Goals;Hazardous Waste;Health;Human;Individual;Indoor Air Quality;Industry;Infrastructure;Inhalation Exposure;Interview;Joints;Kentucky;Knowledge;Measurement;Measures;Membrane;Modeling;North Carolina;Outcome;Outcome Study;Pathway interactions;Policies;Poly-fluoroalkyl substances;Polymers;Public Health;Regulation;Reporting;Research;Research Project Grants;Risk;Risk Reduction;Route;Sampling;Science;Services;Site;Superfund;Surveys;System;Techniques;Temperature;Testing;Tetrachloroethylene;Time;Toxic effect;Transcend;Translational Research;Transport Process;Trichloroethylene;Uncertainty;United States;Volatilization;Water;Water Supply;aged;base;community engagement;contaminant transport;data interoperability;data management;data modeling;drinking water;engineering design;epidemiology study;field study;ground water;health literacy;hookah;indoor air;informant;mass flux;novel;nutrition;predictive modeling;pressure;prevent;research facility;sensor;sensor technology;stakeholder perspectives;superfund chemical;superfund site;tool;vapor intrusion;ventilation;water quality

public_health_relevance:
PROJECT NARRATIVEThe overarching goal of this project is to advance fate and transport research to identify and reduce exposurerisks associated with trichloroethene (TCE) tetrachloroethene (PCE) and PFAS. Field study results verify andcalibrate new models that predict contaminant mass flux associated with damaged subsurface piping networkswhich serve as preferential pathways for contaminants to be transported throughout communities. Evidence-based practices serve as a framework to promote environmental health literacy so that communitystakeholders representatives from regulatory agencies and industry groups can provide information todevelop solutions that will ensure Superfund mandates are addressed and public health is protected.


application_id: 10335966
project_number: 5P42ES007380-24
project_title: Responsive Membranes and Advanced Materials for Sensing and Remediation of Halo-organics
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5742
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
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 SUMMARYChlorinated organic compounds such as polychlorinated biphenyls (PCBs) and trichloroethylene (TCE PCE)and polyfluoroalkyl substances (PFAS) continue to pose both remediation challenges and human health risks.Despite decades of remediation effort chloro- and perfluoro-organic compounds remain Superfund pollutantsof national health concern due to their high toxicity persistence and varied sources of distribution in theenvironment. Many current treatments (microbial transformation carbon adsorption etc.) for the reclamation ofcontaminated water sources are chemical-intensive energy-intensive and/or require post-treatment due tounwanted by-product formation. Project 3 proposes trans-disciplinary integration of the materials surfacescience and engineering concepts including responsive polymer and reduced graphene oxide 2D membranescience nanostructured metals and nutrition and food science using approaches common in the biomedicalresearch field to develop more efficient methods of organic detoxification. The development of nanosized iron-based materials has brought important and promising techniques into the field of environmental remediation. Inrecent years zero-valent nanoscale metal (especially bimetallic) particles have attracted growing attention ingroundwater remediation of chlorinated solvents. Our overarching goals are to create catalytic domains inrobust polymer hollow fibers and in 2D graphene-based membranes for both reductive and oxidativedegradation and temperature-responsive polymers for PFAS and PCB sorption/ desorption. Two specific aimsare to: 1) to create robust polymeric/gel and 2-D material-based (reduced graphene oxide and composites)metal catalyzed functionalized membranes and materials to enhance TCE PCE PCB degradation efficiencyand reduce material usage and demonstration of the use of catalytic membrane filters for two site-basedapplications (2) to concentrate and regenerate PFAS and PCB individual compounds using ultra high sorptioncapacity temperature responsive hydrogel/membranes or localized heating through AMF (alternating magneticfield) using magnetite nanoparticles and to create functionalized smart adsorptive filters and sensors for PFASdetoxification applications with real-world water samples. Each of these objectives represent highly significantmaterial science advancement in terms of confined reactive nanosized metals in robust membrane domainand novel temperature swing adsorption/desorption through creation of responsive materials. The applicationsof our technologies will include collaborations with Rockwell International Site in Russellville Kentucky forPCBs and the ATKEMIX TEN Site in Louisville Kentucky for TCE PCE chloroform and carbon tetrachloridemixture identified water utilities in Eastern Kentucky for PFAS sorption application and Arcadis Corporationinvolved with remediation activities.

project_terms:
Adsorption;Advanced Development;Aftercare;Area;Attention;Biomedical Research;Carbon;Carbon Tetrachloride;Catalysis;Catalytic Domain;Chemicals;Chloroform;Collaborations;Consumption;Detection;Development;Drug Metabolic Detoxication;Engineering;Environment;Environmental Health;Fiber;Funding;Gel;Goals;Hazardous Waste Sites;Health;Heating;Human;Hydrogels;Individual;Industrialization;International;Iron;Kentucky;Lead;Magnetism;Membrane;Metals;Methods;Nanostructures;Natural regeneration;Nutritional Science;Oxidants;Oxides;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Polymers;Property;Public Health;Research;Risk;Science;Site;Soil;Solvents;Source;Sulfate;Superfund;Surface;System;Techniques;Technology;Temperature;Tetrachloroethylene;Toxic effect;Toxicant exposure;Trichloroethylene;Water;base;contaminated water;cost;cost effective;design;drinking water;food science;global environment;graphene;ground water;magnetic field;magnetite ferrosoferric oxide;materials science;microbial;nanocomposite;nanoparticle;nanoscale;nanosized;novel;nutrition;particle;pollutant;prevent;reaction rate;remediation;sensor;superfund chemical;superfund site;water sampling

public_health_relevance:
PROJECT NARRATIVEThe persistence of toxic pollutants at Superfund sites poses a major environmental public health problem anda serious need for environmental solutions to reduce risk. Our research is expected to lead to cost-effectivetechnologies for remediation of chemicals such as TCE PCE and PCBs to nontoxic and biodegradableintermediates and for superfast sorption of PFAS compounds with responsive polymer materials. Ourapproaches to develop new polymer membrane and 2D-based materials to detoxify water and low energyconsuming adsorption/desorption technologies should lead to an advanced technology solution in the field ofremediation science and engineering from Superfund sites to water utility companies.


application_id: 10335965
project_number: 5P42ES007380-24
project_title: Postnatal Complications and Interventions against Halogenated Organics during Pregnancy
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5741
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYChildhood obesity rates have more than tripled over the last 40 years with 18.5% of children and adolescentswho are now obese. Endocrine-disrupting chemicals particularly obesogens such as polychlorinated biphenyls(PCBs) and per- and polyfluoroalkyl substances (PFAS) are contributing to the rapid increases in obesity.Recent studies indicate that prenatal exposures to PCBs and PFAS contribute to gender-specific obesitydevelopment in children. Both groups of contaminants share a common underlying mechanistic pathway thatof oxidative stress and their actions arise from the considerable crosstalk between transcription factorsincluding nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the aryl hydrocarbon receptor. Others havefound that treating cells in culture directly with PCBs or PFAS [perfluorooctanesulfonic acid (PFOS) andperfluorooctanoic acid (PFOA)] influences adipogenesis using human and mouse cells. Importantly PFOSinduced adipogenesis and glucose uptake by acting through Nrf2. Using a mouse model as part of theprevious round of funding similar observations were made in that offspring exposed perinatally to PCBs hadsignificantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Furthermature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring fromvehicle-treated dams. Importantly a healthy behavioral intervention maternal voluntary exercise duringpregnancy improved offspring disease risk associated with in utero PCB exposure. The proposed project willcontinue to use an in vivo mouse model as well as transition to human samples in order to examine themolecular impact of environmental contaminant toxicity during a narrow window of susceptibility. Aim 1 will testwhether voluntary exercise during pregnancy or in the offspring themselves can be used as an interventionstrategy to protect against the long-term metabolic detriments associated with in utero PCB exposure. Aim 2will elucidate the mechanism of impaired glucose tolerance and altered body composition in offspring born toPCB-exposed dams (including the use of Nrf2 knockout mice) and will determine how maternal exercise isprotecting offspring from these impairments. Aim 3 will use human cells to identify biomarkers of the specificharm associated with in utero halogenated organic pollutant exposures and to elucidate the potentialmechanisms that contribute to increased obesity and diabetes risk in exposed infants. Our work will measureactual contaminant exposure levels in maternal and cord serum and quantify adipocyte differentiation directlyin cells isolated from the same neonates. Anticipated results are particularly significant in that they highlightearly developmental stages as potential periods of particular vulnerability to program lasting obesity anddiabetes effects of toxic environmental insults.

project_terms:
Address;Adipocytes;Adolescent;Adult;Agonist;Aryl Hydrocarbon Receptor;Behavior Therapy;Biochemical;Body Composition;Breast;Cells;Child;Collaborations;Development;Diabetes Mellitus;Discipline of Nursing;Endocrine Disruptors;Environmental Exposure;Environmental Impact;Environmental Pollution;Epidemic;Erythroid;Evaluation;Exercise;Exposure to;Fatty acid glycerol esters;Female;Funding;Future;Gender;Glucose Clamp;Glucose Intolerance;Goals;Gold;Hazardous Substances;Health;Home;Human;Human Development;Impairment;Infant;Insulin Resistance;Intervention;Kentucky;Knockout Mice;Life Style;Liver;Measures;Mesenchymal Stem Cells;Metabolic;Methods;Modeling;Molecular;Mus;Muscle Cells;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Pathway interactions;Perinatal;Perinatal Exposure;Phenotype;Play;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Predisposition;Pregnancy;Process;Research;Risk;Role;Running;Sampling;Serum;Superfund;Testing;Thinness;Time;Tissues;Toxic effect;Umbilical cord structure;Universities;Work;adipocyte differentiation;base;biological adaptation to stress;blood glucose regulation;cohort;cost effective;dechlorination;detection method;diabetes risk;diphenyl;disorder risk;exercise intervention;fetal;glucose uptake;impaired glucose tolerance;improved;in utero;in vivo;innovation;insight;insulin sensitivity;insulin signaling;lipid biosynthesis;male;mouse model;neonate;nutrition;obesity development;obesity in children;obesity risk;obesogen;offspring;offspring obesity;perfluorooctane sulfonate;perfluorooctanoic acid;perinatal development;pollutant;postnatal;prenatal exposure;preventive intervention;programs;sedentary;specific biomarkers;superfund chemical;transcription factor;trend

public_health_relevance:
PROJECT NARRATIVEObesity and diabetes are at epidemic levels and the toxicity of environmental contaminants during perinataldevelopment could be a significant contributor to these trends. The proposed studies will offer innovative newinsights to understanding the role of exercise in mitigating the health impacts of in utero contaminantexposures. Project 2 clearly addresses three of the Superfund Research Program primary objectives: Mandate1 advanced techniques for detection assessment and evaluation of the effect of hazardous substances onhuman health Mandate 2 methods to assess the risks to human health presented by hazardoussubstances and Mandate 4 methods to reduce the amount and toxicity of hazardous substances.


application_id: 10335964
project_number: 5P42ES007380-24
project_title: Superfund Chemicals Nutrition and Multi-Organ Cardiovascular Risk
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5740
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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 overall goal of Project 1 is to understand the signaling pathways and metabolic or biological changes bywhich bioactive nutrients modulate impacts of acute or chronic exposure to persistent organic pollutants suchas polychlorinated biphenyls (PCBs) and long-chain per- and polyfluoroalkyl substances (PFAS). Suchpersistent pollutants express significant chemical stability in the environment and toxic insults from POPs areknown to correlate with a range of post-exposure human health impacts including vascular inflammation.Atherosclerosis a chronic inflammatory disease remains the leading cause of death in the United States.Biological events associated with inflammation and atherosclerosis can be modified by circulating toxicantsand bioactive nutrients and their metabolites which dictate final redox changes and inflammatory outcomes byaltering NF-kB and Nrf2 signaling. For example preliminary data demonstrate down-regulation of PCB 126-mediated toxicity and inflammation by plant-derived bioactive nutrients e.g. polyphenols and fiber (e.g.inulin). Importantly it is known that the pathology of atherosclerosis is dependent on the health and cross-talkof multiple tertiary organ systems including the liver and gut as exemplified by recent findings linking PCBexposure with increased plasma levels of trimethylamine N-oxide (TMAO) a diet-derived metabolite formedthrough cross-talk between gut microbiota and hepatic oxidation and associated with risk of atherosclerosis.Preliminary findings indicate that persistent organic pollutants and especially PCBs caused liver dysfunctionand alterations of gut microbiota and that prior liver injury exacerbated PCB-mediated systemic inflammation.Metabolomic profiling further suggested that increased formation of pro-atherogenic metabolites (e.g.ceramides) may drive multi-organ inflammation and increased cardiovascular risk. Based on these findingsthree specific aims test the hypotheses that 1) administration of PCB 126 and/or PFAS to mice increasescardiometabolic disease risk by increasing ceramide production via modulation of hepatic gene expressionand/or the gut microbiota; 2) administration of green tea catechins and/or soluble inulin fiber in vivo decreasesceramides and thereby stabilizes cellular redox status modulating NF-kB and Nrf2 signaling and pro-atherosclerotic pathologies as determined by en face and lipid staining in atherogenic LDL receptor-deficientmice; and 3) exposure to PCBs and/or PFAS increases pro-atherogenic metabolites (e.g. ceramides) throughincreased de novo synthesis in preclinical models. Transcriptomic and metabolomic technologies will be usedto explore the mechanistic interactions between pollutant exposure nutritional intervention and cardiovasculardisease (CVD) risks. These data will be confirmed in biobanked samples of humans with CVD. Results willsupport the paradigm that healthful nutrition interventions offer a powerful strategy to reduce disease risksassociated with environmental toxic insults and to prevent inflammatory diseases such as atherosclerosis thathave been linked to exposure to Superfund pollutants.

project_terms:
Acute;Address;Animal Model;Antibiotics;Atherosclerosis;Binding;Biological;Biological Markers;Blood Vessels;Cardiometabolic Disease;Cardiovascular Diseases;Cause of Death;Ceramides;Chemicals;Chronic;Data;Data Set;Development;Diet;Dietary Fiber;Dietary Intervention;Dioxins;Disease;Down-Regulation;Endothelium;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Science;Enzymes;Epigallocatechin Gallate;Event;Exposure to;Fiber;Functional disorder;Future;Gene Expression;Genes;Goals;Green tea;Hazardous Waste Sites;Health;Hepatic;Hepatocyte;Human;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Inulin;Link;Lipids;Liver;Liver Dysfunction;Low Density Lipoprotein Receptor;Mediating;Metabolic;Metabolic dysfunction;Metabolism;Methionine;Modeling;Molecular;Mus;NF-kappa B;Nutrient;Outcome;Oxidation-Reduction;Pathology;Peripheral;Permeability;Persons;Plants;Plasma;Poison;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Population;Pre-Clinical Model;Process;Production;Public Health;Reporting;Research;Resistance development;Risk;Sampling;Signal Pathway;Signal Transduction;Sphingolipids;Stains;Superfund;Technology;Testing;Toxic effect;United States;Vascular Endothelial Cell;Volatile Fatty Acids;animal data;atherosclerosis risk;base;biobank;body system;cardiovascular disorder risk;cardiovascular risk factor;chemical stability;choline deficient diet;chronic inflammatory disease;disorder risk;experimental study;exposed human population;gut bacteria;gut microbiota;in vivo;lipid metabolism;liver injury;macrophage;metabolic profile;metabolomics;nutrition;oxidation;persistent organic pollutants;pollutant;polyphenol;prebiotics;prevent;programs;response;stable isotope;superfund chemical;systemic inflammatory response;toxicant;transcriptomics;trimethyloxamine;vascular inflammation

public_health_relevance:
PROJECT NARRATIVEThis project explores connections between two major public health concerns that are highly relevant toSuperfund Research Program (SRP) stakeholders and the SRP: widespread contamination of the environmentby a class of long-lasting toxic chemical contaminants known as PCBs and PFAS. These contaminants havebeen linked to a leading U.S. health challenge cardiovascular diseases and also linked to the liver and gut.The project addresses specifically SRP Mandate 4 by testing dietary interventions that may disrupt diseaseprocesses by stabilizing the gut bacteria and liver and reducing cardiovascular risks initiated by exposure topollutants particularly in people who reside near Superfund or other hazardous waste sites where PCBs andother pollutants are prevalent.


application_id: 10335963
project_number: 5P42ES007380-24
project_title: Research Experience and Training Coordination Core
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5739
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
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 Superfund Research Center (UK-SRC) e addresses a major environmental issuefocusing on halogenated organics occurring at Superfund sites and that persist in the ground and watersources in many other locations nationwide. The Research Experience and Training Coordination Core(RETCC) aims to train students to investigate these issues via exposing trainees to interdisciplinaryapproaches to training providing opportunities to enhance their professional career development and throughextensive outside laboratory experiences program that coordinates opportunities for participation in theCommunity Engagement Core and the Administrative Cores research translational function and engagingthem with the Data Management and Analysis Core (DMAC). These diverse activities will give the traineesbroad exposure to environmental issues that affect their surroundings and equip them with a unique toolset tomake disruptive impacts to the field. Addressing environmental challenges requires an integrative approachthat leverages knowledge from disparate disciplines and perspectives. A combination of knowledge andscientific methods from biomedical and environmental science and engineering-based disciplines are requiredwhile also considering the social impact of these issues on the surrounding communities. While the RETCCpromotes strong cross-disciplinary training it also encourages the interdisciplinary thinking needed to developproblem-solving skills and to become effective environmental communicators. The specific aims are: 1) tointroduce innovative training components designed to spur disruptive impacts and spark creative solutions tocomplex environmental problems. The RETCC will fund trainee-developed pilot grants that necessitate cross-disciplinary collaborations (e.g. data science/bioinformatics) among the projects and cores; 2) to integratecareer development training activities critical for academic and nonacademic interests developed throughinteractions with the Kentucky Center for Clinical and Translational Science and newly developed DMAC andoffer specific skills training (responsible conduct of research and grantsmanship) that prepare students forsuccess in academic governmental and industrial research careers; and 3) to increase integration of thetrainees throughout all aspects of the Center to enhance overall productivity and to expand trainingopportunities from recruitment of the next generation of trainees to reporting the Centers activities and traineeoutcomes to the SRP.

project_terms:
Address;Affect;Bioinformatics;Clinical;Clinical Sciences;Collaborations;Communities;Complex;Data Analyses;Data Collection;Data Science;Development;Discipline;Doctor of Philosophy;Education;Educational workshop;Environmental Engineering technology;Environmental Health;Environmental Science;Exposure to;Funding;Goals;Government;Grant;Health;Individual;Industrialization;Industry;Interdisciplinary Study;Kentucky;Knowledge;Laboratory Research;Leadership;Life Style;Location;Medical Ethics;Mentors;Methods;Mind;Modeling;Modernization;Outcome;Policies;Positioning Attribute;Postdoctoral Fellow;Problem Solving;Productivity;Public Health;Recording of previous events;Reporting;Research;Research Project Grants;Resources;STEM field;Science Technology Engineering and Mathematics;Scientist;Series;Signal Recognition Particle;Social Impacts;Source;Students;Superfund;Technology;Thinking;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Training and Education;Translational Research;Universities;Water;Writing;base;career;career development;clinical center;community engagement;data management;data sharing;design;experience;flexibility;innovation;interdisciplinary approach;interest;laboratory experience;meetings;multidisciplinary;next generation;novel;nutrition;outreach;pollutant;programs;recruit;remediation;responsible research conduct;skills;skills training;student training;success;superfund chemical;superfund site;training opportunity;webinar

public_health_relevance:
PROJECT NARRATIVEThe focus of University of Kentucky Superfund Research Center (UK-SRC) is committed to developing an in-depth understanding of environmental health associated with exposure to organic pollutants as well as thedevelopment of protective technologies to aid in reduction of such exposure incidents. The proposedinterdisiplinary training activites of the UK-SRC will be led and coordinated by the Research Experience andTraining Coordination Core to successfully train skilled individuals who will positively impact our environmentalhealth and the overall health of our nation.


application_id: 10335962
project_number: 5P42ES007380-24
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5738
contact_pi_person_id: 12559398
contact_pi: BREWER, DAWN
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 The research proposed by the University of Kentucky Superfund Research Center (UK-SRC) uses basic biological chemical and physical methods through nutrition and physical activity to reduce the amount and toxicity of hazardous substances (Superfund Research P Mandate #4). Incorporating good nutrition and physical activity strategies in conjunction with increasing environmental health literacy focused on nutrition and contaminant exposures aligns with the central theme of the UK-SRC  reducing risk posed by environmental contaminants in vulnerable communities  and with the prevention/intervention activities implemented by CEC. The CEC will continue to engage in bi-directional communication with its longest standing community partner of 12 years the Harlan community located in southeastern Kentucky near the National Priorities List (NPL) site in Dayhoit Kentucky. At this NPL site disposal of chlorinated solvents affected plant workers and neighbors living in a nearby mobile home park and surrounding area. New partnerships have been formed in eastern Kentucky Letcher County which has concerns related to the negative health consequences associated with air and water pollution derived from coal mining. The CEC also brought environmental pollutant and healthy lifestyle-focused interventions to older adults in central Kentucky. Although not exposed to a particular environmental contaminant the older adult population is an important one to include in its engagement activities due to the rapid growth of this population sector. By virtue of being an older adult these individuals have been exposed to more environmental contaminants and with age the detoxification capacity of the liver and kidneys has declined putting older adults at greater risk of experiencing more pronounced negative health effects of environmental contaminants. The innovation of the CEC to engage communities is apparent in the six prevention/intervention activities outlined in this proposal. The six programs are grounded in evidence-based approaches by intervening at multiple levels of the social ecological model of health behavior change including the individual community and organizational levels which allows the CEC to implement healthy lifestyle and environmental pollution education into existing community programs that reach populations across the lifespan. Major community partners include county Cooperative Extension Service Family and Consumer Science (FCS) and Horticulture Agents county senior centers community centers and farmers markets. The CEC plans to incorporate the science of the UK-SRC into existing community programs including walking programs FCS Extension health programs gardening programs senior center health programs and youth day camp programs. The gardening program will not only foster collaboration with community entities but also with the Duke SRC as it combines the expertise of both. Overall collaboration with community partners will benefit residents by providing opportunities to improve health and receive new knowledge pertaining to using healthy lifestyles to reduce exposure to environmental contaminants.

project_terms:
Address;Adopted;Affect;Age;Air Pollution;Area;Back;Behavior;Biological;Chemicals;Chronic Disease;Coal Mining;Collaborations;Communication;Communities;Consumption;Country;County;Development;Drug Metabolic Detoxication;Education;Elderly;Environmental Hazards;Environmental Health;Environmental Pollutants;Environmental Pollution;Evaluation;Exposure to;Family;Focus Groups;Fostering;Goals;Hazardous Substances;Health;Health Benefit;Health behavior;Health behavior change;Home;Individual;Intervention;Interview;Journals;Kentucky;Kidney;Knowledge;Lead;Life Style;Liver;Longevity;Methods;Modeling;Needs Assessment;Outcome;Peer Review;Physical activity;Physiological;Plants;Policies;Polychlorinated Biphenyls;Population;Population Growth;Populations at Risk;Prevention;Public Health;Recommendation;Reporting;Research;Research Activity;Research Project Summaries;Resources;Risk;Science;Scientist;Services;Site;Solvents;Superfund;Surveys;System;Toxic effect;Translating;United States;Universities;Water Pollution;Work;Youth;behavior change;community center;community engagement;community organizations;design;environmental change;evidence base;experience;farmers markets;good diet;health knowledge;health literacy;healthy lifestyle;improved;innovation;meetings;novel;nutrition;pollutant;prevent;preventive intervention;programs;rapid growth;social;superfund chemical;superfund site;symposium;tool;tool development;vulnerable community;walking program

public_health_relevance:
PROJECT NARRATIVE The Community Engagement Core (CEC) works to achieve public health benefits within communities and supports the UK-SRC by encouraging Superfund Research Program (SRP) stakeholders to protect their health from exposure to environmental contaminants by consuming a healthy diet and increasing physical activity to reduce the bodily amount and toxicity of hazardous substances (mandate #4). The proposed CEC prevention/ intervention activities are community-driven solution-oriented programs that translate the science of the UK- SRC and addresses the needs of SRP stakeholders with concerns regarding exposure to hazardous substances. The CEC programs achieve this by providing community residents with the opportunity to improve nutrition increase physical activity and enhance environmental health literacy among community residents.


application_id: 10335961
project_number: 5P42ES007380-24
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5737
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY 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 SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) Data Management and Analysis Core(DMAC) has a goal to provide an overarching technology and research support infrastructure for themanagement and integration of data and information assets. Given that interdisciplinary research requiresresearchers to use methods and data from a range of disciplines this goal addresses a critical need forinterdisciplinary research to overcome hurdles posed by discipline-specific methods that impede progresswhen many disciplines attempt to share data. The DMAC is designed in alignment with FAIR (FindableAssessable Interoperable and Reusable) data principles to encourage interaction of data users and sharing ofdata. The specific aims are: 1) coordination of projects and cores; 2) foster data integration sharing andinteroperability; 3) ensure data quality assurance and quality control (QA/QC). The datasets to be managedand curated within the DMAC encompass the full range of basic research to translational work from animal-based studies to chemical analysis from experimental studies evaluating remediation of hazardoussubstances to community engagement activities. The DMAC will engage regularly with project/core leaders toprioritize data sets. It will streamline analytic resources data management data quality validation and dataintegration across projects and cores to improve efficiencies and reproducibility enhance project coordinationand promote resource sharing. The DMAC will promote interoperability by incorporating FAIR guidingprinciples in its data dashboards data archives and its query exploration interface to permit projects and coresto better integrate. By developing common terminologies data dictionaries training etc. the DMAC willfacilitate a common data resource to foster sharing within and beyond the UK-SRC. To facilitate interactionwith investigators and trainees there will be (on-site and electronic) opportunities for regular interaction withbiostatisticians data scientists and informaticians where formal and informal training can occur. Theseactivities will be coordinated and advertised closely with the Research Experience Training Coordination Core(RETCC). The DMAC will create a new WHY ENVIRONMENT module to enable projects and cores to engagein investigator-initiated research translation activities to allow them to form new questions and hypotheses thatcan be tested in projects and cores and shared beyond the confines of UK-SRC. Lastly the DMAC willincorporate best practices outlined by Data Observation Network for Earth (DataONE.org). It will establish aplan for data QA/QC so that UK-SRC research will not be subjected to pitfalls associated with poor qualitydata.

project_terms:
Academy;Address;Adverse effects;Animals;Awareness;Basic Science;Biometry;Chemicals;Collaborations;Common Data Element;Communities;Complex;Computational Science;Consensus;Data;Data Analyses;Data Science;Data Scientist;Data Set;Deposition;Development;Discipline;Documentation;E-learning;Educational workshop;Ensure;Environment;Environmental Health;Environmental Science;Formulation;Fostering;Goals;Government Agencies;Grant;Hazardous Chemicals;Hazardous Substances;Information Resources;Infrastructure;Interdisciplinary Study;Investigator-Initiated Research;Kentucky;Knowledge;Knowledge Discovery;Life Cycle Stages;Metadata;Methods;National Institute of Environmental Health Sciences;Online Systems;Ontology;Outcome;Planet Earth;Population;Problem Solving;Process;Protocols documentation;Public Health;Quality Control;Registries;Reproducibility;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Risk;Science;Scientist;Secure;Series;Site;Superfund;Technology;Terminology;Testing;Toxic effect;Training;Translational Research;Universities;Validation;Work;application programming interface;base;biomedical informatics;community engagement;dashboard;data archive;data dictionary;data ecosystem;data integration;data management;data quality;data resource;data sharing;data standards;data tools;design;experience;experimental study;improved;innovation;interoperability;meetings;member;nutrition;programs;quality assurance;remediation;repository;superfund chemical;symposium;tool;training opportunity;training project;webinar

public_health_relevance:
PROJECT NARRATIVEThe Data Management and Analysis Core (DMAC) of the University of Kentucky Superfund Research Center(UK-SRC) provides an integral new resource by functioning as a nexus for interactions across projects andcores. It systematically integrates data assets through the entire lifecycle of the grant and facilitates interactionof investigators and trainees to assist them in conducting research that addresses Superfund mandates. TheDMAC will foster data sharing within and beyond UK-SRC including researchers as well as communitystakeholders and governmental agencies committed to protecting public health from the adverse effects ofhazardous chemicals.


application_id: 10335960
project_number: 5P42ES007380-24
project_title: Biomonitoring and Environmental Analytical Chemistry Core
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5736
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis core provides analytical services to UK-SRC investigators who are engaged in studies of the sensingdistribution and remediation of environmental toxicants and who are investigating their mechanisms of toxicityapproaches to mitigate these toxic effects. This research is important because exposure to these kinds ofenvironmental chemicals contributes to risk of non-communicable diseases such as cancer and cardiovasculardisease in humans. The core provides access to state-of-the-art gas and liquid chromatography coupled massspectrometer systems that are used for measurements of environmental chemicals their metabolites anddegradation products and other biomolecules of interest including biomarkers of diet nutrition and disease risk.Core services encompass targeted and untargeted analytical methods using liquid chromatography and gaschromatography coupled multistage/high resolution mass spectrometry. The core provides established/routineservices and can develop new services or adapt services from literature methods. The core is managed by theDirector who works with the Administrative Core to oversee the business operation scheduling andprioritization of services which are provided by experienced PhD level staff. A Laboratory InformationManagement System is used for sample tracking enforcement of standard operating procedures qualitymanagement and data reporting to project leaders and the Data Management and Analysis Core (DMAC).Services are further validated by participation in external proficiency testing programs. The goals of the corewill be accomplished by addressing the following specific aims: 1. To provide analytical chemistry servicesto UK SRC investigators. The core provides services to all the component projects. These includemeasurements of chemical pollutants in environmental matrices including water and soil for studies of theirtransport distribution sensing and remediation conducted by projects 1 and 2. Services provided to thebiomedical projects 1 and 2 include measurements of environmental pollutants in studies using in vitro systemsand preclinical models. Untargeted analytical methods using high resolution mass spectrometry will supportsystems level studies of the effects of diet nutrition and exercise on biological processes that are proposed tomitigate the deleterious health effects of exposure to environmental pollutants. 2. To conduct biomonitoringmeasurements for population health studies. The core will enable interactions between UK-SRCinvestigators and collaborators who have completed or ongoing clinical/population health studies that providean opportunity to investigate relationships between environmental exposures and health outcomes as aconduit for clinical translation of advances made by the biomedical projects. In coordination with DMAC thecore will conduct large scale measurements of environmental chemicals their metabolites and degradationproducts and biomarkers of exposure or lifestyle associated stressors using both targeted and untargetedapproaches to examine association of environmental exposures and interventions with clinical outcomes.

project_terms:
Address;Amendment;Analytical Chemistry;Basic Science;Biological;Biological Markers;Biological Monitoring;Biological Process;Businesses;Cardiovascular Diseases;Chemicals;Clinical;Clinical Management;Cohort Studies;Collaborations;Communities;Consent;Coupled;Data Analyses;Data Analytics;Data Reporting;Data Science;Data Storage and Retrieval;Detection;Development;Diet and Nutrition;Disease;Doctor of Philosophy;Ensure;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Pollutants;Environmental Science;Equipment;Evaluation;Exercise;Exposure to;Funding;Gas Chromatography;Gas-Liquid Chromatography;Goals;Grant;Health;High Pressure Liquid Chromatography;Human;Human Resources;In Vitro;Institutional Review Boards;Intervention;Investigation;Laboratories;Lead;Life Style;Link;Liquid Chromatography;Literature;Malignant Neoplasms;Management Information Systems;Mass Spectrum Analysis;Measurement;Medical center;Methods;National Institute of Environmental Health Sciences;Outcome;Pre-Clinical Model;Preparation;Procedures;Protocols documentation;Publications;Quality Control;Reaction;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resolution;Risk;Role;Sampling;Schedule;Service provision;Services;Soil;Source;Superfund;Support System;System;Technology;Testing;Toxic Environmental Substances;Toxic effect;United States Department of Veterans Affairs;United States National Institutes of Health;Veterans Health Administration;Vulnerable Populations;Water;Work;analytical method;base;cardiovascular disorder risk;clinical translation;computerized data processing;data management;disorder risk;environmental chemical;environmental chemical exposure;environmental intervention;experience;human disease;improved;instrument;instrumentation;interest;laboratory facility;lipidomics;mass spectrometer;metabolomics;nutrition;offspring;operation;pollutant;population health;preclinical study;programs;quality assurance;ranpirnase;remediation;stressor;superfund chemical;water sampling

public_health_relevance:
PROJECT NARRATIVEExposure to environmental chemicals increases the risk of many non-communicable human diseases. The UK-SRC serves our stakeholders and the broader objectives of the Superfund Research Program by conductingstudies to understand mechanisms linking exposure to environmental chemicals with human disease risklifestyle based approaches to mitigate these risks and strategies for improved sensing and remediation of toxicenvironmental chemicals. This core component provides UK-SRC investigators with measurements of theseenvironmental chemicals their metabolites and degradation products and other biological molecules ofrelevance to human health.


application_id: 10335959
project_number: 5P42ES007380-24
project_title: Administration Core
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5735
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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 Superfund Research Center (UK-SRC) will focus on a prevention and interventionparadigm with an overarching goal to promote healthy lifestyles (i.e. healthful nutrition and increased physicalactivity) to reduce disease risks associated with exposure to a subclass of persistent halogenated chemicals(e.g. PCBs TCE and PFAS). Our biomedical research will be coupled with environmental science/engineeringresearch that uses novel sensing remediation and fate and transport science to prevent or reduce exposurerisks in the environment. Our biomedical research is integrated around a full life-span perspective and aparadigm that uses animal studies to identify possible hypotheses that can be tested against existing humandatabases to further identify potential intervention strategies. Our environmental science research is integratedaround a project cross-talk that uses fate and transport science to help inform technology development usingnovel material science designed to reduce exposure to organic pollutants and that can then be deployed infield applications. Both biomedical and environmental science projects are crosslinked around a common set ofpollutants and the use of animal models to test the toxicity of these pollutants and different remediation by-products. To provide an optimal support environment and the requisite infrastructure to accomplish theCenters goal we propose four specific aims for our Administrative Core (ADMC): 1) activities managementand integration 2) bi-directional communication strategies 3) partnerships and technology transfer and 4)evaluation and management processes. Management and integration functions are facilitated by monthlyCenter meetings and ADMC leadership and trainee interns are drawn from the individual research projects. Bi-directional communication with other SRP centers and agency scientists and research translation to otherstakeholders are now fully integrated within the ADMC and overseen by a dedicated research translationcoordinator with support from a communications director. The ADMC effectively facilities investigator-initiatedresearch translation and technology transfer functions by leveraging a new integrated Data Management andAnalysis Core along with multidirectional internal (e.g. NIH funded UK Center for Clinical and TranslationalScience (CCTS) WHY program UK P30 pilot grants Kentucky Water Institute) and external (e.g. EPAADSTR Kentucky Cabinet for Energy and the Environment (KYEEC) ARCADIS Consultants individual waterutilities) partnerships. Evaluation and management processes are overseen by the ADMC director as assistedby the program administer. The focus of the ADMC on the establishment and maintenance of a continuousimprovement development processes along with internal and external relationships positions the UK-SRC tocontribute not only important scientific findings but also to the collaborative processes and innovativeendeavors associated with the national Superfund Research Program.

project_terms:
Academia;Address;Advisory Committees;Analytical Chemistry;Animal Model;Animals;Appalachian Region;Biological Monitoring;Biomedical Research;Chemicals;Clinical Sciences;Communication;Communities;Community of Practice;Complex;Coupled;Data;Data Analyses;Databases;Detection;Development;Educational workshop;Engineering;Ensure;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Science;Evaluation;Event;Exercise;Exposure to;Funding;General Population;Goals;Government Agencies;Grant;Health;Human;Human Resources;Individual;Industry;Information Dissemination;Infrastructure;Institutes;Internships;Intervention;Investigator-Initiated Research;Kentucky;Leadership;Life Style;Link;Longevity;Maintenance;Mentorship;National Institute of Environmental Health Sciences;Physical activity;Polychlorinated Biphenyls;Positioning Attribute;Prevention;Process;Productivity;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Risk;Role;Science;Scientist;Structure;Superfund;Targeted Research;Technology;Technology Transfer;Testing;Toxic effect;Toxicity Tests;Training;Training Activity;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Water;arm;base;clinical center;community engagement;crosslink;data management;design;disorder risk;experience;healthy lifestyle;innovation;materials science;meetings;member;multidisciplinary;novel;nutrition;pollutant;prevent;programs;ranpirnase;remediation;superfund chemical;technology development;webinar

public_health_relevance:
PROJECT NARRATIVEThe Administrative Core of the UK-SRC will continue to promote problem-based solution-oriented research toreduce exposure and/or negative health impacts associated with exposure to a subclass of persistenthalogenated chemicals (e.g. PCBs TCE and PFAS). This will be accomplished by using an innovativetransdisciplinary research approach that brings together biomedical and environmental scientists engineersand trainees using an integrative administrative structure that links together individual projects and cores. TheAdministrative Core will ensure the continued relevance of the proposed research through bi-directionalcommunication with the SRP and SRP staff academia the general public and relevant federal and statecommunities of practice (e.g. EPA ATSDR KYDEP) as well as communities of impact in Appalachia.


application_id: 10335958
project_number: 5P42ES007380-24
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2022-03-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D(SF)
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Aging;Appalachian Region;Awareness;Binding;Biochemical;Biological;Biological Markers;Biological Models;Biological Monitoring;Biomedical Engineering;Biomedical Research;Biomimetics;Chemicals;Communication Research;Communities;Complex;Consumption;Data;Data Analyses;Diet and Nutrition;Diffusion;Disease;Disease Outcome;Economically Deprived Population;Engineering;Environment;Environmental Engineering technology;Environmental Health;Environmental Pollutants;Environmental Pollution;Environmental Science;Evaluation;Exercise;Exposure to;Fiber;Fostering;Funding;Future;Goals;Hazardous Substances;Health;Human;Industry;Intake;Interdisciplinary Study;Intervention;Iron;Kentucky;Life;Life Style;Link;Membrane;Metabolic;Metals;Methods;Molecular;Nanostructures;National Institute of Environmental Health Sciences;Nutrient;Outcome;Oxides;Pathway interactions;Physical activity;Physiological;Plants;Policy Maker;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevention;Prevention strategy;Primary Prevention;Problem Sets;Recommendation;Research;Research Project Grants;Research Training;Resources;Risk;Risk Assessment;Risk Management;Science;Scientist;Services;Site;Superfund;System;Techniques;Technology;Tetrachloroethylene;Toxic effect;Toxicant exposure;Training;Translational Research;Trichloroethylene;Universities;Vulnerable Populations;base;chemical stability;chronic inflammatory disease;community engaged research;community engagement;community intervention;community involvement;data management;detection method;dietary;disadvantaged population;disorder prevention;disorder risk;environmental chemical;environmental chemistry;experience;exposure pathway;graphene;healthy lifestyle;human old age (65+);improved;innovation;insight;interdisciplinary approach;lifestyle intervention;lipidomics;metabolomics;next generation;novel;nutrition;organic contaminant;policy recommendation;pollutant;polyphenol;prevent;programs;remediation;social;superfund chemical;superfund site;tool;vulnerable community


application_id: 10335927
project_number: 5R01AG064234-03
project_title: Regulation of Microglial Activation State by a Lipid Transporter
administering_ic: NIA
award_notice_date: 2021-12-08
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 064234
program_official: OPANASHUK, LISA A
project_start_date: 2020-03-01
project_end_date: 2024-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
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:
AbstractFunctional genome wide association studies have indicated that dysregulated microglia activationis a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease(AD). Thus regulating the microglia activation state could have profound therapeutic potential forAD. However the underlying mechanisms by which microglia transition between different statesduring normal and disease conditions are largely unknown. S1P-signaling has been implicated toplay important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports.On one hand the level of S1P is reduced in postmortem AD patient brains suggesting aprotective role of S1P. On the other hand there are also reports indicating that S1P might playthe opposite. Although has been tested in A-related AD mouse models the role of FTY720 intau pathology is elusive. Further FTY720 can have different function depending on the cellularcontext and treatment procedure which makes interpretation of S1P's role challenging. Thus thefunction of S1P-signaling in AD is more complex than assumed and demands further investigationOur preliminary studies suggest that Spinster homolog 2 (Spns2) an S1P transporter criticallymodulates microglial transition from inflammatory to anti-inflammatory states when treated withA peptide. This data is interesting in that it reveals microglia states could be regulated throughSpns2 and/or S1P. Since microglia form the first and major line of immune defense in the centralnervous system we will mainly investigate the function of Spns2 on microglia activation in thisapplication. The role of astrocytes the other major glial cell type and other S1P transporters suchas ABCA1 will also be evaluated. Our goal is to define the function and underlying mechanismof Spns2 in microglial responses in AD. Our goal is to define the function and underlyingmechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced byAD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microgliainduced by AD-related stimuli (2) Spns2/S1P promotes NFB and p38 MAPK pro-inflammatorysignaling induced by A and tau in microglia and (3) Spns2 deficiency ameliorates AD-relatedphenotypes in murine AD models. By focusing on the S1P transporter Spns2 this proposal holdsa unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.

project_terms:
ATP binding cassette transporter 1;Affect;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Autopsy;Brain;Ceramides;Chronic;Clinical;Clinical Data;Complex;Conflict (Psychology);Data;Disease;Drug Kinetics;Exposure to;Extracellular Space;Goals;Homologous Gene;Immune;Impaired cognition;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inorganic Phosphate Transporter;Investigation;Knockout Mice;Lipids;MAPT gene;Mediating;Microglia;Mus;NF-kappa B;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Onset of illness;Pathogenesis;Pathology;Pathway interactions;Peptides;Phagocytosis;Phenotype;Play;Procedures;Process;Proteins;Public Health;Regulation;Reporting;Research;Role;Senile Plaques;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Stimulus;Testing;Therapeutic;amyloid pathology;antagonist;astrogliosis;cell type;cognitive function;extracellular;genome wide association study;improved;mouse model;neuroinflammation;novel;novel therapeutic intervention;p38 Mitogen Activated Protein Kinase;pre-clinical;response;sphingosine 1-phosphate;sphingosine kinase;tau Proteins

public_health_relevance:
The function of S1P-signaling in AD is more complex than assumed and demands furtherinvestigation. Our research will test a novel hypothesis that the S1P transporter Spns2 contributesto AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-relatedstimuli. By focusing on Spns2 this proposal holds a unique premise to reveal novel aspects ofS1P-signaling in AD


application_id: 10335909
project_number: 5R01AG070830-02
project_title: Contributions of astrocyte RelA signaling in aging-related neurodegenerative sequelae following TBI
administering_ic: NIA
award_notice_date: 2021-12-08
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_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 of activation protein;Memory impairment;Methods;Microglia;Modality;Modeling;Molecular;Multiple Sclerosis;Mus;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;knowledge base;knowledgebase;loss of function;male;mouse model;network dysfunction;neural circuit;neural network;neuroinflammation;new therapeutic target;novel;progressive neurodegeneration;protein profiling;relating to nervous system;response;response to injury;restoration;single-cell RNA sequencing;tau-1;transcription factor;transcriptome sequencing;transcriptomics;young adult


application_id: 10335152
project_number: 5F31DE029661-02
project_title: Development of zafirlukast derivatives against Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2021-12-08
opportunity_number: PA-20-246
application_type: 5
activity_code: F31
ic: DE
serial_number: 029661
program_official: SARE, RACHEL
project_start_date: 2021-01-22
project_end_date: 2022-08-19
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 15186564
contact_pi: HOWARD, KAITLIND
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Research project: Gum disease also known as periodontal disease is an infection that can lead to damageand inflammation of the gum and bone that surround the teeth. The early stage of gum disease is gingivitiswhich consists of gums that bleed when brushing or flossing teeth. When left untreated the late stage ofperiodontal disease periodontitis can lead to teeth that will loosen or even fall out. Periodontitis is associatedwith a Gram-negative anaerobic bacterium called Porphyromonas gingivalis which is a keystone pathogenmeaning that the damage caused by P. gingivalis is not proportional to its abundance. The lack of guidelinesfor selecting an antibiotic regimen for the treatment of periodontitis has led to bacteria that are less susceptibleto or even resistant to the antibiotics currently used. Therefore there is a need for novel antibacterial agentsto selectively combat P. gingivalis to treat periodontitis. Recently a screening of a drug-repositioning librarylooking for antibacterial compounds led to the discovery of zafirlukast (ZAF) as a lead compound showingactivity against P. gingivalis. For my project I want to develop ZAF derivatives with activity against P. gingivalis.In order to do this I have come up with three research aims. The first is to synthesize novel ZAF derivativeswith activity against P. gingivalis. The second aim is to determine the true potential of these derivatives asantibacterial agents through percent growth inhibition minimum inhibitory concentration resistance andcytotoxicity experiments. If the compounds are found to be potent with low toxicity to mammalian cells theexperiments will provide insight into which functional groups are beneficial or detrimental to the activity of thecompounds and allow for further optimization of lead compounds. The third aim is to determine themechanism of action of ZAF and its derivatives in P. gingivalis. Training plan: In addition to gaining newtechnical skills in chemistry biochemistry and microbiology this Fellowship will allow for development ofother important skills for my future career in industry (e.g. communication (via poster/oral presentations andwriting of manuscripts and grant applications) networking attendance at conferences development ofleadership and mentoring skills etc). Environment: The environment at the University of Kentucky is highlyconducive to preparing me for a successful career in industry with state-of-the-art equipment seminar seriescourses workshops and opportunities to develop collaborations with other Colleges on campus.

project_terms:
Adhesions;Alzheimer's Disease;Amoxicillin;Anaerobic Bacteria;Animals;Anti-Bacterial Agents;Antibiotic Resistance;Antibiotics;Applications Grants;Bacteria;Biochemistry;Biological;Cardiovascular Diseases;Cells;Chemicals;Chemistry;Collaborations;Communication;Development;Diabetes Mellitus;Disease;Disease Progression;Doxycycline;Drug Design;Drug Targeting;Drug resistance;Educational workshop;Environment;Epithelial Cells;Equipment;Evaluation;FDA approved;Feedback;Fellowship;Future;Generations;Gingiva;Gingivitis;Goals;Gram-Negative Anaerobic Bacteria;Gram-Positive Bacteria;Growth;Guidelines;Human;Hydrogen Peroxide;Industry;Infection;Inflammation;Kentucky;Lead;Left;Libraries;Mammalian Cell;Manuscripts;Mental disorders;Mentors;Metronidazole;Microbial Biofilms;Microbiology;Minimum Inhibitory Concentration measurement;Modification;Oral;Parents;Pathogenicity;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Pharmaceutical Chemistry;Pharmaceutical Preparations;Porphyromonas gingivalis;Property;Public Health;Regimen;Research;Research Project Grants;Resistance;Resistance development;Rheumatoid Arthritis;Series;Streptococcus sanguis;Structure;Structure-Activity Relationship;Technical Expertise;Tissues;Tooth structure;Toxic effect;Training;Treatment Protocols;Universities;Virulence Factors;Writing;bacterial resistance;bone;career;college;combat;commensal bacteria;cytotoxic;cytotoxicity;drug candidate;drug development;drug resistant bacteria;dysbiosis;experimental study;falls;functional group;gingipain;insight;lead optimization;leadership development;metal chelator;mutant;novel;novel therapeutics;oral biofilm;oral cavity epithelium;pathogen;pathogenic bacteria;polymicrobial biofilm;posters;screening;skills;symposium

public_health_relevance:
The proposed research project is relevant to public health because it could lead to a new antibacterialcompound that specifically targets P. gingivalis which will allow for better treatment of periodontal diseasessuch as periodontitis. I will derivatize the drug ZAF to selectively combat P. gingivalis. The proposed researchwill have major impact on public health in three ways: (1) structure-activity relationships can lead to chemicalmodifications that enhances selectivity for P. gingivalis (2) lead to better efficacy and treatment ofperiodontitis and (3) determining the mechanism of action of these antibacterial compounds can aid in theunderstanding of how these compounds interact with P. gingivalis.


application_id: 10334487
project_number: 5R01EY027805-05
administering_ic: NEI
award_notice_date: 2022-02-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 027805
program_official: SONG, HONGMAN
project_start_date: 2018-02-01
project_end_date: 2024-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 14475772
contact_pi: FAMULSKI, JAKUB K
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: 2022-02-01
project_title:
Comprehensive analysis of periocular mesenchyme composition specification and function during anterior segment formation

project_abstract:
PROJECTSUMMARY:Inheritedcongenitalanteriorsegmentdysgenesis(ASD)disordersareamajorcauseofvisionimpairmentandblindness.Theyincludedevelopmentaloculardeficienciesoftheiriscorneaandlensinadditiontosignificantpredisposition~50%toglaucoma.Fromvariousstudiesinrecentyearsithasbecomeclearthatmanycongenitaldisordersandpredispositionsarisefromearlydevelopmentaldefectsbothmajorandsubtle.Examiningthedevelopmentalprocessgivingrisetotheseessentialcomponentsofthevisualsystemisthereforeafruitfulapproachtostudyingthedisease.Theanteriorsegmentderiveslargelyfromtheearlymigratingneuralcrestcellsthattargetspecificallytotheanteriorofthedevelopingretinaandarelooselyclassifiedasperiocularmesenchyme(POM).POMdeficiencyhasbeendemonstratedincertaincasesofASD.IbelieveamajorroadblockineffortstotreatandunderstandASDhasbeenthelimitedexaminationofPOMbiologyandfunctionduringearlyoculardevelopment.ThishamperseffortstocharacterizetheetiologyofdiseaseandscreeninginASDfamiliesinadditiontodelayingattemptsatiPSC-mediatedapproachesfortreatmentofASD.TocircumventtheseproblemsweaimtocomprehensivelycharacterizePOMcellspecificationmigrationtargetingdifferentiationandultimatelycontributiontoanteriorsegmentdysgenesis.ThisisthenextlogicalandnecessarystepinorderforthefieldtocontinuetheevolutionoftherapyandscreeningforglaucomaandASDdisorders.OurimmediategoalistotestthehypothesisthatPOMcellsdelineateintovarioussubpopulationsandspecifytobecometheanteriorsegmentmesenchyme(ASM).TotestourhypothesisweproposetoemploythehighlyversatilezebrafishembryomodelsystemandcomprehensivelyexaminePOMcelldevelopmentwhilecatalogingtheircontributiontotheanteriorsegmentthroughgeneticmolecularandcuttingedgeinvivoimagingapproaches.Ourspecificaimsare:Aim1:CharacterizespecificationanddefinethecompositionoftheASMtheusingacombinationofgeneexpressionanalysispairedwithlight-sheetinvivotimelapseimagingandconfocalmicroscopy.Aim2:TrackthemigratorybehaviorandlineagetracedistinctpopulationsofASMduringanteriorsegmentformationusinglight-sheetinvivotimelapseimagingandconfocalmicroscopypairedwithanovelfatemappingoptogenetictracingmechanism.Aim3:GenerateacomprehensiveASMtranscriptomeforscreeningnoveltargetsinASDpatientsamplesusingacombinationofflowcytometrycoupledtoRNAseqandnextgenerationexomesequencing.

project_terms:
Affect;Animal Model;Anterior;Anterior segment dysgenesis;Behavior;Biological Assay;Biological Models;Biology;Blindness;Candidate Disease Gene;Cataloging;Cells;Cellular biology;Chick;Ciliary Muscle;Classification;Color;Comprehension;Confocal Microscopy;Congenital Disorders;Cornea;Corneal Endothelium;Coupled;Defect;Development;Developmental Process;Disease;Disease model;Embryo;Etiology;Event;Evolution;Eye Development;Family;Flow Cytometry;Future;Gene Combinations;Gene Expression Profiling;Genes;Genetic;Genetic Counseling;Genome engineering;Genomics;Glaucoma;Goals;Health;Human;Image;In Situ Hybridization;Individual;Inherited;Iris;Knowledge;Lesion;Light;Location;Maps;Mediating;Mesenchyme;Microscopy;Molecular;Mus;Neural Crest Cell;Optics;Patients;Pattern;Persons;Phenotype;Population;Predisposition;Regulation;Reporter;Research;Retina;Sampling;Sclera;Structure;Testing;Time;Tissues;To specify;Transgenic Organisms;Vision;Visual impairment;Visual system structure;Zebrafish;clinical practice;confocal imaging;exome sequencing;gain of function;imaging approach;in vivo;in vivo imaging;induced pluripotent stem cell;lens;migration;next generation;novel;optogenetics;orbit muscle;screening;stem cell therapy;time use;transcription factor;transcriptome;transcriptome sequencing

public_health_relevance:
PROJECTNARRATIVE/RELEVANCETOHUMANHEALTH:Anteriorsegmentdysgenesis(ASD)disordershavedevelopmentalunderpinningsthatarecrucialtoourcomprehensionofvisiondiseaseandadvancementoftherapy.Clinicalpracticewilldirectlybenefitfromstudiesofanimalmodelslikezebrafishwhichprovidestremendousresearchadvantagesincludingexuterodevelopmentopticaltransparencythroughoutdevelopmentandcapacityforgenomeengineeringanddiseasemodeling.ThegoalofourproposalistogeneratethefirstcomprehensiveclassificationofperiocularmesenchymecellsinordertofacilitateeffortsinscreeningforASDpredispositionandenablefutureinvivostemcelltherapy.


application_id: 10333392
project_number: 5P20GM130456-03
project_title: Chemical biology of type IV secretion systems
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
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;Address;Antibiotic Resistance;Bacteria;Bacterial DNA;Bacterial Genome;Basic Science;Biochemical;Biochemical Genetics;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;base;carcinogenicity;cell envelope;design;extracellular;genetic approach;high throughput screening;inhibitor;innovation;insight;interdisciplinary approach;invention;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: 10333388
project_number: 5P20GM130456-03
project_title: Computational Core
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
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8068
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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  COMPUTATIONAL COREWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Within this context the CPRI Computational Core directed by Dr. Chang-Guo Zhan willleverage unique computational expertise commercial and in-house software/methods and UKs formidablecomputational processing network to support a range of computational services to advance COBRE project andpilot objectives. The Core will provide services individually tailored to project/pilot needs that facilitate thedevelopment of new hypotheses/models and streamline the prioritization of experimental studies. Specificallythe Core will enable molecular modeling/simulation of macromolecular targets and target-ligand complexesADMET prediction studies structure-based virtual screening for ligand discovery de novo ligand design andartificial intelligence-based methods. This suite of services has been strategically designed to integrate with andcomplement the support provided by the CPRI Translational Core and the CPRI-affiliated COBRE for MolecularMedicine Organic Synthesis Core. Together CPRIs corresponding fully integrated suite of research supportcapabilities and expertise will accelerate innovative preclinical translational research and facilitate juniorinvestigator career development.

project_terms:
Address;Artificial Intelligence;Basic Science;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Complement;Complex;Computer Hardware;Computer software;Computing Methodologies;Consultations;DNA;Data Analyses;Development;Devices;Diffusion;Disease;Doctor of Philosophy;Excretory function;Faculty;Goals;Gold;Health;Individual;Infrastructure;Kentucky;Lead;Leadership;Ligands;Macromolecular Complexes;Mentors;Mentorship;Metabolism;Methods;Modeling;Molecular;Molecular Medicine;Organic Synthesis;Pharmacologic Substance;Pilot Projects;Process;Proteins;Protocols documentation;Research;Research Design;Research Personnel;Research Support;Resources;Science;Scientist;Services;Structure;Techniques;Toxic effect;Training;Translational Research;Universities;Validation;absorption;base;career development;clinical application;design;experimental study;faculty research;innovation;intermolecular interaction;models and simulation;molecular dynamics;molecular modeling;multidisciplinary;nanoparticle;particle;pre-clinical;prevent;primary outcome;protein complex;simulation;stem;synergism;tool;virtual screening


application_id: 10333387
project_number: 5P20GM130456-03
project_title: Translational Core
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
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8067
contact_pi_person_id: 8227789
contact_pi: LEGGAS, MARKOS
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  TRANSLATIONAL COREWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Within this context the CPRI Translational Core will provide key infrastructure and expertiseto support experimental studies central to probe/lead/materials discovery. Under the co-direction of Drs. MarkosLeggas and Jon Thorson the Core will support assay design development validation and implementation; pilotscreening campaigns; a suite of in vitro absorption distribution metabolism excretion and toxicity (ADMET)assays; and first in animal ADMET/pharmacokinetics (PK) studies. Support in the Core will be tailored towardspecific COBRE project/pilot needs and screening services will also leverage CPRI-exclusive compoundcollections (both natural products and synthetics). The Cores services have been strategically designed tointegrate with and complement the support provided by the CPRI Computational Core and the CPRI-affiliatedCOBRE for Molecular Medicine Organic Synthesis Core. Together CPRIs corresponding fully integratedresearch support capabilities and expertise will accelerate innovative translatable transdisciplinary researchand facilitate junior investigator career development.

project_terms:
Address;Adhesions;Animals;Basic Science;Biological Assay;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Collection;Complement;Consultations;Data Analyses;Development;Devices;Disease;Doctor of Philosophy;Drug Kinetics;Excretory function;Faculty;Goals;Health;In Vitro;Infrastructure;Kentucky;Lead;Leadership;Libraries;Mentors;Mentorship;Metabolism;Methods;Microbial Biofilms;Modeling;Molecular Medicine;Natural Products;Organic Synthesis;Pharmacologic Substance;Pilot Projects;Reporter;Research;Research Design;Research Personnel;Research Support;Resources;Science;Scientist;Services;Toxic effect;Translational Research;Type IV Secretion System Pathway;Universities;Validation;absorption;antimicrobial;base;career development;clinical application;cytotoxicity;design;experimental study;faculty research;immunoregulation;innovation;instrumentation;multidisciplinary;pre-clinical;prevent;primary outcome;screening;screening services;stem;synergism;tool;transcription factor


application_id: 10333386
project_number: 5P20GM130456-03
project_title: Administrative Core
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
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 8066
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  ADMINISTRATIVE CORE We propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Research and Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary center focused on translational chemical biology [the nexus of chemical biology (the application of chemical biology principles to develop validated probe/models to advance our understanding of biology) and pharmaceutical science (the application of pharmaceutical principles to advance leads/materials/devices that address unmet clinical needs)]. The COBRE will leverage and develop unique translational chemical biology research support infrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedical research probe/tool/model/materials development and validation and the early advancement of potential translatable assets. Within this context the CPRI Administrative Core will support center communication coordination oversight and integration of all COBRE operations activities projects pilots and research support cores. The Core will provide fiscal management and resource oversight overall coordination of mentoring and career development activities resource allocation and program evaluation to ensure program effectiveness. The Administrative Core will also facilitate interactions with related UK programs and centers to foster synergy and coordination of resources. The Core will facilitate the Centers engagement of junior faculty researchers and mentors from UK Colleges (Agriculture Food & Environment; Arts and Sciences; Engineering; Medicine; Pharmacy and others) to create a vibrant center that seamlessly integrates resources personnel and knowledge across disciplinary boundaries and fosters scientific innovation and career development.

project_terms:
Address;Agriculture;Arts;Biological;Biology;Biomedical Research;Cancer Center;Cardiovascular Diseases;Career Mobility;Centers of Research Excellence;Chemicals;Clinical;Clinical Sciences;Communication;Decision Making;Development;Development Plans;Devices;Discipline;Disease;Education;Engineering;Ensure;Evaluation;Faculty;Fostering;Goals;Health;Human Resources;Infrastructure;Kentucky;Knowledge;Leadership;Medicine;Mentors;Mentorship;Modeling;Molecular Medicine;Obesity;Oral;Outcome;Pharmacologic Substance;Pharmacy facility;Process;Program Effectiveness;Program Evaluation;Research;Research Personnel;Research Priority;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Structure;Systemic disease;Translational Research;Translations;Universities;Validation;base;career;career development;clinical application;clinical center;college;faculty research;food environment;improved;innovation;interdisciplinary collaboration;multidisciplinary;operation;outreach;prevent;primary outcome;programs;stem;success;supportive environment;synergism;tool;tumor metabolism


application_id: 10333385
project_number: 5P20GM130456-03
project_title: Center of Biomedical Research Excellence in Pharmaceutical Research and Innovation
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: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9(C1)
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT - OVERALLWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Key COBRE infrastructure to be developed and implemented in Phase I includes the CPRIAdministrative Core and two research support cores (the Translational Core and the Computational Core) andthe COBRE will also further develop and leverage the COBRE for Molecular Medicines Organic Synthesis Coreto support CPRI junior faculty projects/pilots. CPRI will initially support four outstanding junior investigatorsworking in three therapeutic areas (cancer infectious disease and cardiovascular disease). Our overarching hypothesis is that CPRIs translational chemical biology focus presents a distinctly uniqueUK platform to: i) engage integrate and mentor junior faculty from a broad range of fundamental applied andclinical disciplines; ii) facilitate the development of new impactful probes/tools/models and advance innovativetransdisciplinary research; and iii) bridge the gap between basic academic research discoveries andcommercial/clinical application via education mentorship and key support infrastructure. CPRIs distinct focuson translational chemical biology and early translation fills a notable preclinical research gap for many of UKsexceptional research centers strategically focused on understanding treating and preventing the major diseasesthat contribute to Kentuckys disproportionate health challenges. Anticipated COBRE outcomes include anincrease in the number and diversity of UK junior faculty engaged in translational chemical biology research andbetter-prepared to develop and employ innovative biomedical probes/tools/models/materials new sustainableUK translational chemical biology research support infrastructure and capabilities an increase in the number ofUK junior faculty with independent research funding and a boost in the number potentially translatable UKpreclinical assets.

project_terms:
Address;Area;Biology;Biomedical Research;Cardiovascular Diseases;Centers of Research Excellence;Chemicals;Clinical;Collaborations;Communicable Diseases;Communication;Core Facility;Development;Devices;Discipline;Disease;Education;Environment;Faculty;Fostering;Funding;Goals;Health;Infrastructure;Kentucky;Malignant Neoplasms;Mentors;Mentorship;Modeling;Molecular Medicine;Organic Synthesis;Outcome;Pharmacologic Substance;Pharmacy facility;Phase;Pilot Projects;Research;Research Personnel;Research Project Grants;Research Support;Science;Scientist;Testing;Therapeutic;Translational Research;Translations;Universities;Validation;career development;clinical application;college;experience;faculty research;innovation;interdisciplinary collaboration;interest;multidisciplinary;pre-clinical;pre-clinical research;prevent;tool


application_id: 10333211
project_number: 5P20GM135004-03
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8112
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy using immune checkpoint inhibitors (ICIs; e.g. anti-PD-1 anti-CTLA-4 antibodies) has revolutionized the treatment of metastatic lung cancer resulting in long-term complete responses for many patients. Nevertheless there remains an urgent need for new strategies because not all patients respond to ICIs; moreover resistance can occur in those that do. Myeloid-derived suppressor cells (MDSCs) in particular monocytic MDSCs (MMDSCs) are potent immunosuppressive innate immune cells that actively inhibit CD8+ T cell tumor homing and activation. Since M-MDSC levels are elevated in multiple human cancers and correlate with decreased patient survival we postulate that these cells contribute to anti-PD-1 resistance. The purine nucleoside adenosine is produced in copious amounts within the tumor microenvironment (TME) where it serves to suppress the immune system and promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediate resistance to ICIs. Immune suppressive adenosine is produced via the enzymatic conversion of extracellular AMP by the cell surface enzyme CD73 (ecto-5-nucleotidase; AMP  adenosine). Our preliminary studies demonstrate that tumor cell-derived prostaglandin E2 (PGE2) maintains M-MDSC suppressive activity in large part by directly inducing cell surface CD73 expression via a novel PGE2cAMPCREB/STAT3 pathway leading to increased immune suppressive adenosine within the TME. The overall hypothesis of this proposal is that tumor cell-derived PGE2 dictates CD73 expression in M-MDSCs leading to substantial increases in adenosine-dependent inhibition of anti-tumor CD8+ T cell activation resulting ultimately in anti-PD-1 immunotherapeutic resistance A major goal of this proposal is to test the antitumor efficacy of a novel cancer immunotherapy involving systemic administration of adenosine deaminase (ADA)an enzyme that irreversibly converts adenosine into inosine a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA) is already FDA-approved for use as an enzyme replacement therapy in children with ADA-associated severe combined immunodeficiency (ADA-SCID). We hypothesize that depletion of adenosine-mediated T cell immune suppression by PEG-ADA sensitizes tumors to PD-1 inhibitor therapy and improves clinical outcomes for NSCLC patients. To fulfill the stated objectives the following aims are proposed: 1) Delineate the signaling pathway and molecular mechanisms by which PGE2 induces CD73 expression in M-MDSCs; 2) Determine whether inhibition of the PGE2cAMPCREB/STAT3CD73adenosine pathway attenuates anti-PD-1 resistance in a mouse model of lung cancer; and 3) Validate PGE2  CD73+ M-MDSC  adenosine mediated anti-PD-1 resistance pathway in lung cancer patients receiving pembrolizumab therapy. Our proposed study will provide important insights towards developing a safe and novel immunotherapy to attenuate ICI resistance in lung cancer patients.

project_terms:
5'-Nucleotidase;Adenosine;Adopted;Advanced Malignant Neoplasm;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;CREB1 gene;Cancer Center;Cancer Model;Cancer Patient;Cattle;Cell physiology;Cell surface;Cells;Child;Clinical;Consumption;Critical Pathways;Cyclic AMP;Data;Dinoprostone;Disease;Enzymes;Epidermal Growth Factor Receptor;FDA approved;Frequencies;Generations;Goals;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In Vitro;In complete remission;Inosine;Knock-out;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator of activation protein;Molecular;Mus;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nucleosides;Outcome;PD-1 inhibitors;Pathway interactions;Patients;Polyethylene Glycols;Prostaglandin Inhibition;Purine Nucleosides;Regulation;Resistance;STAT3 gene;Severe Combined Immunodeficiency;Signal Pathway;Signal Transduction;T-Cell Activation;T-Lymphocyte;Testing;Transgenic Model;Tumor Immunity;Tumor-Derived;adenosine deaminase;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer immunotherapy;clinically relevant;conditional knockout;effector T cell;enzyme replacement therapy;extracellular;improved;in vivo;inhibitor;inhibitor therapy;insight;monocyte;mouse model;neoplastic cell;novel;objective response rate;pembrolizumab;programmed cell death ligand 1;response;therapeutic target;therapy development;therapy resistant;transcription factor;tumor;tumor growth;tumor immunology;tumor microenvironment


application_id: 10333210
project_number: 5P20GM135004-03
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8111
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-02-01
project_title:
Defining tumor-infiltrating B cell signatures associated with T cell mediated antitumor immunity in human lung adenocarcinoma

project_abstract:
Lung cancers are the most common malignancies and are the leading cause of cancer-related deaths worldwide.Immunotherapies are transforming treatment regimes and trials conducted in lung cancer have alreadydemonstrated improvements in long-term survival outcomes. However existing therapies are not effective in allpatients stressing a need to better characterize the complex molecular and immunological processes associatedwith treatment responsiveness and disease progression. Although T cells have been the primary target ofimmunotherapies in lung cancer there is a growing appreciation that T cell-mediated anti-tumor immunity canbe influenced by actions of other immune cells within the tumor microenvironment (TME). Tumor-infiltrating(TI) B cells have been shown to have dual roles in tumor progression generally but in non-small cell lungcancers (NSCLC) specifically adenocarcinomas (LUAD) particular B cell subsets have been shown to bothpromote T cell anti-tumor responses and positively impact long-term survival outcomes. Indications of a role forspecific antibody (Ab) responses in LUAD have also recently been reported including evidence of focused tumorantigen-specific responses. However characterizations of anti-tumor B cells and their functional signatures havebeen limited by the study of only a small number of pre-selected surface markers in relatively small numbers ofpatients. Nonetheless it is evident that B cell-mediated roles in LUAD tumor progression are variable amongpatients and indicates that a more comprehensive and integrated characterization of TI B cell phenotypicvariation and the associated effects on the anti-tumor T cell response has great potential to inform ourunderstanding of disease progression as well as the development of novel potentially personalized therapies.The overall goal of this proposal is to define TI B cell signatures that are associated with the T cell-mediatedanti-tumor response in human lung cancer. To achieve this goal we will leverage several cutting-edgetechniques to first comprehensively profile lymphocytes (B and T cells) in tumor and paired normal tissues froma large cohort of early-stage LUAD patients including the first pairing of this type of data with Ab repertoiresequencing as a means to interrogate critical functional Ab response signatures in LUAD B cells. Importantlythe single-cell profiling approach proposed will leverage B cell markers already determined to be associated withlong-term LUAD survival outcomes so that distinct functional B cell profiles and their associations with TI T cellscan be identified specifically in the context of disease progression (Aim 1). These large-scale statisticalassociations will be validated and then serve as a framework for conducting functional in vitro culture and serum-based analyses to assess whether prognostically favorable B cell subsets identified have distinct functionalphenotypes associate with tumor antigen-specific Ab responses and have differential effects on T cell activationand effector function (Aim 2). Successful completion of this project will facilitate novel discovery and biomarkerscritical for the development of novel therapeutics in human lung cancer.

project_terms:
Adenocarcinoma;Antibodies;Antibody Repertoire;Antibody Response;Antigen Presentation;Antigen-Antibody Complex;Antigens;Antitumor Response;B-Cell Activation;B-Cell Neoplasm;B-Lymphocyte Subsets;B-Lymphocytes;Biological Assay;Biological Markers;CD8B1 gene;Cancer Center;Cancer Etiology;Cell physiology;Cell surface;Cells;Cessation of life;Clinical;Coculture Techniques;Complex;Data;Data Set;Development;Disease Progression;Exhibits;Foundations;Frequencies;Funding;Future;Generations;Goals;Human;IgE;Immune;Immunoglobulin G;Immunoglobulin M;Immunologics;Immunotherapy;In Vitro;Individual;Lung Adenocarcinoma;Lung Neoplasms;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Molecular;Nature;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Phenotype;Plasmablast;Population;Prevalence;Process;Prognosis;Regulatory T-Lymphocyte;Reporting;Role;Secure;Serum;Stress;Structure of parenchyma of lung;Surface;T cell response;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Testing;Transcript;Treatment Efficacy;Treatment outcome;Tumor Antigens;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Variant;Work;base;biomarker panel;cancer immunotherapy;cohort;design;effective therapy;effector T cell;exhaustion;improved;insight;novel;novel therapeutics;outcome prediction;patient stratification;peripheral blood;personalized medicine;phenotypic biomarker;phenotypic data;prognostic;response;survival outcome;therapy design;tumor;tumor immunology;tumor microenvironment;tumor progression


application_id: 10333209
project_number: 5P20GM135004-03
project_title: Mechanisms of resistance to immune therapy in NSCLC
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8110
contact_pi_person_id: 14384874
contact_pi: LI, QINGSHENG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Despite having been approved as first and second line therapy for non-small cell lung cancer (NSCLC) anti-PD- 1 antibodies still fail in a substantial proportion of lung cancer patients. The mechanism that underlies the failure of anti-PD-1 therapy in the majority of NSCLC patients is not yet fully understood. We have discovered that in the anti-PD-1-resistant LSL-KrasG12D murine lung adenocarcinoma mouse model treatment induces a T-cell activation profile that favors Th17/T17 reinvigoration over CD8+ T cell activation. In contrast when administered in conjunction with an anti-IL-17 neutralizing antibody anti-PD-1 treatment results in a dramatic enhancement of CD8+ T-cell cytotoxicity with near-complete eradication of established disease. These findings provide the premise for our central hypothesis that in NSCLC the failure of anti-PD-1 is at least in part due to reinvigoration of PD-1+ type 17 T cells (Th17/T17) which actively undermine anti-PD-1-mediated restoration of cytotoxic function in CD8+ T-cells. Based on additional murine data we are also advancing the extended hypothesis that the severity of pre-existing T17 activity in the neoplastic lung is determined by commensal bacteria and that the lung microbiota signature can ultimately predict responsiveness to anti-PD-1 therapy. The goal of this proposal is to demonstrate the relevance of these findings to human prior to initiating an R01 application. Specifically in Aim 1 we will establish whether intrinsic lung T17/CTL ratio is predictive of anti-PD- 1 responsiveness in NSCLC patients independent of neoantigen burden. In Aim 2 we will determine whether specific human lung microbiota individually or in defined combinations drive the ontogeny of intrinsic T17 immunity and ultimately resistance to ICI therapy. The proposed study is conceptually impactful as it addresses an important clinical conundrum; is mechanistically novel; and has translational relevance since it introduces therapeutic/prognostic approaches that can rapidly move to the clinic.

project_terms:
Address;Bioinformatics;Biopsy Specimen;CD3 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Center;Cancer Model;Cancer Patient;Cells;Clinic;Clinical;Data;Disease;FDA approved;Failure;Generations;Germ-Free;Goals;Grant;Growth;Human;IL17 gene;Immune checkpoint inhibitor;Immunity;Immunotherapy;Individual;Interleukin-17;KRASG12D;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lymphocyte;Lymphocyte Activation;Macrophage Activation;Malignant neoplasm of lung;Mediating;Mus;Neoadjuvant Therapy;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Patients;Production;Progression-Free Survivals;Psoriasis;Resistance;Severities;Specimen;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;base;cancer immunotherapy;checkpoint therapy;clinically relevant;commensal bacteria;cytotoxic;cytotoxicity;design;human microbiota;in vivo;interstitial;lung microbiota;lymphoid neoplasm;macrophage;microbiota;microbiota profiles;mouse model;neoantigens;neoplastic;neutralizing antibody;novel;predict responsiveness;prognostic;programmed cell death protein 1;prospective;resistance factors;resistance mechanism;response;restoration;standard of care;therapy outcome;tumor;tumor immunology;tumorigenic; T cells


application_id: 10333208
project_number: 5P20GM135004-03
project_title: Ongoing inflammation following chemotherapy induces immunosuppression
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8109
contact_pi_person_id: 9855558
contact_pi: DING, CHUANLIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Conventional chemotherapy has been thought to act through the direct killing of tumor cells. Howeveraccumulating evidence indicates that immune competence is crucially required for chemotherapy efficacy. It isexpected that loss of this immunity during chemotherapy has a negative effect on its efficacy. Therefore theimpact of chemotherapy on anti-tumor immunity needs further investigation in order to rationally designcombinatorial regimens for conventional chemotherapy. In the preliminary studies we have demonstrated thatrepeated chemodrug gemcitabine (GEM) treatment promoted the expansion and differentiation ofimmunosuppressive Ly6Chigh monocytic-MDSC (M-MDSC). Tumor-derived soluble factors such as GM-CSF andsoluble ICAM-1(sICAM-1) were up-regulated upon chemo-drug treatment. In tumor-free nave mice GEMtreatment induced the immunosuppressive activity of Ly6Chigh myeloid cells in the bone marrow (BM). Thechemokine CX3CL1 and its receptor CX3CR1 expression levels were elevated in the BM. Higher levels ofmitochondrial reactive oxygen species (mtROS) were also observed in tumor cells and BM stromal cells followingchemotherapy. Furthermore chemotherapy induced NF-B activation leading to the hyperproduction of GM-CSFby tumor cells. Based on these preliminary data we hypothesize that chemotherapy enhances the production ofmtROS in tumor cells and BM stromal cells which increases the expressions of GM-CSF and sICAM-1 as wellas CX3CL1 leading to the enhanced immunosuppression of M-MDSC in the TME. These hypotheses will beaddressed by two Specific Aims. Aim 1 defines the roles of GM-CSF and sICAM-1 in chemotherapy-induceddifferentiation of immunosuppressive Ly6Chigh myeloid cells and the mechanisms underlying mtROS andupregulation of GM-CSF and sICAM-1 in tumor cells; Aim 2 determines the mechanisms by which host cell-derived chemokine CX3CL1 regulates the accumulation and immunosuppressive function of inflammatoryLy6Chigh myeloid cells in the BM. The findings from these studies will allow us to gain a better understanding theunderlying mechanisms by which ongoing inflammation following multi-dose clinical regimens of chemotherapymodulates anti-tumor immunity and rationally design a novel therapeutic approach by combining chemotherapywith mitochondria-targeted antioxidants for cancer treatment.

project_terms:
Address;Antioxidants;Bone Marrow;Breast Cancer Patient;Breast Cancer cell line;CX3CL1 gene;Cancer Center;Cells;Centers of Research Excellence;Chemotherapy-Oncologic Procedure;Clinical;Clinical Management;Data;Dose;Fluorouracil;Granulocyte-Macrophage Colony-Stimulating Factor;Hematopoiesis;Hematopoietic stem cells;Human;Immune response;Immune system;Immunity;Immunocompetence;Immunosuppression;In Vitro;Inflammation;Inflammatory;Intercellular adhesion molecule 1;Investigation;Mitochondria;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Oxidative Phosphorylation;Paclitaxel;Peripheral;Pharmaceutical Preparations;Pharmacotherapy;Production;Reactive Oxygen Species;Recruitment Activity;Regimen;Role;Side;Stromal Cells;Testing;Time;Tissues;Tumor Immunity;Tumor-Derived;Tumor-associated macrophages;Up-Regulation;anti-tumor immune response;antitumor effect;base;cancer immunotherapy;cancer therapy;chemokine;chemotherapy;combinatorial;cytokine;gemcitabine;in vivo;monocyte;neoplastic cell;novel;novel therapeutic intervention;rational design;receptor;response;tumor;tumor immunology;tumor microenvironment;tumor progression


application_id: 10333207
project_number: 5P20GM135004-03
project_title: Functional Immunomics Core
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8108
contact_pi_person_id: 9620088
contact_pi: LI, BING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY (Functional Immunomics Core)The primary goal of the Functional Immunomics Core (FIC) is to serve as the central infrastructure entity thatsupports all the investigators in the Center for Cancer Immunology and Immunotherapy (CCII) COBRE. FICwill utilize new equipment purchased with institutional funds and leverage existing facilities at the University ofLouisville to provide molecular/cellular immune profiling for mouse and human projects in the CCII. SpecificAim 1 is to build a functional immunomics facility at the University of Louisville. With the support of CCII wewill establish a streamlined state-of-the-art immunomics facility in a central location by incorporating theexisting resources of the University of Louisville. This unique resource will act as a vital integrative componentof the CCII through providing centralized services not only for its members but also for the Institution as awhole. Specific Aim 2 is to utilize the comprehensive and integrative FIC platform to ensure the success ofCCII-supported projects. The major goal of the FIC will be to support the development progress and successof proposed CCII projects in all phases of their research. Particularly the FIC will provide human sampleanalytics expertise and technical services to support the specific aims of the CCII projects. Specific Aim 3 isto facilitate translational cancer immunology/immunotherapy research and develop a self-sustaining entity ofthe CCII through University/region-wide services. In summary by integrating with the existing resources at theUofL the newly-established FIC will provide a comprehensive immunomics service center for the success ofthe proposed CCII projects and the translation of novel experimental discoveries to clinical applications.

project_terms:
Applications Grants;Area;Biological Specimen Banks;Blood;Cancer Center;Cancer Patient;Cell Separation;Cells;Centers of Research Excellence;Clinic;Clinical;Contract Services;Core Facility;Cytometry;DNA;Data;Databases;Development;Ensure;Extramural Activities;Fee-for-Service Plans;Flow Cytometry;Freezing;Funding;Future;Genomics;Goals;Human;Human Resources;Immune;Immune system;Immunofluorescence Immunologic;Immunologic Monitoring;Immunologics;Immunooncology;Immunotherapy;Infrastructure;Institution;Investments;Kentucky;Location;Malignant Neoplasms;Molecular;Mus;Paraffin Embedding;Patients;Phase;Phenotype;Process;Proteins;Protocols documentation;Publications;RNA;Research;Research Personnel;Research Support;Resources;Running;Sampling;Services;Site;Slide;Specimen;Stains;Technology;Tissues;Training;Training and Education;Translations;Tumor Tissue;Tumor-Associated Process;Universities;University resources;Writing;cancer immunotherapy;clinical application;design;equipment acquisition;innovation;instrument;instrumentation;interest;member;new therapeutic target;novel;operation;prospective;success;tissue processing;tissue/cell preparation;transcriptomics;treatment strategy;tumor immunology


application_id: 10333206
project_number: 5P20GM135004-03
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8107
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The goal of the CCII COBRE is to establish a thematic multidisciplinary research center of excellence at theUniversity of Louisville that focuses on improving our understanding of cancer immunology and developingnovel immunotherapeutic approaches. Importantly with the recent clinical successes of immune checkpointinhibitors and oncolytic viruses there is great interest and momentum in understanding the interaction betweenthe host immune system and neoplastic cells. Our projects proposing basic immunology research coupled withtranslational and human specimen studies are expected to ultimately lead to entirely new immunotherapeuticapproaches as well as strategies for overcoming resistance to existing agents. The Administrative Core (AC)will coordinate the professional activities of the more than 40 individuals who will constitute the new Center forCancer Immunology and Immunotherapy (CCII). The AC will provide administrative fiscal and scientificoversight and planning for junior investigators mentors projects the research core a pilot program andadvisory committees. In addition to governance functions the AC will provide key research and mentoringsupport. This will include the awarding of project grants assignment of mentors provision of a grant writingmentorship program biostatistics and bioinformatics support compliance and regulatory oversight mentoringof pilot projects and encouragement of diversity and inclusion. Internal advisors and an External AdvisoryCommittee (EAC) that consists of five leading scientists in the CCII thematic area will guide the AC. The EACwill provide scientific guidance and constructive feedback regarding center/project progress and be involved inCCII strategic planning and in the selection of replacement and pilot projects. The two PIs of the overall CCIIprogram will direct the AC with key support from two co-Is who have extensive experience administering multi-component grant programs and from two additional co-Is who are well qualified to oversee the essentialbiostatistics and bioinformatics support. Their efforts will supplement a mentoring program that is anchored byeight senior investigators who are experienced mentors and have been highly productive and well funded inthe thematic area. The three specific aims of this Administrative Core that encompass all of these functions areto: (1) Establish procedures for CCII administration planning and decision-making; (2) Provide a mentorshipprogram to accelerate the careers of the CCII junior investigators; and (3) Create a CCII pilot grant programthat will stimulate new projects and collaborations. Innovative features of the AC are built on lessons learnedfrom establishing other multidisciplinary thematic centers and include a shared governance approach that aimsto ensure engagement of all participants and a holistic mentoring strategy that provides comprehensiveguidance for our CCII junior investigators. By the end of the 5-year funding program we expect that 4-6 CCIIjunior investigators will have been awarded R01 grants and that many of these graduates will remain keymembers of this new COBRE focused on cancer immunology and immunotherapy.

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


application_id: 10333205
project_number: 5P20GM135004-03
project_title: Center for Cancer Immunology and Immunotherapy (CCII)
administering_ic: NIGMS
award_notice_date: 2022-02-21
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4(C1)
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
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_terms:
Adoptive Cell Transfers;Advanced Malignant Neoplasm;Advisory Committees;Animals;Antibodies;Area;Award;Basic Science;Bioinformatics;Biological Markers;Biomedical Research;Biometry;Bladder;CAR T cell therapy;CTLA4 gene;Cancer Center;Cancer Death Rates;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Conduct Clinical Trials;Country;Cytometry;Development;Diagnosis;Discipline;Disease remission;Disseminated Malignant Neoplasm;Early Diagnosis;Financial Support;Flow Cytometry;Funding;Future;Genomics;Goals;Grant;Growth;Head and neck structure;Home;Human;Human Resources;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologic Surveillance;Immunologist;Immunotherapeutic agent;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;International;Kidney;Lead;Lung;Malignant Neoplasms;Mediating;Mentors;Mission;Molecular;Mus;Names;Oncolytic viruses;Outcome;Paper;Patients;Persons;Phase;Pilot Projects;Proteins;Publications;Recording of previous events;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Sampling;Savings;Seminal;Services;Specimen;Study Section;T cell therapy;Talents;Testing;Training;Translating;Translational Research;Universities;Vaccines;Work;anti-cancer;base;cancer cell;cancer clinical trial;cancer immunotherapy;cancer therapy;cancer type;career development;checkpoint therapy;cohort;equipment acquisition;immune checkpoint;improved;innovation;interest;melanoma;member;microbiome research;new therapeutic target;novel strategies;optimism;programmed cell death ligand 1;programmed cell death protein 1;programs;recruit;research and development;response;senior faculty;side effect;success;systemic toxicity;treatment strategy;tumor;tumor immunology


application_id: 10330955
project_number: 5R35GM130349-04
project_title: Functional Analysis of Programmed Genome Rearrangement
administering_ic: NIGMS
award_notice_date: 2022-01-13
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: 2024-01-31
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;Light;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;germline stem cells;histone methylation;migration;next generation;novel;novel strategies;pluripotency;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: 10329927
project_number: 5R01EY030933-03
project_title: Blood outer retina barrier regulation
administering_ic: NEI
award_notice_date: 2022-02-03
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:
Adaptor Signaling Protein;Age;Animal Model;Apical;Arrestins;Automobile Driving;Back;Binding;Birth;Blood;Blood Circulation;Cell Death;Cells;Choroid;Clathrin;Complex;Cone;Cytoplasm;Cytoskeletal Modeling;DNA;Dark Adaptation;Development;Disease;Disease Progression;Down-Regulation;Endocytosis;Environment;Epigenetic Process;Epithelial Cells;Event;Face;Family;Family suidae;Feedback;Feeds;GLUT 4 protein;Gene Expression;Genes;Glucose;Glucose Transporter;Hypoglycemia;Injections;Insulin;Integrins;Investigation;Label;Light;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Mutation;Neurons;Nutrient;Pathway interactions;Peripheral;Phagocytosis;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;TXNIP gene;Time;Transplantation;Vision;Visual;Work;alpha ketoglutarate;coated pit;cofactor;epigenome;experimental study;functional loss;glucose metabolism;glucose transport;glucose uptake;histone demethylase;inhibitor;loss of function;macrophage;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: 10329150
project_number: 3R15MH121445-01A1S1
administering_ic: NIMH
award_notice_date: 2021-05-27
opportunity_number: PA-21-071
application_type: 3
activity_code: R15
ic: MH
serial_number: 121445
suffix: A1S1
program_official: CHAVEZ, MARK RAY
project_start_date: 2021-06-15
project_end_date: 2023-06-14
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-06-15
project_title:
Diversity Supplement for 'Personalized Networks and Sensor Technology Algorithms of Eating Disorder Symptoms Predicting Eating Disorder Outcomes'

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are severe mental illnesses with the highest mortality rate of anypsychiatric disorder in part due to the high rates of suicide found within the EDs. Despite thedocumented relations between suicidal ideation (i.e. thinking about planning or consideringsuicide)7 and behaviors (i.e. potentially injurious behavior with an intent to die)7 and EDs therehas been little research examining how suicidality relates to ED symptoms. Further there havebeen no examinations to date of how SIB impact the process of ED remission. New statisticalapproaches that incorporate state-based measurement of momentary symptoms are necessaryin understanding the dynamic relations between suicidality and ED symptoms across time.Further we need a way to develop personalized models of such dynamic relations to capturethe individual differences and high levels of heterogeneity found across the EDs. The specificaims are of the proposed project are: (1) examine whether suicidality moderate networks of EDsymptoms (i.e. the way in which ED symptoms interrelate) (2) use personalized networks toexamine how central symptoms vary at the individual level for ED participants high in suicidalityand (3) determine whether central symptoms of those with elevated eating disorders andsuicidality are predictive of ED outcomes and remission. This project will be an important initialstep towards better understanding the relations between eating disorders suicidality andoutcomes in eating disorders. Importantly the career development and mentorship plan outlinedin this diversity supplement application will promote Ms. Hunt's success as a minorityresearcher and contribute to the initiative of building a scientific workforce.

project_terms:
Algorithms;Award;Behavior;Disease remission;Eating Disorders;Feeling suicidal;Heterogeneity;Individual;Individual Differences;Measurement;Mental disorders;Mentorship;Minority;Modeling;National Research Service Awards;Outcome;Participant;Process;Research;Research Personnel;Sorbus;Suicide;Symptoms;Thinking;Time;base;career development;doctoral student;mortality;sensor technology;severe mental illness;success;suicide rate

public_health_relevance:
PROJECT NARRATIVEThis project is a diversity supplement to support PhD student Rowan Hunt. The careerdevelopment and mentorship plan outlined in this diversity supplement application will promoteMs. Hunt's success as a minority researcher and contribute to the initiative of building ascientific workforce. Further it will prepare Ms. Hunt to submit a NRSA F31 application at theend of the award period.


application_id: 10328929
project_number: 5R01EY028911-04
project_title: Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing
administering_ic: NEI
award_notice_date: 2022-01-27
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: 2024-01-31
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:
Address;Advanced Development;Affinity;Anatomy;Animal Model;Antineoplastic Agents;Bacteria;Binding;Biochemical;Biological Assay;Biology;Biomedical Engineering;Blindness;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;Epithelial Cells;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;Pharmaceutical Preparations;Pharmacology;Prevalence;Primary Health Care;Procedures;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;base;cancer type;cell growth;cell motility;cell replacement therapy;corneal epithelial wound healing;corneal epithelium;corneal surgery;cytokine;cytotoxicity;desensitization;drug development;experience;heat injury;improved;in silico;in vivo;inhibitor;innovation;interest;knock-down;limbal;nanomolar;novel;novel therapeutics;particle;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: 10328845
project_number: 3R44DC018763-01S1
project_title: Plug-And-Play Cochlear Electrode Array - Diversity Supplement.
administering_ic: NIDCD
award_notice_date: 2021-05-07
opportunity_number: PA-21-071
application_type: 3
activity_code: R44
ic: DC
serial_number: 018763
suffix: S1
program_official: MILLER, ROGER
project_start_date: 2021-03-15
project_end_date: 2022-04-30
contact_pi_person_id: 11208190
contact_pi: JOHNSON, ANGELIQUE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 969965800
primary_uei: NPHRMGVU99E8
duns_number: 969965800
uei: NPHRMGVU99E8
fips: US
organization_id: 10030414
organization_name: MEMSTIM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022654
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractWorldwide approximately 466 million people suffer from disabling hearing loss. When conventional hearingaids provide no appreciable benefit cochlear implants are a solution. Current cochlear implants whilebeneficial in their use are limited in their capabilities by hand-assembly of wire-bundled electrode arrays. Handassembly is very costly extremely labor-intensive and inadequate in implementing new strategies inOtolaryngology for improving speech recognition and music appreciation.MEMStim LLC proposes a plug-and-play advanced-manufacturing solution that relies heavily on 3D printing.By printing conductive and nonconductive silicones biocompatible pluggable arrays can be printed to any sizelength shape or thickness from several microns to tens of millimeters. Most importantly the integratedconnectors plug readily onto stimulators by way of a novel micro-socket technology. The micro-sockets arecompatible and slide right onto the feedthrough pins. The printer resolution can output pluggable connectorsthat are compatible with pin-to-pin pitches smaller than 100 m (edge-to-edge) allowing for enhancedminiaturization.The 3D printed soft elastomeric arrays differ from wire-bundle cochlear implants in that they are lessstiff and more susceptible to small changes in strain [add reference?]. They fall within a category ofdevices called bioelectronics which have a Youngs Modulus (100 Pa-10MPa) in the range of mostbiological matter such as nerve tissue. Due to this difference the candidate will strengthen our caseto the FDA and cochlear manufactures themselves by conducting further electrical and mechanicaltests to prove the functionality and durability under strain. The tests will also help us betterunderstand the durability and reliability limits of our plug-and-play arrays for other neurostimulatorapplication areas such as spinal cord stimulators and deep brain stimulators.

project_terms:
3D Print;Address;Area;Biological;Categories;Cochlea;Cochlear Implants;Devices;Electrodes;Hand;Hearing Aids;Lasers;Length;Mechanics;Metals;Microfabrication;Miniaturization;Modulus;Music;Nature;Nerve Tissue;Otolaryngology;Output;Play;Printing;Resolution;Shapes;Silicones;Slide;Spinal Cord;Technology;Testing;Thick;biomaterial compatibility;cost;deep brain stimulator;design;elastomeric;falls;hearing impairment;improved;manufacturing process;millimeter;new technology;novel;parent grant;pre-clinical;speech recognition

public_health_relevance:
Project NarrativeWorldwide approximately 466 million people suffer from disabling hearing loss andCochlear implants are limited in their capabilities by the hand-assembly of wire-bundledelectrode arrays. Advanced-manufacturing (microfabrication laser-machining etc.) hasbeen deemed a superior replacement to the hand-assembly of electrode arrays but areincompatible with commercial stimulators. A new soft electronic manufacturing processhas been proposed through the parent grant. A diversity supplement candidate underMEMStim LLC will design and implement preclinical electrical and mechanical testsparticular to the bioelectronic nature of the novel technology. The tests will strengthenour case to the FDA and address strain concerns that are particular to elastic metal.The tests will also help us better understand the durability and reliability limits of ourplug-and-play arrays for other neurostimulator application areas such as spinal cordstimulators and deep brain stimulators.


application_id: 10327300
project_number: 5F31DE027585-05
project_title: Exploitation of the host immune response by Aggregatibacter actinomycetemcomitans mediated by QseBC
administering_ic: NIDCR
award_notice_date: 2021-12-29
opportunity_number: PA-16-308
application_type: 5
activity_code: F31
ic: DE
serial_number: 027585
program_official: SARE, RACHEL
project_start_date: 2018-01-01
project_end_date: 2022-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14913835
contact_pi: OZUNA, HAZEL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Aggregatibacter actinomycetemcomitans (Aa) has been strongly associated with localized aggressiveperiodontitis (1-3). At the anaerobic environment of the sub-gingival pocket Aa is exposed to changes inhomeostasis yet little is known about the processes used by Aa to acquire the necessary nutrients such as:iron in order to adjust to changes and persist. The study the mechanism used by Aa to sense and respond toenvironmental stress is essential in order to to develop therapeutic treatments for periodontal disease andfurther the knowledge in the field of microbial endocrinology. A two component system (TCS) known asQseBC is expressed by Aa and it plays an important role in the process of adaptation and survival in theanaerobic environment. The sensor molecule QseC was found to play a role in growth and virulence of Aa (1).Further the signals responsible for the activation of this TCS were identified as being catecholamines and iron(CAT-Fe) (Weigel 2015). The protein YgiW has no known function and it is co-expressed with the QseBCTCS. The regulation of the enterobactin operon genes were found to remain unchanged in the presence ofCAT-Fe (Weigel 2015) when other genes involved in iron uptake were downregulated suggesting that it mustplay an important role for Aa persistence in the anaerobic environment. Among the four genes encoded in theenterobactin operon there is an outer membrane enterobactin receptor FepA (4) yet Aa does not producesiderophores (5). Localized aggressive periodontitis promotes increased infiltration of polymorphonuclear(PMNs) leukocytes or neutrophils (6). PMNs have been shown to release catecholamines (CAT) a type ofsiderophore suggesting that the inflamed sub-gingival pocket may serve as a CAT-Fe rich environment.Therefore the proposed hypothesis is that Aa utilizes catecholamines from the host environment and viaQseBC priming metabolism for growth in the anaerobic sub-gingival environment and then acquiringiron through the uptake of CAT-Fe via the enterobactin complex. The hypothesis will be tested byaddressing the following aims: 1) to characterize the synthesis storage and release of CAT by PMNsstimulated with Aa 2) to define the interaction of CAT-Fe with QseC and/or YigiW and 3) determine thecontribution of YgiW on QseC activation. The research design will consist of exposing human PMNs directly towild type and virulence factors mutants of Aa and measuring CAT levels by ELISA to confirm their ability torelease CAT (Aim 1a) and identify the signals required for their release (Aim 1b). The granules of PMNs willbe isolated and screened using CAT antibodies to identify where CAT are stored (Aim 1c). Next biding kineticanalysis will be used to characterize the interaction of CAT-Fe to QseC and/or YgiW (Aim 2a) and surfaceplasmon resonance will be used to define YgiW contribution to QseC activation (Aim 2b). Lastly bindingkinetic analysis will be employed to determine the binding interaction of CAT-Fe to FepA (Aim 3a) and thechronic periodontitis animal model will be use to asses the role of the enterobactin operon in Aa virulence (Aim3b).

project_terms:
Actinobacillus actinomycetemcomitans;Address;Anaerobic Bacteria;Animal Model;Antibodies;Binding;Catecholamines;Complex;Cytoplasmic Granules;Development;Endocrinology;Enterobactin;Environment;Enzyme-Linked Immunosorbent Assay;Exposure to;Foundations;Future;Gene Expression;Genes;Growth;Homeostasis;Hormones;Human;Immune response;Infection;Infiltration;Inflammatory;Iron;Kinetics;Knowledge;Ligands;Location;Measures;Mediating;Membrane;Metabolism;Microbial Biofilms;Nutrient;Operon;Organism;Outcome;Periodontal Diseases;Periodontitis;Phagocytes;Play;Process;Proteins;Regulation;Research Design;Respiration;Role;Siderophores;Signal Transduction;Stress;Surface Plasmon Resonance;System;Testing;Therapeutic;Transferrin;Virulence;Virulence Factors;Work;design;enteric pathogen;environmental change;exposed human population;macrophage;microbial;mutant;neutrophil;periplasm;receptor;response;sensor;therapeutic target;uptake

public_health_relevance:
Project NarrativeThe mechanisms of Aggregatibacter actinomycetemcomitans (Aa) to sense and adjust to environmentalchanges will expand the knowledge and serve as a guide to work with similar organisms found in comparableniches. In addition findings will further the field of microbial endocrinology and iron acquisition systems. Thestudy of the proposed mechanism by which Aa exploits the host response to acquire iron presents theopportunity for future therapeutic targets for periodontal disease.


application_id: 10327287
project_number: 5R34AT010370-03
administering_ic: NCCIH
award_notice_date: 2022-01-07
opportunity_number: PAR-18-417
application_type: 5
activity_code: R34
ic: AT
serial_number: 010370
program_official: MURRAY, PETER DANIEL
project_start_date: 2020-01-01
project_end_date: 2023-12-31
study_section: ZAT1-PJ(06)
contact_pi_person_id: 77923454
contact_pi: CONLEY, CAITLIN ELIZABETH-WHALE
other_pis: VRANCEANU, ANA-MARIA
congressional_district: 06
department: ORTHOPEDICS
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: 2022-01-01
project_title:
Development of a Mind Body Program to Reduce Knee Pain in Obese Osteoarthritis Patients with Comorbid Depression

project_abstract:
PROJECT SUMMARYDevelopment of a mind body program to reduce cartilage breakdown and knee pain in obese osteoarthritispatients with comorbid depression This is a R34 application that follows the recently released IMMPACT criteria and the InternationalClassification of Functioning Disability and Health (ICF) framework to adapt a multimodal theory groundedmind body program (The Relaxation Response Resilience Program; 3RP) with prior success in patients withmedical illness in pilot and effectiveness studies for the needs of obese patients with knee osteoarthritis (OA)and depression and to specifically target increased physical activity (p3RP-OA). Depression obesity and OAexacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines reflecting a complex mind-body interaction. Current treatments for knee OA offerlittle to no benefit over a placebo and do not emphasize mind-body practices or physical activity to target theunderlying pathophysiology. Physical activity alone has shown benefit in the treatment of depression obesityand OA individually but adequate implementation remains challenging. Our guiding hypothesis is that thesynergistic interaction between mindfulness adaptive thinking positive psychology and healthy living skills ofthe 3RP adapted for the needs of OA patients and to target increased physical activity reduces pro-inflammatory cytokine expression while also promoting optimal mechanical loading of the cartilage will slowthe progression of symptomatic knee OA. Toward this goal this R34 proposal aims to 1) adapt the 3RP for theneeds of knee OA patients with depression (PHQ-910) and obesity (BMI30 kg/m2) with a focus of increasingphysical activity; and 2) establish the feasibility credibility and acceptability of the programs and researchprocedures. Using the R34 NCCIH mechanism we propose to use an iterative mixed methods strategy to adaptthe 3RP for the specific needs of obese OA patients with depression including increased activity to maximizetheir feasibility acceptability and credibility. This R34 grant will set the stage for us to conduct a fully poweredRCT through the R61/R33 mechanisms to assess the biopsychosocial mechanisms associated with OAprogression.

project_terms:
Accelerometer;Address;Adherence;Age;Attention;Biochemical;Biological;Biological Markers;Blood;Blood specimen;Body Weight;Body Weight decreased;Body mass index;Cartilage;Catabolism;Classification;Clinic;Clinical;Clinical Trials;Complex;Data;Data Collection;Degenerative polyarthritis;Detection;Development;Eligibility Determination;Focus Groups;Functional disorder;Goals;Grant;Health;Individual;Inflammation;Inflammatory;Instruction;Interleukin-1;Interleukin-1 beta;International;Intervention;Interview;Kentucky;Knee;Knee Osteoarthritis;Link;Logistics;Manuals;Measures;Mechanics;Medical;Mental Depression;Methods;Mind-Body Intervention;National Center for Complementary and Integrative Health;Obesity;Pain;Participant;Patient Preferences;Patient Self-Report;Patients;Phase;Physical Function;Physical activity;Pilot Projects;Placebos;Population;Procedures;Program Acceptability;Protocols documentation;Psychology;Relaxation;Reporting;Research;Secure;TLR4 gene;Testing;Thinking;Time;Travel;Universities;Urine;Walking;acceptability and feasibility;arthropathies;articular cartilage;biopsychosocial;body-mind;cartilage degradation;chronic pain patient;comorbid depression;comorbidity;coping;cytokine;depressive symptoms;disability;effectiveness study;high risk;improved;knee pain;mechanical load;medical schools;mind body interaction;mindfulness;multimodality;obese patients;osteoarthritis pain;overexpression;pilot trial;programs;psychologic;recruit;resilience;response;sample collection;satisfaction;screening;skills;statistics;success;symptomatology;systemic inflammatory response;telehealth;theories

public_health_relevance:
Project Narrative The proposed feasibility clinical trial will adapt the Relaxation Response ResiliencyProgram (3RP) for telehealth delivery to meet the needs of obese osteoarthritis patients withdepression. We will finalize study procedures necessary for a fully powered RCT through theR61/R33 mechanisms to assess the biopsychosocial mechanisms associated with osteoarthritisprogression.


application_id: 10326398
project_number: 5R01NS100996-05
project_title: Modulating Inhibitory Action Control Systems With Subthalamic Nucleus Stimulation
administering_ic: NINDS
award_notice_date: 2022-01-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 100996
program_official: SIEBER, BETH-ANNE
project_start_date: 2018-01-15
project_end_date: 2023-12-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 11898901
contact_pi: VAN WOUWE, NELLEKE C.
other_pis: NEIMAT, JOSEPH S
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:
Neurological (Parkinson's and Huntington's diseases) and neuropsychiatric disorders (Attention-DeficitHyperactivity Disorder Tourette syndrome) associated with frontal-basal ganglia dysfunction are accompaniedby deficits in stopping or suppressing actions. Action inhibition deficits can have devastating effects and havebeen linked to clinical motor symptoms (e.g. falling freezing dyskinetic movements) poor functional skills(e.g. driving) and behavioral disorders (e.g. poor impulse control). Unfortunately there are few options fortreatment deficits in inhibitory control. One potential way to modulate inhibitory control processes is directstimulation of relevant neural circuitries. Specifically it is possible to stimulate a key node in the brain'sinhibitory control circuitry the subthalamic nucleus (STN) and directly modulate inhibitory control capabilitiesincluding improving them. The STN is linked to two distinct forms of inhibitory control: (1) a stopping controlmechanism that rapidly inhibits an initiated or ongoing action (2) a conflict control mechanism that selectivelysuppresses strong initial motor impulses that conflict and interfere with goal-directed actions. Our recent workand preliminary data lead to the hypothesis that these control mechanisms can be directly modulated andimproved by stimulating the STN in patients with Parkinson's disease (PD). Moreover our preliminary findingsare strongly suggestive that modulating these distinct forms of inhibitory control requires stimulating in differentSTN subterritories. Additionally a proposed but scarcely tested idea is that inhibitory control mechanismsinvolve a predominantly right hemisphere circuitry. These state of findings leads to our specific hypotheses thatinhibitory control circuitries can be directly modulated and improved by stimulating in distinct subregions andhemispheres in the STN. We propose experiments to systematically test the precise relationship between STNneural circuitry and inhibitory action control mechanisms. We propose novel interrogations of STNsubstructures and neurophysiology to define links between inhibitory control mechanisms and STNsubterritories and hemispheres. In Specific Aim 1 we use innovative electrode localization and stimulationmethods (both post-operatively as well as in the operating room) to test the hypothesis that stimulating dorsaland ventral subregions in the left and right STN produce dissociable effects on stopping control and on conflictcontrol mechanisms. In Specific Aim 2 we investigate the relationships between inhibitory control mechanismsand STN neurophysiology by recording single unit neural activity in bilateral STN during intraoperativeplacement of DBS electrodes in PD patients. While the cognitive neuroscience of inhibitory control deficits inPD will benefit directly from this work the project is designed with broader applications in mind as theneurosurgical community explores how DBS in the STN and other basal ganglia structures can improveinhibitory control deficits in individuals with Huntington's disease Tourette's syndrome and otherneuropsychiatric disorders associated with basal ganglia circuitry dysfunction.

project_terms:
Aging;Attention deficit hyperactivity disorder;Automobile Driving;Basal Ganglia;Basal Ganglia Diseases;Behavior Control;Behavior Disorders;Bilateral;Brain;Characteristics;Clinical;Cognitive;Cognitive deficits;Communities;Conflict (Psychology);Contralateral;Coupled;Data;Deep Brain Stimulation;Development;Devices;Diffuse;Disease;Disease model;Dorsal;Electrodes;Forms Controls;Freezing;Frequencies;Functional disorder;Gilles de la Tourette syndrome;Goals;Grant;Human;Huntington Disease;Impairment;Individual;Intervention;Knowledge;Lead;Left;Link;Measures;Methods;Microelectrodes;Mind;Modeling;Monitor;Motor;Movement;Movement Disorders;Neurocognitive;Neurodegenerative Disorders;Neurologic;Neurons;Obsessive-Compulsive Disorder;Operating Rooms;Operative Surgical Procedures;Parkinson Disease;Patients;Performance;Physiology;Play;Postoperative Period;Process;Property;Publishing;Research;Role;STN stimulation;Side;Signal Transduction;Structure;Structure of subthalamic nucleus;Suggestion;System;Technology;Testing;Work;cognitive control;cognitive neuroscience;cognitive process;design;experience;experimental study;falls;implantation;improved;innovation;motor control;motor impulse;motor symptom;nervous system disorder;neural circuit;neurophysiology;neuropsychiatric disorder;neuropsychiatry;next generation;novel;novel strategies;programs;relating to nervous system;response;skills;theories;voltage

public_health_relevance:
NARRATIVENeurologic and neuropsychiatric disorders characterized by basal ganglia dysfunction are accompanied bydrastic deficits in the ability to inhibit movement and actions. The subthalamic nucleus a principle target indeep brain stimulation (DBS) therapies for those diseases is also hypothesized to be a key node in inhibitorycontrol circuitries that stop action urgently and suppress conflicting response impulses suggesting that DBSmay act in part by modulating inhibitory control deficits. Using a Parkinson's disease model we investigatehypotheses about how neurophysiological properties and deep brain stimulation of specific subregions andhemispheres of the subthalamic nucleus are linked to inhibitory action control mechanisms in the brain.


application_id: 10323624
project_number: 1R43DK129132-01A1
project_title: Noninvasive Biomarker Detection of Early Kidney Disease in Patients with Insulin Resistance
administering_ic: NIDDK
award_notice_date: 2021-07-22
opportunity_number: PA-20-260
application_type: 1
activity_code: R43
ic: DK
serial_number: 129132
suffix: A1
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2021-08-01
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1 DKUS-B (11)]
contact_pi_person_id: 16353305
contact_pi: CARRITHERS, AARON L
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 117377822
primary_uei: WD6FZBCZV5Q3
duns_number: 117377822
uei: WD6FZBCZV5Q3
fips: US
organization_id: 10058501
organization_name: AMDX PROGNOSTX INCORPORATED
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYThere are over 420 million people living with type 2 diabetes mellitus (T2DM) in the world today and about 165million also have chronic kidney disease (CKD). The prevalence of CKD is up to 5-fold higher in those withT2DM  in fact >50% of all T2DM patients will develop CKD in their lifetime. The presence of comorbid CKD indiabetes shortens average life expectancy by ~16-years and results in ~$250 billion/yr in healthcare costs.Annual mortality rates manifestation of life-impairing comorbidities like cardiovascular disease and overallhealthcare spending are all greatly increased as CKD severity progresses in T2DM. There is a significantunmet clinical need to identify CKD early in the course of diabetes. Impact of early diagnosis (and proactiveimplementation of CKD management) in the beginning stages of insulin resistance has been recognized bymultiple international societies yet no early diagnostic test exists. Prediabetes the precursor condition toT2DM currently affects an estimated 88 million U.S. adults and nearly 90% are unaware of their conditionsuggesting that many of these patients are uninhibitedly progressing. While therapeutic intervention is knownproactive medical treatment for every prediabetic patient is impractical since most are low-risk for acutelydeveloping T2DM or kidney disease. Recent findings suggest that a hitherto unclassified pathophysiologicalprocess results in rapid progression of prediabetes to T2DM as well as early development of late-stage CKD.Yet there is currently no mechanism in place to predict or stratify this high-risk subpopulation withinprediabetes (that would benefit from early implementation of targeted medical therapy). AMDX PROGNOSTX willproduce a new ELISA test that indicates the presence of an ongoing subclinical pathological processthat accelerates T2DM-associated comorbidities and rapid development of irreversible CKD in thosewith insulin resistance as early as the prediabetic stage. Our test is based on the use of a novel biomarkerthat reflects critical events in the pathophysiology of CKD progression within this specific prediabetic/earlyT2DM population. Preliminary results demonstrate that patients with elevated levels of this biomarker eitheralready have or rapidly develop CKD and have a particularly high mortality rate. In this Phase I proposal wewill further develop and test our prototype mAb-based assay on longitudinal human samples to evaluate itsability to discern between two populations: i) prediabetic patients who readily developed CKD and T2DM afterthe onset of their diagnosis and ii) prediabetic patients who never develop any form of CKD and/or T2DM.Results of this test will offer physicians a new dimension of insight that will redefine the field of diabetes andCKD management and offer advancements in the clinical decision-making process by prompting early medicaltreatment that will slow and possibly prevent progression to late-stage CKD. We request Phase I support totest feasibility of our project and optimize a test that will aid physicians in identifying these high-risk patients inthe earliest stages of CKD. Ultimately we intend to obtain FDA-approval and CMS coverage/reimbursement.

project_terms:
Acute;Address;Adult;Affect;Age;Archives;Biological Assay;Biological Markers;Blood Glucose;Cardiovascular Diseases;Chemosensitization;Chronic;Chronic Kidney Failure;Clinical;Communities;Contractor;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Dimensions;Disease;Disease Management;Disease Progression;Early Diagnosis;Early identification;Early treatment;End stage renal failure;Enzyme-Linked Immunosorbent Assay;Epidemic;Erythrocytes;Erythropoiesis;Etiology;Event;Financial Hardship;Functional disorder;Health Care Costs;Healthcare;Healthcare Systems;Human;Hyperglycemia;Hypoxia;Impairment;Individual;Insulin Resistance;International;Intervention;Kidney;Kidney Diseases;Life;Life Expectancy;Link;Measures;Medical;Monoclonal Antibodies;Morbidity - disease rate;Noise;Non-Insulin-Dependent Diabetes Mellitus;Organ;Outcome;Pathologic;Pathologic Processes;Patient Care;Patients;Phase;Physicians;Population;Prediabetes syndrome;Prevalence;Preventive treatment;Process;Proteins;Public Health;ROC Curve;Rattus;Reagent;Renal Tissue;Retrospective Studies;Risk;Sampling;Severity of illness;Signal Transduction;Societies;Specificity;Subgroup;Symptoms;Test Result;Testing;Therapeutic Intervention;arteriole;base;cardiovascular risk factor;clinical Diagnosis;clinical decision-making;comorbidity;diabetic;diabetic patient;early detection biomarkers;experience;feasibility testing;high risk;improved;insight;islet amyloid polypeptide;kidney interstitial tissue;mortality;novel marker;patient population;polyclonal antibody;prevent;prototype;renal damage;research and development;scale up;screening;success;tissue injury;treatment planning;validation studies

public_health_relevance:
PROJECT NARRATIVE Kidney disease is a common condition within the diabetic community with an increasing prevalence thatis associated with significant morbidity and mortality and is responsible for a large financial burden on the U.S.healthcare system. There is a substantial unmet clinical need to identify patients early in the course of insulinresistance  who are at a particularly high-risk for rapidly developing type 2 diabetes (T2DM) and late-stagechronic kidney disease (CKD)  with a non-invasive accurate sensitive and objective measure that stratifiesthe prediabetic patient population and promotes early preventative treatments before irreversible life-impairingkidney damage incurs. To help address this recognized public health crisis AMDX PROGNOSTX is requestingsupport to develop our RBCAmy-CKD Assay to prove feasibility and determine accuracy for early identificationof subclinical CKD in prediabetic and early-stage T2DM patients.


application_id: 10322392
project_number: 5R01ES032396-02
project_title: A university-community partnership to reduce exposure to disinfection byproducts in Appalachia
administering_ic: NIEHS
award_notice_date: 2021-10-28
opportunity_number: RFA-ES-20-002
application_type: 5
activity_code: R01
ic: ES
serial_number: 032396
program_official: O'FALLON, LIAM
project_start_date: 2021-01-01
project_end_date: 2025-10-31
study_section: ZES1-ARL-K(R)
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
other_pis: HOOVER, ANNA GOODMAN
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acids;Address;Appalachian Region;Birth;Businesses;Cardiovascular system;Characteristics;Chemicals;Chemistry;Chloramines;Chlorates;Chlorine;Coal;Collaborations;Communication;Communities;Congenital Abnormality;Consultations;County;Data;Disinfectants;Disinfection;Economics;Environmental Health;Exposure to;Funding;Goals;Grant;Halogens;Health;Home;Human;Infrastructure;Intervention;Kentucky;Knowledge;Laws;Location;Malignant neoplasm of urinary bladder;Methods;Modeling;National Institute of Environmental Health Sciences;Operating System;Ozone;Participant;Persons;Pilot Projects;Population;Process;Public Health;Regulation;Research;Research Personnel;Resources;Risk;Route;Rural Community;Sampling;Scientist;Source;Surface;System;Testing;Training and Infrastructure;Trihalomethanes;Trust;Ultraviolet Rays;United States;United States Environmental Protection Agency;Universities;Variant;Water;West Virginia;base;citizen science;community partnership;drinking water;exposure route;ground water;health communication;health literacy;improved;indoor air;predictive modeling;public drinking;ranpirnase;rural America;rural dwellers;social;spatial temporal variation;water quality


application_id: 10322117
project_number: 5R01NS110169-04
project_title: Regulation of swallow and the effects of high cervical spinal cord injury
administering_ic: NINDS
award_notice_date: 2021-12-01
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: 2023-11-30
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;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;Oropharyngeal;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;Work;airway muscle;antagonist;artery infusion;central pattern generator;experimental study;improved;insight;novel;novel therapeutics;nutrition;pre-clinical;preservation;pressure;prevent;protective behavior;recruit;rehabilitation strategy;response;restoration;spinal pathway;therapeutic effectiveness;thoracic pressure;treatment effect;vertebral artery

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: 10321964
project_number: 5R01AG066724-02
administering_ic: NIA
award_notice_date: 2021-12-28
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: 10128997
contact_pi: KOSMAC, KATE
other_pis: PETERSON, CHARLOTTE A.
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: 2021-12-01
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;Pharmacology;Phase;Population;Property;Proteins;Reperfusion Injury;Reperfusion Therapy;Reporting;Sampling;Severity of illness;Skeletal Muscle;Stress Fibers;Supervision;Testing;Theoretical model;Training;Walking;biobank;cohort;coping;disability;efficacious intervention;exercise intervention;follow-up;functional adaptation;functional decline;functional disability;functional outcomes;improved;improved functioning;indexing;mitochondrial dysfunction;nerve supply;novel;oxidative damage;predictive modeling;preservation;prevent;reinnervation;response;tool


application_id: 10321610
project_number: 5R01CA223164-04
project_title: Integrin alpha6beta4 regulation of cancer epigenetics
administering_ic: NCI
award_notice_date: 2022-01-14
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: 2023-12-31
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;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;base;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;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: 10320997
project_number: 4U01DA053903-02
project_title: Wastewater Assessment for Coronavirus in Kentucky: Implementing Enhanced Surveillance Technology
administering_ic: NIDA
award_notice_date: 2022-04-14
opportunity_number: RFA-OD-20-015
application_type: 4
activity_code: U01
ic: DA
serial_number: 053903
program_official: ANGELONE, LEONARDO MARIA
project_start_date: 2021-01-01
project_end_date: 2025-05-31
study_section: ZDA1-TXW-S(61)R
contact_pi_person_id: 10311819
contact_pi: BERRY, SCOTT M
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:
Wastewater Assessment for Coronavirus in Kentucky  Implementing Enhanced SurveillanceTechnologySurveillance for SARS-CoV-2 is hindered by the availability of testing particularly in remote and ruralareas. Screening of wastewater for SARS-CoV-2 viral biomarkers offers a viable alternative to individualtesting and it can identify communities and facilities that are at risk of becoming hotspots.Wastewatersurveillance overcomes several limitations of clinical surveillance such as the need for robust healthcareand laboratory infrastructure and the lack of representative and comprehensive testing withincommunities. Conventional wastewater surveillance takes samples from sewer systems or wastewatertreatment facilities and uses a series of extraction steps prior to advanced PCR technology to quantitatethe viral biomarker (RNA). This approach is time and resource-intensive which limits its wide-scaleapplication. Developing next generation technology to simplify wastewater RNA extraction andquantitation will make it feasible to use more broadly at facilities and in rural communities. The limitedclinical testing for COVID-19 in rural Southeastern Kentucky hampers disease surveillance and preventsinformed public action to mitigate and contain the spread of disease. Wastewater testing for SARS-CoV-2 in these communities using field-friendly technology will provide important information to localauthorities and citizens about the spread and trend of SARS-CoV-2 infection in their communities. Ourproject will accomplish two aims: 1) Develop next generation wastewater assessment technology and 2)Implement and evaluate the next generation wastewater assay. For Aim 1 we adapt technology inventedby our team termed exclusion-based sample preparation (ESP) to simplify and improve RNA extractionfrom wastewater. We will pair ESP with loop-mediated isothermal amplification (LAMP) technology forRNA detection to create a sensitive robust and field-friendly platform for testing wastewater for SARS-CoV-2 RNA. We will compare the next generation assay with established techniques on metrics ofsensitivity specificity and usability (e.g. assay time number of assay steps). For Aim 2 we will firstvalidate the next generation assay in the field at congregate living facilities in a side-by-side comparisonwith conventional wastewater surveillance. Next building on existing relationships in AppalachianKentucky we will recruit and train a purposive group of wastewater treatment plant operators watershedwatch citizen scientists and school science teachers to test wastewater in their communities and schoolsusing the field-friendly next generation wastewater assay. Field results will be validated in the lab. Arobust mixed methods evaluation using the RE-AIM framework will assess community perceptions offeasibility acceptability and utility of wastewater surveillance for SARS-CoV-2 and identify communitymeasures taken in response to test results.

project_terms:
2019-nCoV;Appalachian Region;Biological Assay;Biological Markers;COVID-19 assay;COVID-19 detection;COVID-19 outbreak;COVID-19 surveillance;COVID-19 testing;Characteristics;Cities;Clinical;Cold Chains;Communities;Coronavirus;Detection;Disease;Disease Surveillance;Evaluation;Exclusion;Feces;Goals;Healthcare;Heating;Hour;Individual;Infection;Infection prevention;Infrastructure;Kentucky;Laboratories;Measures;Mediating;Methods;Molecular Biology Techniques;Monitor;Nursing Homes;Perception;Performance;Persons;Plants;Population;Preparation;Prevention Measures;Prisons;RADx Radical;RNA;RNA Degradation;Reach Effectiveness Adoption Implementation and Maintenance;Resources;Reverse Transcriptase Polymerase Chain Reaction;Ribonucleases;Risk;Rural;Rural Appalachia;Rural Community;Rural Population;SARS-CoV-2 infection;Sampling;Schools;Sensitivity and Specificity;Series;Side;Signal Transduction;Surveillance Methods;Syncope;System;Techniques;Technology;Technology Assessment;Test Result;Testing;Time;Training;United States;United States National Institutes of Health;Universities;Viral;Vulnerable Populations;authority;base;citizen science;community based participatory research;experience;field study;high risk;improved;innovation;isothermal amplification;new technology;next generation;point of care;prevent;recruit;research clinical testing;response;rural area;rural setting;sample collection;science teacher;trend;usability;wastewater samples;wastewater sampling;wastewater screening;wastewater surveillance;wastewater testing

public_health_relevance:
PROJECT NARRATIVEThe goal of this project is to develop a next generation assay for the identification of SARS-CoV-2 inwastewater which serves as a biomarker of community infection in contrast to more expensive and labor-intensive clinical testing. Existing wastewater assays have several limitations that reduce their accuracy andprevent use in remote and rural settings where disease surveillance could inform public action. Thus we plan todevelop optimize and validate a new point-of-acquisition SARS-CoV-2 assay that enables us to rapidlyquantify the amount of coronavirus RNA in a wastewater sample such that additional precautions (e.g.individual testing infection prevention measures) can be taken when needed.


application_id: 10320985
project_number: 4U18TR003787-02
project_title: A Handheld Microchip for GC analysis of breath to screen for COVID-19
administering_ic: NCATS
award_notice_date: 2022-02-14
opportunity_number: RFA-OD-20-017
application_type: 4
activity_code: U18
ic: TR
serial_number: 003787
program_official: CROUCHER, LEAH TOLOSA
project_start_date: 2020-12-21
project_end_date: 2024-01-31
study_section: ZTR1-DPI-9(01)
contact_pi_person_id: 10807170
contact_pi: FU, XIAO-AN
other_pis: NANTZ, MICHAEL H
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary The COVID-19 pandemic has caused unprecedented societal suffering and economic disruption. In theUnited States more than six million people have contracted COVID-19 and more than one hundred ninetythousand patients have died of this disease to date. Although current COVID-19 diagnostic testing technologiesare critical for slowing the spread of the virus and preventing future outbreaks they are not practical for field use.Current diagnostic tests are cumbersome to perform because they use aqueous solutions require multiple stepsand hours-to-days to obtain results. Since the US began to reopen the economy in May there has been asignificant increase in the number of COVID-19 cases. Therefore there is an urgent need to develop a diagnosticapproach that is non-invasive portable and can rapidly provide test results. The overall goal of the project is to develop a mobile breath analysis technology for rapid screening forCOVID-19 using a handheld breath collection tool and a portable GC with a photoionization detector (PID). Thehandheld tool will be a closed system for trapping select volatile organic compounds (VOCs) on a microfabricatedchip. The captured VOCs will be eluted with ethanol and then analyzed using a commercially available portableGC-PID instrument. Artificial intelligence (AI) and machine learning algorithms will be applied to recognize theVOC pattern that correlates with COVID-19 infection. The central innovation is the microfabricated chip thatcaptures carbonyl compounds in exhaled breath and thus serves as a preconcentrator which enables analysisof carbonyl VOCs by the portable GC-PID. The hypothesis is that the carbonyl metabolome in exhaled breath isdirectly related to the bodys reaction to the novel coronavirus infection and changes in the carbonyl VOCcomposition in exhaled breath relative to healthy controls can be used to detect both symptomatic andasymptomatic COVID-19 patients. Three specific aims are proposed to fulfill the overall goal. Aim 1 is to build a disposable handheld breathanalyzer tool for concentrating carbonyl VOCs. Aim 2 is to identify VOC patterns in the breath of COVID-19patients by machine learning algorithms. Aim 3 is to integrate portable GC technology with the breath samplingtool for COVID-19 screening guided by an AI system. The University of Louisville is uniquely suited to rapidlytransition the microchip technology to field use because of the PI and Co-PIs experience in breath analysis andtranslational research and the project teams experience in virology infectious diseases biostatistics andartificial intelligence as well as the state-of-the-art facilities that include a MicroNano Technology CenterBiosafety Level 3 Regional Biocontainment Lab and an NIH-funded REACH program.

project_terms:
2019-nCoV;Acute;Address;Artificial Intelligence;Biochemical Process;Biometry;Breath Tests;COVID-19;COVID-19 detection;COVID-19 diagnostic;COVID-19 pandemic;COVID-19 patient;COVID-19 screening;COVID-19 test;Cancer Detection;Clinic;Collaborations;Collection;Communicable Diseases;Contracts;Coronavirus Infections;Detection;Device or Instrument Development;Devices;Diagnosis;Diagnostic tests;Disease;Disease Outbreaks;Economics;Epithelial Cells;Ethanol;Exhalation;Expert Systems;Foundations;Funding;Future;Goals;Hour;Human;Influenza;Institutes;Institution;Laboratories;Machine Learning;Malignant neoplasm of lung;Mass Fragmentography;Medical Device;Modeling;Monitor;Nasal Epithelium;Oxidative Stress;Patients;Pattern;Persons;Process;Production;Protocols documentation;Rapid screening;Reaction;Reagent;Research Project Grants;Role;SARS-CoV-2 infection;Sampling;Sensitivity and Specificity;Signal Transduction;Silicon;Sterilization;System;Technology;Test Result;Testing;Training;Translational Research;Tuberculosis;United States;United States National Institutes of Health;Universities;Vial device;Viral;Viral Respiratory Tract Infection;Virulent;Virus;Virus Diseases;adduct;aqueous;asymptomatic COVID-19;biosafety level 3 facility;bronchial epithelium;carbonyl compound;detection sensitivity;detector;diagnostic strategy;experience;innovation;instrument;machine learning algorithm;metabolome;microchip;mobile computing;novel coronavirus;photoionization;point of care;portability;prevent;programs;prototype;reagent testing;symptomatic COVID-19;tool;virology;volatile organic compound

public_health_relevance:
8. Project Narrative This project will develop a mobile breath analysis technology for rapid screening for COVID-19 using ahandheld breath collection tool and a portable GC with a photoionization detector (PID). Artificial intelligence andmachine learning algorithms will be used to analyze the detected signals of volatile organic compounds (VOCs)in exhaled breath by the portable GC for detection of COVID-19 patients. UofL is uniquely suited to develop thisapproach because of the PIs expertise in breath analysis for detection of Tuberculosis and lung cancer and theteams experience in virology infectious diseases biostatistics and artificial intelligence.


application_id: 10320676
project_number: 1UG3DA054799-01
administering_ic: NIDA
award_notice_date: 2021-09-24
opportunity_number: PAR-20-092
application_type: 1
activity_code: UG3
ic: DA
serial_number: 054799
program_official: HERRMANN, EVAN SULLIVAN
project_start_date: 2021-09-30
project_end_date: 2025-08-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 15430214
contact_pi: GULLO, KRISTEN LEANN
other_pis: SEBURG, RANDAL
congressional_district: 03
department: Unavailable
primary_duns: 117542566
primary_uei: NLTVUPB2NJL5
duns_number: 117542566
uei: NLTVUPB2NJL5
fips: US
organization_id: 10061427
organization_name: USWM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402411086
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-09-30
project_title:
Development of Lofexidine as a First-line Non-Opioid Pharmacologic Treatment for Neonatal Opioid Withdrawal Syndrome

project_abstract:
PROJECT SUMMARY:An alarming increase in the rate of opioid abuse among the general population has resulted in a public healthemergency since 2017. The striking rise in opioid use disorder has affected Americans broadly includingpregnant women with a resulting increase in infants born suffering from opioid withdrawal or Neonatal OpioidWithdrawal Syndrome (NOWS). The NOWS epidemic has led to significant increases in healthcare costs andburden on the healthcare system due to increased length of hospital stay and level of required care. In 2016 anormal infant averaged 3 days of hospital care post-birth costing $15000 whereas an infant born with NOWSaveraged 16.4 days of inpatient care costing $70000. Currently there are no FDA-approved medicationsavailable for treatment of NOWS. Current approaches to pharmacotherapy rely on the off-label use of opioidsand other agents. Opioid therapy contributes to the extended hospitalization of NOWS infants as continuousmonitoring for safety observations is necessary due to the risk of respiratory depression.Through a successful collaboration with NIDA USWM developed lofexidine for the mitigation of opioid withdrawalsymptoms in adults. The Food and Drug Administration (FDA) approved lofexidine tablets (LUCEMYRA) forthis indication in May 2018. Due to the anticipated utility of lofexidine for the treatment of opioid withdrawal inchildren USWM has initiated a development program evaluating lofexidine for neonate patient use. Initialrequirements to begin clinical trials of lofexidine for NOWS have been agreed upon with the FDA and includenonclinical safety studies development of a pediatric-specific formulation and an evaluation of thepharmacokinetics (PK) of the pediatric formulation in healthy adults. Through a strategic alliance with NIDAUSWM has completed or is on track to complete all prerequisites to initiate clinical testing in NOWS prior to theanticipated start of funding for the current application. USWM now proposes to extend the co-developmentprogram through investigation of the safety and efficacy of the new pediatric formulation of lofexidine in NOWS.The goal of this project is to develop lofexidine as a first-line medication for the treatment of NOWS. Use of awell-characterized safe and effective neonatal formulation of a non-opioid therapy is expected to result in fewerpatients requiring opioids and/or reduce opioid dose/duration permitting safer treatment with shorter hospitalstays. The scope of the proposed research includes chemistry manufacturing and control (CMC) activities andthe clinical development program required to support registration of the pediatric formulation for mitigation ofwithdrawal symptoms in patients with NOWS. Key milestones of the program include: i) a technology transferand manufacturing activities to support late phase clinical trial material (CTM) production (UG3 Aim 1) ii) a first-in-neonate PK and dose-response study in NOWS to support dose selection and pivotal study design decisions(UG3 Aims 2 & 3) iii) manufacture of Phase 3 CTM and completion of the CMC registration package (UH3 Aim1) and iv) a pivotal study to establish safety and efficacy of lofexidine for use in NOWS (UH3 Aims 2 & 3).

project_terms:
Adrenergic Agonists;Adult;Adverse event;Affect;American;Benefits and Risks;Biological Availability;Birth;Blood specimen;Brain;Caring;Chemistry;Child;Childhood;Clinical;Clinical Research;Clinical Trials;Clinical Trials Data Monitoring Committees;Collaborations;Cytoplasmic Granules;Data;Databases;Development;Distress;Dose;Double-Blind Method;Drug Kinetics;Electrocardiogram;Enrollment;Epidemic;Evaluation;Exposure to;Formulation;Funding;GMP lots;General Population;Goals;Health Care Costs;Healthcare Systems;Hospitalization;Hospitals;Incidence;Infant;Inpatients;Investigation;Label;Length;Length of Stay;Measures;Monitor;Morphine;Narcotics;National Institute of Drug Abuse;Neonatal;Neonatal Abstinence Syndrome;Opioid;Oral;Orphan;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Phase;Phase III Clinical Trials;Population;Pregnant Women;Process;Production;Program Development;Publishing;Randomized;Recommendation;Regimen;Reporting;Research;Research Design;Risk;Safety;Sample Size;Severities;Signs and Symptoms;Site;Symptoms;System;Tablets;Technology Transfer;Treatment Protocols;United States Food and Drug Administration;Ventilatory Depression;Weight;Withdrawal Symptom;Work;base;care costs;clinical development;cohort;cost;design;effectiveness measure;efficacy evaluation;efficacy study;efficacy trial;improved;in utero;inpatient service;lofexidine;neonate;neurodevelopment;non-opioid analgesic;novel therapeutics;off-label use;open label;opioid abuse;opioid epidemic;opioid therapy;opioid use;opioid use disorder;opioid withdrawal;pharmacokinetic model;placebo controlled study;programs;public health emergency;research clinical testing;response;safety assessment;safety study;scale up;standard of care;treatment risk;volunteer

public_health_relevance:
PROJECT NARRATIVE:The nations opioid epidemic has remained a public health emergency since 2017 marked by high rates of opioiduse and abuse among adults and a correlated rising incidence of Neonatal Opioid Withdrawal Syndrome(NOWS) in infants exposed to opioids in utero. There are no FDA-approved pharmacotherapies for the treatmentof NOWS to manage the distressing symptoms from the condition which results in reliance on off-label use ofnarcotic medications not formulated for use in neonates containing ingredients which are not recommended ininfants due to safety concerns and lacking well-studied dosing recommendations that adequately characterizethe benefits and risks of treatment particularly their effects on the developing brain. The proposed researchprogram will complete manufacturing and clinical trial activities necessary to evaluate and support approval of apediatric-appropriate formulation of lofexidine a non-opioid medication approved for mitigation of opioidwithdrawal symptoms in adults as a first line-therapy in NOWS patients through 2 clinical trials to i) identify anoptimal dosing regimen of lofexidine for treatment of NOWS and ii) evaluate the risks and benefits of its use inimproving withdrawal symptoms limiting infant exposure to other off-label narcotic medications and shorteningthe infants overall stay in the hospital.


application_id: 10320665
project_number: 1R34DA053140-01A1
project_title: Integrated PrEP Interventions for People Who Inject Drugs in Rural Kentucky
administering_ic: NIDA
award_notice_date: 2021-07-16
opportunity_number: PA-18-780
application_type: 1
activity_code: R34
ic: DA
serial_number: 053140
suffix: A1
program_official: JENKINS, RICHARD A
project_start_date: 2021-08-01
project_end_date: 2024-07-31
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTRural areas in the United States are increasingly impacted by HIV tied to the ongoing opioid epidemicgrowing stimulant use and widespread drug injection. Kentucky (KY) is among seven states identified withheavy rural HIV burden and increasing rates of new HIV diagnoses attributable to injection drug use. RuralHIV outbreaks among people who inject drugs (PWID) have occurred recently in KYs neighboring stateshighlighting the urgent need to implement proven HIV prevention and harm reduction strategies for PWID inKYs rural areas. A key pillar of Ending the HIV Epidemic (EHE): A Plan for America is the prevention of newHIV infections through scale up of evidence-based interventions including syringe service programs (SSPs)and Pre-exposure prophylaxis (PrEP). Our R21 in KYs Appalachian region demonstrated consistent utilizationof rurally located SSPs by high-risk PWID making SSPs a critical venue to scale delivery of comprehensiveHIV prevention services in rural areas. In a prior RCT conducted by the PI of this application strengths-basedcase management (SBCM) interventions were shown to be effective in increasing HIV testing and overcomingbarriers to medical care among people who use drugs. Building on this prior work and ongoing collaborationwith rural SSPs in KY this R34 will adapt and integrate a novel PrEP initiation intervention at point ofcare in rural SSPs in two KY counties that are among the nations top 10 most vulnerable to HIVamong PWID and conduct a preliminary test of its efficacy. The Specific Aims are to: 1) Assess clientprovider organization and structural-level facilitators and barriers to integration of a PrEP focusedSBCM (SBCM-PrEP) intervention into routine SSP practice. Guided by the PRISM model we will conductsemi-structured key informant interviews with PWID clinical care and harm reduction service providers andfacility administrators in our targeted SSP implementation locations to identify individual organizational andstructural challenges and opportunities to adapt the SBCM-PrEP to enhance client acceptability accessibilityand compatibility with clinical workflow; 2) Adapt an evidence-based SBCM protocol to provide PrEPintervention services for PWID in SSP sites. Using in-depth interview data from Aim 1 we will adapt refineand incorporate HIV prevention content most salient to PrEP care into the SBCM-PrEP following the ADAPTITT framework; and 3) Examine feasibility acceptability and preliminary efficacy of the adapted SBCM-PrEP. 80 participants will be randomized into: CDC-PrEP (an in-use PrEP intervention based on CDCguidelines) or SBCM-PrEP. Primary outcomes include feasibility and acceptability (measured by interventionattendance engagement and satisfaction) during the active intervention period and preliminary efficacy onPrEP initiation (measured by dispensed PrEP prescription) 3- and 6- months post-baseline. The proposedstudy fills a gap in evidence for PrEP studies among rural PWID by testing brief interventions that address bothindividual and structural challenges to PrEP uptake through an integrated point of care service delivery model.

project_terms:
AIDS prevention;Address;Administrator;Americas;Appalachian Region;Caring;Case Management;Centers for Disease Control and Prevention (U.S.);Client;Clinical;Collaborations;County;Data;Disease Outbreaks;Drug user;Education;Environment;Epidemic;Equipment;Evidence based intervention;Guidelines;HIV;HIV Infections;HIV diagnosis;Harm Reduction;Human immunodeficiency virus test;Incidence;Indiana;Individual;Infrastructure;Injecting drug user;Injections;Intervention;Interview;Kentucky;Knowledge;Literature;Location;Measures;Medical;Monitor;Needle-Exchange Programs;North Carolina;Participant;Pharmaceutical Preparations;Practical Robust Implementation and Sustainability Model;Prevention;Protocols documentation;Provider;Randomized;Risk;Rural;Rural Community;Service delivery model;Services;Site;Sterility;Structure;Syringes;Testing;United States;West Virginia;Woman;Work;acceptability and feasibility;barrier to care;base;brief intervention;clinical care;drug testing;evidence base;health care availability;high risk;informant;injection drug use;men;novel;opioid epidemic;organizational structure;point of care;pre-exposure prophylaxis;prevention service;preventive intervention;primary outcome;risk perception;rural area;satisfaction;scale up;screening;service intervention;service providers;social stigma;stimulant use;tool;transmission process;uptake

public_health_relevance:
PROJECT NARRATIVEKentucky (KY) is among seven states identified with heavy rural HIV burden and increasing rates of new HIVdiagnoses attributable to injection drug use. The expansion of PrEP has been strongly endorsed as a keystrategy for impacting the course of the HIV epidemic however PrEP trials among people who inject drugs arelargely absent in rural areas. This R34 application will adapt and integrate a novel PrEP initiation interventionat point of care in rural syringe service programs in two KY counties that are among the nations top 10 mostvulnerable to HIV among PWID and fills a gap in evidence by testing brief interventions that address bothindividual and structural challenges to PrEP uptake.


application_id: 10320584
project_number: 7R21MH122368-02
administering_ic: NIMH
award_notice_date: 2021-02-02
opportunity_number: PA-18-590
application_type: 7
activity_code: R21
ic: MH
serial_number: 122368
program_official: JOSEPH, JEYMOHAN
project_start_date: 2020-01-06
project_end_date: 2022-12-31
study_section: HIV Molecular Virology, Cell Biology, and Drug Development Study Section[HVCD]
contact_pi_person_id: 11573326
contact_pi: SMITH, MELISSA LAIRD
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-01-01
project_title:
Characterization of clonal expansion in the CNS-restricted reservoir using HIV SMRTcap a novel single molecule assay providing simultaneous resolution of   proviral genomes and integration sites

project_abstract:
PROJECT SUMMARYHIV infection of the CNS is an important source of morbidity and mortality in the chronic phase of diseasedespite availability of combination Antiretroviral Therapy (cART). Although early and wide use of cART hasreduced the occurrence of the more severe CNS pathologies milder neurocognitive impairment is documentedin 20-50% of infected individuals. HIV invasion of the CNS is thought to occur within the first two weeks ofinfection where the virus infects perivascular macrophages and microglia in addition to CD4+ central memoryT cells (TCCM) the primary infected cell in the periphery. The vast majority of the peripheral reservoir exists asa very minor fraction of resting CD4+ TCCM and is thought to be maintained by the clonal expansion of latentlyinfected cells. Thus far HIV reservoir characterization has focused on either identifying and classifyingintegration sites or examining the integrity of the integrated proviral genomes rarely both concurrently. Latencystudies are most often performed with patient-derived PBMC and may not adequately represent uniquefeatures of tissue-specific reservoirs. In particular studies of the CNS-specific HIV reservoir are few and limitedby sample access. The expanded cell tropism of brain HIV and the potential for low level ongoing viralreplication are suggestive that reservoir dynamics may be dramatically different in the CNS compared toplasma; however the CNS reservoir remains poorly characterized with regard to proviral genome integrityintegration sites emergence and reservoir fixation of viral variants and the contribution of clonal expansion toreservoir maintenance. Moreover while CD4+ T memory cells can proliferate; terminally differentiated myeloidand glial cells the primary targets of HIV infection in the brain are long-lived with limited capacity for self-renewal. Standard methods for profiling HIV reservoirs are dependent on short read next generationsequencing (NGS) technologies that require the examination of integration sites to be necessarily divorcedfrom the characterization of their associated proviral genomes. Short read NGS interrogation of integrationsites limits the mapability of the resulting data which may further limit the identification of HIV integration sites;while the use of single genome amplification (SGA) for proviral genome characterization is low throughput andlabor intensive. Here we have developed a novel innovative HIV-specific molecular enrichment approachcombined with single molecule sequencing (HIV SMRTcap) which resolves the complete HIV integron(flanking integration sites and associated provirus) regardless of genomic context. We propose to apply thistechnology to the characterization of HIV-infected CNS and lymphoid tissues provided by the NationalNeuroAIDS Tissue Consortium and including both viremic (n=3) and cART suppressed (n=3) patients todefine for the first time the contribution of clonal expansion to the CNS-restricted reservoir. The resultsgenerated by the proposed project will establish a novel method for directly interrogating the HIV integron andwill permit hypothesis generation surrounding tissue-restricted HIV persistence and reservoir maintenance.

project_terms:
AIDS/HIV problem;Autopsy;Biological Assay;Blood;Brain;CD4 Positive T Lymphocytes;Cell Culture Techniques;Cell Line;Cells;Central Nervous System Infections;Chronic;Chronic Phase of Disease;Clonal Expansion;Custom;Data;Disease;Divorce;Event;Evolution;Frequencies;Generations;Genes;Genetic Transcription;Genome;Genomic DNA;Genomics;HIV;HIV Infections;HIV-1;Immune;Individual;Infection;Integrons;Introns;Knowledge;Length;Lymphoid;Lymphoid Tissue;Maintenance;Maps;Mediating;Methodology;Methods;Microglia;Minor;Modeling;Molecular;Morbidity - disease rate;Myeloid Cells;National NeuroAids Tissue Consortium;Nature;Neuraxis;Neurocognitive Deficit;Neuroglia;Pathology;Patients;Performance;Peripheral;Peripheral Blood Mononuclear Cell;Plasma;Play;Population;Proliferating;Proviruses;Reproducibility;Resolution;Rest;Role;Sampling;Sensitivity and Specificity;Source;Suggestion;T memory cell;Technology;Testing;Time;Tissue Sample;Tissues;Tropism;Variant;Viral;Virus;Virus Replication;analysis pipeline;antiretroviral therapy;cell type;defined contribution;experimental study;genome integrity;innovation;integration site;macrophage;member;memory CD4 T lymphocyte;mortality;next generation sequencing;novel;novel strategies;sample fixation;self-renewal;single molecule;single molecule real time sequencing;site-specific integration

public_health_relevance:
PROJECT NARRATIVEHIV infection of the central nervous system (CNS) is an important source of morbidity and mortality in chronicHIV underlying neurocognitive impairment and disease in 20-50% of infected individuals even with early andwidespread combination antiretroviral therapy (cART) usage. Clonal expansion of latently infected cells isthought to be a critical mechanism for the persistence of the HIV reservoir in the periphery; however the role ofclonal expansion in central nervous system (CNS) reservoir maintenance remains poorly defined and theexpanded cell tropism and distinct compartmentalization of CNS HIV infection suggests that reservoirdynamics may differ in this tissue-specific microenvironment. We propose to use a newly developed novel HIV-specific molecular enrichment strategy combined with long read sequencing (HIV SMRTcap) to simultaneouslyand directly characterize the brain HIV reservoir including both integration sites and associated proviralgenomes at the single provirus level to define for the first time the contribution of clonal expansion to theCNS-restricted HIV reservoir.


application_id: 10320577
project_number: 3R01AT009268-05S1
administering_ic: NCCIH
award_notice_date: 2021-03-31
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: AT
serial_number: 009268
suffix: S1
program_official: TUTTLE, ALEXANDER H
project_start_date: 2017-04-01
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1(02)-M]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
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
project_title:
Diversity Supplement: Mechanisms underlying anabolic effects of cyclic compressive loading in muscle

project_abstract:
SummaryThis administrative supplement is designed to provide training for Alexander Sklivas (Alex) in the laboratory ofDr. Dupont-Versteegden as a predoctoral fellow. It is in response to PA-21-017: Research Supplement toPromote Diversity in Health-Related Research. Alex will be performing experiments proposed in Specific Aim 3of the parent RO1 and will be able to gain experience not only in the technical application of scientific inquirybut will also gain proficiency in writing presenting and hypothesis development. He will perform experimentsthat will provide knowledge about the cross over effect of massage that we have observed in all of ourmassage models. He will investigate the changes in cytokine levels in serum from rats that have undergonemassage. In addition he will perform experiments to show the level of involvement of the nervous system inthe cross over effect of massage. He will be trained in these techniques by the primary mentor as well aspostdoctoral fellow and senior graduate student. He will take classes such as grant writing and academia andbeyond that prepare him for future tasks as a researcher and he will take content related classes such as cellbiology and molecular biology. The main goal of the training program is to prepare Alex for a successfulapplication of a F31 predoctoral fellowship which would provide him with the support needed to gain acompetitive postdoctoral fellowship. As a member of an underrepresented group in the health sciences(Hispanic) he has the capability to be a good role model for other students or postdoctoral fellows as he isalready involved in the area of diversity equity and inclusion (DEI) in the program in which he currently isadmitted. Dr. Dupont-Versteegden will serve as a mentor for Alex and is heavily involved in student mentoringas well as in DEI initiatives. Therefore this supplement will provide Alex the scientific background the writingand presenting skills and the academic knowledge to become an independent investigator in the field of hischoice.

project_terms:
Academia;Acquired Immunodeficiency Syndrome;Address;Administrative Supplement;Adult;Aging;Animals;Area;Atrophic;Attenuated;Biochemical Pathway;Biology;Cellular biology;Clinical;Complementary Health;Complementary therapies;Complex;Congestive Heart Failure;Contralateral;Data;Development;Devices;Disease;Elderly;Endocrine;Exercise;Extracellular Matrix;Fellowship;Focal Adhesion Kinase 1;Focal Adhesions;Future;Goals;Grant;Growth;Health;Health Sciences;Hispanics;Integrative Medicine;Intervention;Investigation;Knowledge;Laboratories;Lead;Limb structure;Maintenance;Malignant Neoplasms;Manipulative Therapies;Massage;Mechanical Stimulation;Mechanics;Mediating;Mentors;Modality;Modeling;Molecular Biology;Morbidity - disease rate;Muscle;Muscle Weakness;Muscular Atrophy;NIH Program Announcements;Nervous system structure;Neurons;Parents;Pathway interactions;Patients;Periodicity;Play;Postdoctoral Fellow;Protein Biosynthesis;Proteins;Quality of life;Rattus;Recovery;Reproducibility;Research;Research Personnel;Rodent;Role;Scientific Inquiry;Serum;Skeletal Muscle;Standardization;Students;Symptoms;Techniques;Testing;Therapeutic Intervention;Training;Training Programs;Underrepresented Populations;Writing;aged;clinical pain;cytokine;design;direct application;disability;diversity and equity;experience;experimental study;functional decline;graduate student;innovation;integrin-linked kinase;mechanotransduction;member;mortality;muscle form;novel;pain relief;patient population;pre-doctoral;prevent;programs;relating to nervous system;response;restoration;role model;skeletal muscle wasting;skills;student mentoring

public_health_relevance:
The loss of muscle mass is a predictor of morbidity and mortality in multiple disease states and during agingand is highly correlated with quality of life. This research application proposes the use of massage as anintervention to decrease muscle atrophy during disuse and to increase the ability to regrow muscle size afterinactivity and will determine underlying mechanisms underlying these beneficial effects. Massage can bedirectly applied clinically for the maintenance and restoration of muscle size and strength in multiple patientpopulations and determining when it will be beneficial is of high significance.


application_id: 10320451
project_number: 5K01HL149984-02
project_title: Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2021-11-26
opportunity_number: RFA-HL-19-026
application_type: 5
activity_code: K01
ic: HL
serial_number: 149984
program_official: HUANG, LI-SHIN
project_start_date: 2020-12-18
project_end_date: 2025-11-30
study_section: ZHL1-CSR-Z(O1)
contact_pi_person_id: 14305741
contact_pi: SHEPPARD, MARY BURCHETT
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_terms:
Adrenergic Receptor;Aneurysm;Angiotensin Receptor;Animal Model;Aorta;Aortic Aneurysm;Aortic Diseases;Aortic Rupture;Area;Atenolol;Attenuated;Basic Science;Biological Assay;Blood Vessels;Cause of Death;Cell Fractionation;Cell membrane;Cellular Membrane;Chest;Cholesterol;Cholesterol Homeostasis;Clinic;Clinical Research;Confocal Microscopy;Cultured Cells;Data;Diagnosis;Disease;Dissection;Elastin;Etiology;FBN1;Faculty;Farnesyl Transferase Inhibitor;Fluorescence-Activated Cell Sorting;Funding;Future;Gel;Gelatinase A;Genetic Diseases;Genetic Predisposition to Disease;Goals;Growth;Human;Hydroxymethylglutaryl-CoA reductase;Hypertension;Immunohistochemistry;Incubated;Infusion procedures;Kentucky;Laboratories;Laboratory Study;Lead;Learning;Leukocytes;Life;Losartan;Marfan Syndrome;Matrix Metalloproteinases;Measurement;Measures;Medical Genetics;Medicine;Mentors;Microscopy;Mus;Operative Surgical Procedures;Patients;Persons;Pharmaceutical Preparations;Pharmacology;Physicians;Plasma;Pravastatin;Production;Proteins;Publications;RAS inhibition;Ras/Raf;Regimen;Renin-Angiotensin System;Research;Research Personnel;Research Project Grants;Retrospective Studies;Risk;Scientist;Senior Scientist;Signal Transduction;Signaling Molecule;Smooth Muscle Myocytes;Syndrome;Techniques;Testing;Therapeutic Uses;Thoracic Aortic Aneurysm;Tissues;Training;Transforming Growth Factor beta;United States National Institutes of Health;Universities;Vascular Diseases;Vascular Smooth Muscle;Work;antagonist;base;career;clinically relevant;college;experimental study;farnesyl pyrophosphate;farnesylation;in vivo;insight;interest;mouse model;new therapeutic target;novel therapeutics;pre-clinical research;prevent;professor;repaired;sexual dimorphism;skills;standard of care;translational study;ultra high resolution;ultrasound


application_id: 10319993
project_number: 5R01DK124112-03
administering_ic: NIDDK
award_notice_date: 2021-12-17
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: 2023-12-31
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: 2022-01-01
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;Cells;Cellular Stress;Ceramidase;Ceramides;Chronic;Chronic Kidney Failure;Cisplatin;Clinic;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;Process;Publishing;Recording of previous events;Recurrent disease;Regimen;Renal Replacement Therapy;Renal function;Reproducibility;Research;Risk;Role;Sodium Chloride;Sphingolipids;Supportive care;Testing;Therapeutic;Toxic effect;Treatment Protocols;Up-Regulation;analog;base;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: 10319759
project_number: 2U01DK074007-16
administering_ic: NIDDK
award_notice_date: 2022-08-29
opportunity_number: RFA-DK-20-504
application_type: 2
activity_code: U01
ic: DK
serial_number: 074007
program_official: SERRANO, JOSE
project_start_date: 2006-04-15
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZDK1 GRB-9 (M2)]
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
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: 2022-09-01
project_terms:
Abdominal Pain;Affect;Anatomy;Autoimmune;Botulinum Toxins;Caring;Characteristics;Chronic;Clinical;Clinical Research;Databases;Devices;Digestive System Disorders;Disease;Electric Stimulation;Electrolytes;Enrollment;Esophagus;Ethnic Origin;Etiology;Feces;Functional disorder;Gastric Emptying;Gastrointestinal Diseases;Gastroparesis;Gender;Genomics;Goals;Health;Health Services Accessibility;Homeostasis;Hormonal;Inflammatory;Intervention Studies;Knowledge;Life;Liquid substance;Malnutrition;Measures;Methods;Microscopic;Mission;Motor;Motor Activity;National Institute of Diabetes and Digestive and Kidney Diseases;Natural History;Nausea;Nausea and Vomiting;Nortriptyline;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmacology Study;Physical Function;Physicians;Physiological;Physiology;Protocols documentation;Psychological Impact;Publishing;Quality of life;Questionnaires;Race;Randomized;Recommendation;Registries;Research;Resolution;Sensory;Series;Severities;Signal Transduction;Stomach;Symptoms;Syndrome;Therapeutic;Time;Tissue Sample;United States National Institutes of Health;Visceral;Vomiting;Weight;Work;clinical center;disability;early satiety;effective therapy;evidence base;frailty;gastrointestinal function;gut-brain axis;improved;metabolomics;motor disorder;neuromuscular;novel;novel strategies;nutrition;persistent symptom;psychologic;recruit;response;social;therapeutically effective;treatment strategy;young woman


application_id: 10319702
project_number: 1R01DK130478-01
administering_ic: NIDDK
award_notice_date: 2021-08-17
opportunity_number: RFA-DK-20-021
application_type: 1
activity_code: R01
ic: DK
serial_number: 130478
program_official: ROY, CINDY
project_start_date: 2021-09-01
project_end_date: 2024-06-30
study_section: Special Emphasis Panel[ZDK1 GRB-G (M3)]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: HUANG, GANG
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-09-01
project_title:
Mechanism of the short- and long-term effects of COVID-19-induced Alarmins on hematopoietic stem and progenitor cells.

project_abstract:
ABSTRACTThe long-term goal of this proposal is to understand the long-term sequalae of acute COVID-19 infection onhematopoietic and immune damages and to identify the key pathways and mechanism by which COVID-19-associated cytokine dysregulation alters HSC function and differentiation. SARS-CoV-2 infection causes localand systemic damages due to dysregulated immune response and cytokine production. Its long-term negativeeffects on body tissue and organ remain largely unknown. Our published work showed that SARS-CoV-2infection dramatically increased neutrophil production and neutrophil-associated S100A8/A9 (Alarmin) release.Persistent high level of S100A8/A9 is a negative prognostic biomarker for the disease severity and mortality.Although the function of S100A8/A9 on mature blood cells have been studied its functional effect onhematopoietic stem cells (HSCs) are unknown. Our preliminary data show that S100A8/A9 causes loss ofquiescence and differentiation of HSC toward myeloid progenitors at the expense of HSCs. Toll-like receptor 4(TLR4) the endogenous receptor of S100A8/A9 is highly expressed in HSCs and S100A8/A9 activates itscanonical downstream MAPK (mitogen-activated protein kinase) pathway. Very interestingly S100A8/A9 causesdownregulation of epigenetic regulator Setd2 leading to the c-Myc upregulation in HSCs. c-Myc is a keydownstream target of both MAPK and Setd2 pathways. MAPK Setd2 and c-Myc are important regulators of HSCproliferation and myeloid differentiation. We hypothesize that SARS-CoV-2-induced S100A8/A9 activates TLR4signaling which converts to c-Myc in HSCs resulting in loss of quiescence and self-renewal myeloiddifferentiation skewing and long-term impairment of hematopoiesis. Since HSC is responsible for the life-longproduction of blood cells including all types of immune cells any functional damages of HSCs would later onhave profoundly negative effects on the immune response. Therefore understanding the cellular and molecularmechanism by which S100A8/A9 regulates HSCs and hematopoiesis would contribute a new evidence base toaccelerate advances in diagnostics therapeutics clinical management of COVID-19 patients in acute infectionand recovery phases.1

project_terms:
2019-nCoV;Acute;Apoptosis;Blood Cells;COVID-19;COVID-19 cytokine storm;COVID-19 pandemic;COVID-19 patient;Cell Differentiation process;Cells;Chronic;Clinical;Clinical Management;Data;Diagnostic;Disease;Disease Progression;Dose;Down-Regulation;Epigenetic Process;Equilibrium;Fluorouracil;Functional disorder;Generations;Goals;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Human;Immune;Immune response;Immunosuppression;Impairment;In Vitro;Infection;Inflammation;Knockout Mice;Knowledge;Life;Lipopolysaccharides;Long-Term Effects;MAP Kinase Gene;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Myelogenous;Myeloid Cells;Myelosuppression;Organ;Outcome;Pathway interactions;Patients;Pharmacologic Substance;Phase;Production;Prognostic Marker;Proteins;Publishing;Recombinants;Recovery;Regulation;Role;S100A8 gene;SARS-CoV-2 infection;Severities;Severity of illness;Signal Transduction;Stress;TLR4 gene;Therapeutic;Tissues;Transgenic Mice;Up-Regulation;Variant;Work;acute infection;adverse outcome;body system;c-myc Genes;cytokine;evidence base;exhaustion;functional disability;hematopoietic stem cell differentiation;hematopoietic stem cell quiescence;human model;loss of function;mortality;mouse model;neutrophil;progenitor;receptor;response;self-renewal;severe COVID-19;stem cell function;stem cell proliferation

public_health_relevance:
PROJECT NARRATIVEWe hypothesize that SARS-CoV-2-induced S100A8/A9 activates TLR4 signaling which alters hematopoieticstem cell (HSC) function and myeloid differentiation. Dissecting the detail mechanisms and pathways responsiblefor adverse and long-term outcomes of SARS-CoV-2 infection will help the diagnostics therapeutics and clinicalmanagement of COVID-19 patients in acute infection and recovery phases.


application_id: 10319572
project_number: 5K01DK116923-04
project_title: Social Network Analysis and Social Support Intervention for Rural Dwelling Older Adults with T2DM
administering_ic: NIDDK
award_notice_date: 2021-12-15
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: 2023-12-31
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;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;base;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;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: 10318587
project_number: 5F31AI147404-03
project_title: Identification of a novel zinc acquisition system in Yersinia pestis
administering_ic: NIAID
award_notice_date: 2021-12-10
opportunity_number: PA-18-671
application_type: 5
activity_code: F31
ic: AI
serial_number: 147404
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2020-01-01
project_end_date: 2022-12-31
study_section: Special Emphasis Panel[ZRG1-F13-Z(20)L]
contact_pi_person_id: 15681925
contact_pi: PRICE, SARAH LEANN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYYersinia pestis is the causative agent of human plague. Every year approximately 2000 cases of human plagueoccur and in the past several pandemics of plague have caused wide spread population loss. Y. pestis posesa threat to modern society due to its potential to be used as a bioterrorism agent the absence of a FDA approvedvaccine and the possibility of antibiotic resistance. The identification of novel targets for therapeutic agents iscritical for public health and safety. Consequently Y. pestis is considered a Tier 1 Select Agent. For survival andvirulence Y. pestis must acquire transition metals such as Fe Zn and Mn and overcome nutritional immunitymechanisms in eukaryotic organisms that restrict nutrients from invading bacteria. During human plagueYersinia pestis is able to overcome Fe limitation via production of the siderophore Yersiniabactin (Ybt). Recentlywe identified an unexpected role for the Ybt system in the ability of Y. pestis to acquire Zn during infection. Whilethe ZnuABC system contributes to in vitro growth in Zn-deficient media a znu mutant is not attenuated in themouse model of plague unless the mutant also lacks genes involved in Ybt synthesis. These data suggest thatY. pestis uses two redundant Zn acquisition systems to cause plague. We hypothesize that Y. pestis producesa novel Ybt synthetase-dependent zincophore required for zinc acquisition and virulence. In Specific Aim 1 wewill use a novel Tn-seq method to define genetic elements involved in the zincophore system. Genes that showa Zn phenotype will be validated through growth assays trans-complementation and biochemical experiments.In Specific Aim 2 we will determine the contribution of the Ybt synthetase-dependent zinc acquisition system tovirulence by utilizing a hemochromatosis mouse model. The hemochromatosis mouse is defective in Fenutritional immunity which will allow us to distinguish between the contributions of Ybt synthetase-dependent Feacquisition and Ybt synthetase-dependent Zn acquisition to Y. pestis virulence. In Specific Aim 3 we willdetermine the impact of calprotectin on Y. pestis virulence by using in vitro and in vivo methods. Completion ofthese Aims will define a novel secreted Zn acquisition system in Y. pestis. Our studies will be the first to determinethe contribution of Zn acquisition to Y. pestis virulence in the mammalian host and the effect of calprotectin onplague infection. Furthermore the involvement of conserved Ybt in this novel Zn acquisition demonstrates thesignificance of these studies to other bacterial pathogens.

project_terms:
ATP-Binding Cassette Transporters;Antibiotic Resistance;Attenuated;Bacteria;Binding;Biochemical;Biological Assay;Bioterrorism;Bubonic Plague;Complement;Data;Defect;Disease;Environment;FDA approved;Gene Silencing;Genes;Gram-Negative Bacteria;Growth;Hemochromatosis;Human;In Vitro;Infection;Invaded;Iron;Leukocyte L1 Antigen Complex;Ligase;Manganese;Mediating;Metals;Methods;Modeling;Modernization;Modification;Mus;Nutrient;Nutritional Immunity;Organism;Pathogenesis;Phenotype;Plague;Play;Pneumonic Plague;Population;Production;Public Health;Role;Safety;Septicemic plague;Siderophores;Site;Societies;System;Techniques;Testing;Transition Elements;Vaccines;Virulence;Virulent;Yersinia pestis;Zinc;antimicrobial;defined contribution;experimental study;genetic element;in vivo;innovation;mouse model;mutant;neutrophil;new therapeutic target;novel;pandemic disease;pathogenic bacteria;targeted treatment;transposon sequencing;yersiniabactin;zinc-binding protein

public_health_relevance:
PROJECT NARRATIVEBacterial pathogens must acquire transition metals such as iron and zinc during infection and recently a novelzinc acquisition system was identified in Yersinia pestis the causative agent of human plague. This project willidentify genetic elements responsible for zinc acquisition and define the contribution of zinc acquisition tovirulence. As a requirement for virulence metal acquisition systems remain viable targets for new therapeutics.


application_id: 10318416
project_number: 1F99NS120365-01A1
project_title: Translating Genetic Risk Factors to Therapies: From Big Data to Druggable Targets
administering_ic: NINDS
award_notice_date: 2021-06-24
opportunity_number: RFA-NS-19-011
application_type: 1
activity_code: F99
ic: NS
serial_number: 120365
suffix: A1
program_official: ULLRICH, LAUREN ELIZABETH
project_start_date: 2021-07-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZNS1 SRB-B (80)]
contact_pi_person_id: 14923227
contact_pi: SHAW, BENJAMIN C.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY Genome-wide association studies (GWAS) provide insight to underlying etiologies of disease not obviousthrough clinical evaluation or pathophysiology alone. Genetic variants associated with complex often refractorydiseases such as Alzheimers Disease (AD) and Multiple Sclerosis (MS) may hold the key for the next generationof treatment options. Leveraging genetic data with current standards of care and known pathophysiology canprovide a strong premise for mechanistic studies and novel drug targets. My current work studies the moleculargenetics of CD33 in AD under Dr. Steve Estus. CD33 normally acts to inhibit microglial activation in the brainsuppressing amyloid clearance. We are investigating how the AD-protective single nucleotide polymorphism(SNP) in CD33 modulates protein and thereby cellular function. This SNP leads to an increase in an alternativeCD33 protein isoform which based on our recent genetic data may promoterather than suppressmicroglialactivation. I will learn new technical skills during the F99 phase of this award and I will use these skills as I switchfocus to MS and progress into the K00 phase to acquire additional powerful techniques and models includingwork with patient samples pluripotent stem cells single-cell sequencing technologies and animal models. In Specific Aim 1 I detail how my training in molecular biology and genetic concepts has allowed me toconceive independent hypotheses and carry out complex experiments. My doctoral work on the moleculargenetics of CD33 and its association with reduced AD risk has provided training in GWAS interpretationquantitative PCR immunoassays such as Western blotting and co-immunoprecipitation and genetic techniquesincluding transfection and genome editing strategies in cell culture. In Specific Aim 2 I will continue to developas a scientist and finish my doctoral work carrying out increasingly complex studies to include high-resolutionconfocal imaging and subcellular localization measuring time- and dose-dependent protein phosphorylation insitu gene expression arrays and functional assays including phagocytosis in vitro. I will also continue developingmy professional skills such as oral and written communication networking and mentorship. In Specific Aim 3 Iwill extend my doctoral training to include work with human tissue samples and mouse models of MS. Ihave not yet identified a specific postdoctoral mentor but my ideal mentor will have experience conductinghuman subjects research using mouse models of MS and have a strong track record of training fellows tobecome tenure-track faculty. I will identify a mentorship team to guide my technical and professionaldevelopment during this phase. I will leverage my current training in molecular genetics to identify MS-associatedfunctional SNPs my training-in-progress to identify the mechanism behind these SNPs at the protein andintracellular signaling levels and my future training with murine models and human subjects to establish a high-impact translational career combining genetic clinical and pathology findings for pharmacologicalbreakthroughs in neuroimmune diseases.

project_terms:
Address;Affect;Alternative Splicing;Alzheimer's Disease;Alzheimer's disease risk;American;Amyloid;Amyloid beta-Protein;Animal Model;Antigen-Antibody Complex;Award;Big Data;Biological Assay;Brain;CRISPR/Cas technology;Caring;Cell Culture Techniques;Cell Line;Cell Surface Receptors;Cell surface;Cells;Cellular biology;Clinical Pathology;Clinical Trials;Co-Immunoprecipitations;Communication;Complex;Confocal Microscopy;Data;Data Analyses;Development;Disease;Dose;Drug Targeting;Educational workshop;Electronic Health Record;Engineering;Enzyme-Linked Immunosorbent Assay;Etiology;Exons;Faculty;Functional disorder;Future;Gene Chips;Gene Expression;Genetic;Genetic Techniques;Goals;Heritability;Human;Human Subject Research;Immune;Immunoassay;Impairment;In Situ;In Vitro;Individual;Institution;Knowledge;Learning;Ligand Binding Domain;Manuscripts;Measures;Mentors;Mentorship;Microglia;Microscopy;Modeling;Molecular Biology;Molecular Genetics;Molecular and Cellular Biology;Multiple Sclerosis;Myeloid Cells;Neurodegenerative Disorders;Neuroimmune;Neurosciences;Oral;PTPN6 gene;Patients;Peptides;Phagocytosis;Pharmacology;Phase;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Pluripotent Stem Cells;Positioning Attribute;Protein Isoforms;Proteins;Proto-Oncogene Proteins c-akt;Quality of life;RNA Splicing;Refractory Disease;Research;Research Personnel;Resolution;Risk Factors;Role;Sampling;Schools;Scientist;Signal Transduction;Single Nucleotide Polymorphism;Small Interfering RNA;Societies;System;TREM2 gene;Technical Expertise;Techniques;Technology;Therapeutic;Time;Tissue Sample;Training;Transfection;Translating;Tyrosine;Variant;Viral;Western Blotting;Work;abeta toxicity;base;brain cell;career;confocal imaging;data mining;druggable target;effective therapy;experience;experimental study;gain of function;genetic risk factor;genetic variant;genome editing;genome wide association study;graduate student;human data;human disease;human subject;human tissue;hyperphosphorylated tau;immunoregulation;improved;induced pluripotent stem cell;inhibitor/antagonist;insight;meetings;monocyte;mouse model;nano-string;neurotoxicity;new therapeutic target;next generation;novel;overexpression;post-doctoral training;receptor;research clinical testing;sample collection;single cell sequencing;single-cell RNA sequencing;skills;symposium;tau Proteins;tenure track;therapeutic target;undergraduate student

public_health_relevance:
PROJECT NARRATIVEGenome-wide association studies of human disease provide a powerful opportunity to uncover novel etiologiesand inform rational drug targets which would otherwise be overlooked. The goal of this project is to elucidate themechanism whereby a genetic variant in CD33 protects individuals from Alzheimers Disease which may providea breakthrough in this devastating disease with no effective treatment options and improve the quality of life formillions of patients. This project will provide exceptional training to an underrepresented and highly motivateddoctoral candidate facilitating his transition to postdoctoral studies and launching his promising career as anindependent neuroscience researcher.


application_id: 10318270
project_number: 1R13AR079883-01
administering_ic: NIAMS
award_notice_date: 2021-07-07
opportunity_number: PA-20-207
application_type: 1
activity_code: R13
ic: AR
serial_number: 079883
program_official: BELKIN, ALEXEY
project_start_date: 2021-07-10
project_end_date: 2022-06-30
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
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
budget_start_date: 2021-07-10
project_title:
24th Annual Meeting of the PanAmerican Society for Pigment Cell Research: Harnessing the Power of Scientific Discoveries in Pigment Cell Research"

project_abstract:
ABSTRACTThe 2021 Annual Meeting of the Pan-American Society for Pigment Cell Research (PASPCR) entitledHarnessing the power of scientific discoveries in pigment cell research will be held in Lexington KentuckySeptember 22-25 2021. Founded in 1988 and made up of approximately 100 members the PASPCR unitesclinicians developmental biologists biochemists immunologists cell biologists photobiologists and chemistsin the study of pigmentation melanin and melanocytes. The overall objective of PASPCR 2021 is to increaseour knowledge of the normal and abnormal chemistry biology and photobiology of the melanocyte acrossspecies and its contribution to human health and disease. Building on the success of partnering with theAmerican Society for Photobiology (ASP) at our last meeting we are planning a joint plenary session focusedon UV damage and repair to stimulate interaction between PASPCR and ASP investigators. In addition weare taking advantage of the robust equine research being done at UK by partnering with the Gluck EquineResearch Center (UK) to consider the horse as a model for pigment cell biology and melanoma in two plenarysessions. The goals of the meeting are to (1) highlight recent advances in melanin structure and analysisacross species in pigment cell response to light and other environmental stimuli and in genome-levelunderstanding of melanocyte function and transformation using relevant animal models and human tissue (2)bring together investigators and clinicians with strong interests in photoprotection melanocyte developmentaland stem cell biology and health disparities in pigmentary disease and (3) provide mentorship to younginvestigators with a specific focus on identifying and overcoming career barriers of women andunderrepresented minorities. We have emphasized the importance of diversity inclusivity and equity (DEI)with two dedicated panel discussions and by inviting faculty from the Skin of Color Society to our meeting. Inresponse to requests by trainees and young investigators we are incorporating a panel discussion focused onpigment cell research in the Industry setting. We have ensured meaningful inclusion of young investigatorswomen and underrepresented minorities among the invited speakers and leadership of PASPCR 2021. Themeeting also features a "Mentorship Mixer" that provides a structured mechanism for students and trainees toobtain scientific and career guidance from well-established scientists. Finally we are planning a hybrid virtualonline/live format with suitable physical distancing measures in response to the COVID-19 pandemic tomaximize participation in the meeting. Led by a strong organizational team PASPCR 2021 promises to be aconference of lasting impact for the pigment cell biology community.

project_terms:
Affect;American;Americas;Animal Model;Area;Asians;Benign;Biology;COVID-19 pandemic;Cells;Cellular biology;Chemistry;Clinical;Color;Communities;Development;Disease;Ensure;Equus caballus;Etiology;European;Faculty;Fostering;Genetic;Genome;Genomics;Goals;Health;Human;Hybrids;Immunologist;Industry;International;Japan;Japanese Population;Joints;Kentucky;Knowledge;Leadership;Light;Malignant - descriptor;Malignant Neoplasms;Measures;Melanins;Mentorship;Modeling;Persons;Photobiology;Pigmentation physiologic function;Pigments;Prevention;Public Health;Research;Research Personnel;Role;Science;Scientist;Societies;Stimulus;Structure;Students;Syndrome;Underrepresented Minority;Vitiligo;Vocational Guidance;Woman;career;disorder prevention;diversity and inclusion;health disparity;human tissue;interest;meetings;melanocyte;melanoma;member;photoprotection;programs;public health relevance;repaired;response;skin color;skin disorder;stem cell biology;success;symposium;ultraviolet damage;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENT / PROJECT NARRATIVE:The 2021 PASPCR Conference in Lexington Kentucky will bring together investigators studying pigmentarydisorders including those disproportionately affecting persons of color such as vitiligo genetic pigmentationsyndromes and melanoma. The theme of the conference - Harnessing the power of scientific discoveries inpigment cell research - is relevant to public health as the conference will disseminate the latest findings on theetiology treatment and prevention of disorders and malignancy of pigment cells. Through formal mentorshipopportunities the conference will foster the participation of young investigators especially women andunderrepresented minorities.


application_id: 10317841
project_number: 1R21NS120498-01A1
project_title: Defining CAMK4 transcript isoforms for axonal plasticity
administering_ic: NINDS
award_notice_date: 2021-06-22
opportunity_number: PA-18-358
application_type: 1
activity_code: R21
ic: NS
serial_number: 120498
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-07-01
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1 BDCN-E (02)]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Affecting axonal growth as a means to enhance recovery and alleviate pathology in conditions of nervoussystem injury insult or disease is a major goal for the healthcare and biomedical research endeavors.Significant effort is directed at inducing neural plasticity to enhance axonal growth to establish functionally-adaptive connections. However these efforts must also prevent and not induce maladaptive plasticity abalance which requires a clear understanding of the processes regulating axon growth. We have recentlydetermined that the mechanisms of the two major forms of axon growth in the adult nervous system  growthof injured axons (Regeneration) and that of non-injured axons (Collateral Sprouting - CS)  differ significantlyand involve distinct transcriptional profiles. We have identified Camk4 as a gene necessary for CollateralSprouting but not involved in Regeneration. We have further determined that during CS Camk4 expression isregulated not at the coding sequence but at the 3 UTR. Camk4 and particularly Camk4 with this novelsprouting-related 3 UTR is expressed in neurons known to have a high degree of constitutive plasticitycapacity such as sensory nociceptors hippocampus cerebellum and cortex. These findings point to additionalpotential mechanisms by which CamK4 may be acting and also opens additional potential therapeutic targets.However tools to examine those mechanisms are lacking. We aim to determine the range and character oftranscript isoforms expressed by neurons at basal state and during plasticity (regeneration and sprouting).These data will have significant value on their own but will be used here to direct the design of a novel mousewith conditional-deletion of the novel long-isoform of the 3 UTR without disrupting the protein codingsequence. This will allow us to determine the role of this important transcript segment in protein expressionand localization and examine other protein-independent functions which may exist. Although vital formechanistic studies of axonal plasticity these data and the new mice will also be useful for any cells whichexpress Camk4 and use the novel long 3 UTR (e.g. testicular cells kidney podocytes adipocytes T cellsetc.) and we have established collaborative arrangements with a range of labs that would like to use these newmice in their research.

project_terms:
3' Untranslated Regions;Address;Adipocytes;Adult;Affect;Axon;Bioinformatics;Biomedical Research;Cells;Cerebellum;Characteristics;Code;Communities;Data;Development;Disease;Dysautonomias;Enterobacteria phage P1 Cre recombinase;Equilibrium;Foundations;Gene Expression Profile;Generations;Genes;Genetic Recombination;Genetic Transcription;Goals;Growth;Health Care Research;Hippocampus (Brain);In Situ Hybridization;Injury;Intrinsic factor;Kidney;Knock-out;Knockout Mice;Laboratories;LoxP-flanked allele;Mammals;Mediating;Molecular;Mus;Natural regeneration;Nervous System Trauma;Nervous system structure;Neurology;Neuronal Plasticity;Neurons;Neurosciences;Nociceptors;Northern Blotting;Pain;Pathology;Pattern;Process;Protein Isoforms;Proteins;Rattus;Recovery;Recovery of Function;Regulation;Research;Role;Sensory;Services;Stroke;T-Lymphocyte;Techniques;Testing;Testis;Tissues;Transcript;Untranslated Regions;axon growth;axon injury;axon regeneration;base;cell type;design;experimental study;mouse model;novel;podocyte;prevent;programs;protein expression;therapeutic target;tool;transcription factor;transcriptome sequencing

public_health_relevance:
We have identified a gene that is necessary for axonal collateral sprouting one of the plasticity mechanismsunderlying recovery of function after injury or stroke but also pain and dysautonomia and its regulationappears to involve use of novel 3 UTR segments of its transcripts. We seek to define the range of transcriptsof a gene we have determined is vital for neural plasticity and use this information to design a novel mousemodel in which the regulatory segment of the transcript is removed without altering the protein-codingsegment. This new mouse model will enable studies of fundamental mechanisms by which the nervous systemcan adapt via growth of non-injured axons to establish new connections and the study of other cells which usethe long-forms of Camk4 3 UTR such as T-cells adipocytes kidney podocytes and cells in testis.


application_id: 10317034
project_number: 5R01HL149351-03
project_title: Atherogenic Mechanisms of Electronic Nicotine Delivery Systems
administering_ic: NHLBI
award_notice_date: 2021-12-02
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: 2023-12-31
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 Model;Animals;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;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 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;air filter;alpha-bungarotoxin receptor;atherogenesis;atherosclerosis risk;base;chronic inflammatory disease;cigarette smoke;cigarette smoking;cigarillos;combustible cigarette;combustion product;cytokine;electronic hookah;electronic liquid;feeding;heart disease risk;hookah;insight;macrophage;mortality risk;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: 10316730
project_number: 2R01CA196634-07
project_title: Improving chemotherapy of castration-resistant prostate cancer.
administering_ic: NCI
award_notice_date: 2021-06-04
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: CA
serial_number: 196634
program_official: FORRY, SUZANNE L
project_start_date: 2016-08-10
project_end_date: 2026-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ablation;Affect;Androgen Receptor;Androgens;Binding;Biochemical;Bromodomain;Castration;Cell Cycle;Cell Cycle Progression;Cell Proliferation;Cells;Chemoresistance;Chromatin;Clinical Research;Data;Development;Disease;Docking;Epigenetic Process;Event;Family;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth and Development function;Health;Investigation;Lead;Lysine;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Mitosis;Mitotic;Molecular;Mutation;Operative Surgical Procedures;Outcome;PLK1 gene;Paclitaxel;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphorylation Site;Phosphotransferases;Proteins;Public Health;Reader;Receptor Signaling;Regulation;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;Site;Specimen;System;Testing;Therapeutic;Therapeutic Agents;Transcriptional Elongation Factors;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;castration resistant prostate cancer;chemotherapy;clinically significant;cyclin T1;design;docetaxel;effective therapy;genetic approach;genomic locus;improved;in vivo;inhibitor/antagonist;innovation;loss of function mutation;member;mouse model;multicatalytic endopeptidase complex;novel;novel strategies;patient derived xenograft model;prostate cancer cell;prostate cancer progression;protein degradation;recruit;standard care;success;therapy resistant;ubiquitin-protein ligase


application_id: 10314056
project_number: 5R01CA222596-05
project_title: Role of Sulfiredoxin in Colorectal Cancer Development
administering_ic: NCI
award_notice_date: 2022-01-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 222596
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2018-01-01
project_end_date: 2023-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10043947
contact_pi: WEI, QIOU
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:
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer deathin both men and women in USA and worldwide. One of the major causes of colorectal cancer mortality is dueto the spreading of cancer cells from primary tumor sites to distant organs a process known as cancer cellinvasion and metastasis. This process is coordinately regulated by various biological molecules and theirassociated signaling pathways. The long-term objective of my research is to understand colon tumorigenesisand metastatic process by identifying critical molecular drivers and to understand their function mechanisms todevelope effective ways for targeted cancer therapy. Sulfiredoxin is a novel redox enzyme that has a criticalrole of promoting tumorigenesis and metastasis of colorectal cancer. In this project our goals are tounderstand molecular mechanisms by which Sulfiredoxin promotes cancer cell invasion and metastasis and totest the efficacy of a novel small molecule inhibitor of Srx in blocking human colorectal cancer invasion andmetastasis using cell culture as well as mouse models.

project_terms:
American Cancer Society;Azoxymethane;Back;Binding;Biological;Biology;C-terminal;Cancer Etiology;Cell Culture Techniques;Cells;Cessation of life;Cetuximab;Clinic;Colorectal Cancer;Data;Deacetylation;Development;Diagnosis;Distant;Drug Kinetics;Enzymes;Epithelial;Fc Receptor;Free Radicals;Future;Goals;Growth;Growth Factor Receptors;Human;Individual;International;Knockout Mice;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Mesenchymal;Mitogen-Activated Protein Kinases;Molecular;Mus;Neoplasm Metastasis;Oncogenic;Organ;Oxidation-Reduction;Oxidative Stress;Oxidoreductase;Pathologist;Patients;Peroxidases;Physicians;Play;Post-Translational Protein Processing;Primary Neoplasm;Process;Receptor Activation;Reporting;Research;Research Personnel;Resistance;Resources;Role;Route;Scientist;Signal Pathway;Signal Transduction;Site;Sodium Dextran Sulfate;Specimen;Subcutaneous Injections;Testing;Therapeutic;Toxic effect;Tyrosine Phosphorylation;Woman;base;cancer cell;cancer diagnosis;colon cancer patients;colon carcinogenesis;colon tumorigenesis;colorectal cancer metastasis;colorectal cancer treatment;dextran sulfate sodium induced colitis;dosage;efficacy study;efficacy testing;enzyme activity;fascin;implantation;insight;men;metastatic colorectal;metastatic process;mortality;mouse model;multidisciplinary;novel;novel therapeutics;panitumumab;patient derived xenograft model;peroxiredoxin;receptor;small molecule inhibitor;targeted cancer therapy;translational applications;tumorigenesis

public_health_relevance:
This project is aimed to understand role of Sulfiredoxin in colon tumorigenesis and molecularmechanism of Sulfiredoxin in promoting colorectal cancer cell invasion and metastasis. Bytesting a novel small molecule inhibitor of Sulfiredoxin in the treatment of colorectal cancer inmouse models we expect to provide proof-of-the-concept data for future translationalapplications.


application_id: 10314015
project_number: 5R01AG061111-03
administering_ic: NIA
award_notice_date: 2022-01-06
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: 2021-12-01
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;CRSP3 gene;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;Drug usage;Elderly;Future;Genes;Heart failure;Hippocampus (Brain);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;Pharmacology;Pharmacotherapy;Phase;Placebo Control;Placebos;Population;Prevention trial;Prospective cohort;Proteins;Proteomics;Publishing;Randomized;Research;Risk;Running;Safety;Techniques;Testing;Universities;Urea;Work;aging population;arterial spin labeling;base;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;magnetic resonance imaging biomarker;neurocognitive test;neuroimaging;neuropathology;novel;novel therapeutics;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: 10312905
project_number: 1F31AG074530-01
project_title: Evaluating the Mechanism for Hyperhomocysteinemia Induced Vascular Pathology
administering_ic: NIA
award_notice_date: 2021-08-20
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: AG
serial_number: 074530
program_official: NEWMAN, ELIZABETH
project_start_date: 2021-09-27
project_end_date: 2024-09-26
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 16323659
contact_pi: EARLY, ALEXANDRIA
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 Vascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes ofdementia along with Alzheimers disease (AD) and approximately 60% of patients with AD also present withVCID. Despite its common clinical manifestation the mechanism underlying VCID remains elusive. Based onextensive data analysis in humans and animal models a specific family of proteinases that degrade essentialcomponents of the blood brain barrier (BBB) in particular matrix metalloproteinase 9 (MMP9) were identifiedas being strongly associated with progression of VCID. MMP9 degrades tight junctions between endothelialcells and the anchoring proteins located at the astrocytic end feet. I hypothesize that upregulation of MMP9results in the dissociation of perivascular astrocytes from their vessels leading to BBB dysfunction and theprogression toward VCID. To test this hypothesis I propose in vivo studies in a hyperhomocysteinemia (HHCy) mouse model ofVCID in both wild type (WT) and MMP9 null mice (Aim 1) alongside astrocyte-specific in vitro studies usingWT and MMP9 null primary astrocytes (Aim 2). We have shown that induction of HHCy in WT mice isassociated with microhemorrhages reduced blood flow neuroinflammation and cognitive impairment indicatingits relevance in recapitulating the clinical manifestations of VCID. Preliminary data shows our HHCy model ofVCID induces decreased contact of astrocytic end-feet with the vasculature. Aim 1 will assess the role ofMMP9 in the progression of VCID pathology in response to HHCy in vivo by examining changes inneurovascular coupling and associations between astrocyte end feet and the cerebrovasculature using two-photon imaging. Aim 2 will investigate the astrocyte-specific role of MMP9 in disruption of the BBB. Usingprimary cells obtained from both WT and MMP9 null mice I will use trans-endothelial electrical resistancemeasurements (TEER) in an astrocyte/endothelial cell co-culture model to assess BBB integrity in response toHHCy. By elucidating the cell specificity and mechanism of MMP9 mediated vascular pathology we cansystematically target the various stages of disease progression and ultimately prevent the progression of VCID. Through completion of this project I will receive training in both in vitro and in vivo models of VCIDwhich coupled with my previous training in human subjects will expose me to all aspects of translationalresearch. Additionally I will regularly present data at both international and national meetings I will be involvedin experimental design and ethics workshops and will gain experience mentoring junior scientists. Theseexperiences coupled with the mentorship of the renowned scientists on my committee will ensure that I amwell prepared to successfully secure a post-doctoral fellowship in the field of neurodegeneration.

project_terms:
Affect;Alzheimer's Disease;Animal Model;Astrocytes;Biochemical;Blood - brain barrier anatomy;Blood Vessels;Blood flow;Cells;Cerebrovascular system;Characteristics;Clinical;Coculture Techniques;Communication;Coupled;Data;Data Analyses;Dementia;Development;Dextrans;Diet;Disease;Disease Progression;Disease model;Dissociation;Dose;Educational workshop;Electrical Resistance;Endothelial Cells;Endothelium;Ensure;Ethics;Experimental Designs;Family;Fellowship;Foundations;Functional disorder;Gel;Gelatinase B;Goals;Histologic;Histology;Homocysteine;Human;Hyperhomocysteinemia;Image;Impaired cognition;Impairment;In Vitro;Inflammatory;International;Intervention;Knockout Mice;Label;Lead;Link;Measurement;Mediating;Mentors;Mentorship;Microglia;Modeling;Molecular Biology;Nerve Degeneration;Outreach Research;Pathologic;Pathology;Patients;Peptide Hydrolases;Plasma;Postdoctoral Fellow;Principal Investigator;Proteins;Quantitative Reverse Transcriptase PCR;Research Ethics;Risk Factors;Role;Scientist;Secure;Series;Source;Specificity;Stimulus;TNF gene;Techniques;Testing;Therapeutic Intervention;Tight Junctions;Time;Training;Transcriptional Activation;Translational Research;Up-Regulation;Wild Type Mouse;astrogliosis;base;blood-brain barrier disruption;blood-brain barrier permeabilization;cerebrovascular;clinically relevant;comorbidity;cytokine;experience;fluorescence imaging;foot;human model;human subject;in vivo;in vivo Model;inflammatory marker;innovation;meetings;mouse model;neuroinflammation;neurovascular coupling;new therapeutic target;prevent;response;targeted treatment;two-photon;vascular cognitive impairment and dementia

public_health_relevance:
PROJECT NARRITIVEVascular contributions to cognitive impairment and dementia (VCID) is independently one of the leadingcauses of dementia along with Alzheimers disease (AD) and importantly VCID often manifests as acomorbidity of AD. The progression of VCID is strongly associated with the upregulation of proteinases thatdegrade essential components of the blood-brain barrier (BBB) in particular matrix metalloproteinase 9(MMP9). Successful completion of this project will identify cellular sources of MMP9 elucidate a mechanismlinking MMP9 mediated BBB disruption to progression of VCID and establish MMP9 as a viable target forteraputic intervention.


application_id: 10311470
project_number: 5R01AR073906-04
project_title: Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling
administering_ic: NIAMS
award_notice_date: 2021-11-19
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AR
serial_number: 073906
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2020-02-25
project_end_date: 2024-11-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 10909082
contact_pi: KIKANI, CHINTAN K
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:
Project SummaryMuscle trauma is one of the most common and repetitive types of injury in humans. Owing to theregenerative functions of Muscle Stem Cells (MuSCs) the injured myotome can fully regain its structural andfunctional integrity within just a few days. In addition to this remarkable regenerative function MuSCs also playa significant role in the maintenance of muscle homeostasis under the normal condition. On the other hand thedecline in MuSCs function is implicated in muscle wasting diseases and several forms of musculardystrophy. The functions of MuSCs are influenced by the niche it occupies. For example the niche emitssignals to regulate MuSCs quiescence in the uninjured state or activation when regeneration is required.Understanding how these signaling pathways control quiescence and activation of MuSCs is essential to devisethe next generation of therapeutic approaches for diseases of MuSCs dysfunction. We recently described anovel signaling pathway in MuSCs that stimulates regenerative myogenesis by epigenetically activating thetranscription of the Myog promoter. In this pathway Per-Arnt-Sim domain Kinase (PASK) phosphorylatesWD40-domain repeat 5 (Wdr5) at the onset of the myogenesis program. Phosphorylated Wdr5 stimulatesthe Myog transcription by inducing histone H3 trimethylation at lysine 4 (H3K4me3) and the recruitmentof the MyoD transcription factor at the Myog promoter. We present evidence that PASK expression and activityis induced in regenerating myoblasts by signaling cues such as insulin and nutrients in mTOR complex 1dependent manner. Functionally loss of Pask in mice retards regenerative myogenesis and over-expressionof PASK depletes the stem cells. Thus we hypothesize that PASK plays a role balancing self-renewal vsdifferentiation during regeneration. Building upon these data in this proposal we will investigate howPASK expression and activity is regulated in the regenerating myoblast (Specific Aim 1). In activatedMuSCs PASK phosphorylated Wdr5 induces H3K4me3 modification MyoD recruitment and nucleosomalremodeling on the Myog promoter yet the mechanism is not clear. In Specific Aim 2 we will extensivelystudy two interacting partners of Wdr5 which could remodel the Myog promoter for its activation. Uponinduction of Myogenin Pax7 expression is down-regulated and terminal differentiation is established. SincePASK is an upstream regulator of the Myog expression we are interested determining how loss or gainof PASK affects the self-renewing population during regeneration and normal aging process which we willstudy in Specific Aim 3. Ultimately these aims will allow us to understand how niche signaling cues controlthe balance between self-renewal and differentiation and how it can be exploited for improvement ofphysiological conditions such as sarcopenia.

project_terms:
Acetylation;Acute;Adult;Affect;Aging;Binding;Cell Count;Cell physiology;Cells;Collaborations;Complex;Cues;Data;Disease;Epigenetic Process;Equilibrium;FRAP1 gene;Functional disorder;Genetic Transcription;Goals;Histone H3;Histones;Homeostasis;Human;Injury;Insulin;Legal patent;Lysine;Maintenance;Messenger RNA;Metabolism;Modeling;Modification;Molecular;Mus;Muscle;Muscle Cells;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myoblasts;Myogenin;Myopathy;Natural regeneration;Nutrient;Pathway interactions;Phosphorylation;Phosphotransferases;Physiological;Play;Population;Process;Proliferating;Property;Protein Kinase;Proteins;Publishing;Reagent;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Testing;Therapeutic;Transcription Process;Transferase;Trauma;WD Repeat;Wasting Syndrome;age-related muscle loss;base;cell injury;functional loss;hormonal signals;human disease;in vivo;inhibitor;interest;member;mouse model;muscle aging;myogenesis;normal aging;novel;novel therapeutics;overexpression;programs;promoter;recruit;regeneration function;regeneration potential;regenerative;response;sarcopenia;self-renewal;stem cell differentiation;stem cell fate specification;stem cell function;stem cells;transcription factor

public_health_relevance:
Project NarrativeDysregulation of Muscle Stem Cell (MuSC) function contributes to many human diseases. Here we describea novel signaling pathway that stimulates MuSC differentiation while suppressing selfrenewal. Wepropose that this pathway can be therapeutically exploited for the treatment of ageassociated musclewasting.


application_id: 10311255
project_number: 5P20GM121327-05
project_title: Identifying Fundamental Mechanisms that Mediate Resistance to Anti-Cancer Therapies
administering_ic: NIGMS
award_notice_date: 2020-12-21
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: MCGUIRL, MICHELE
project_start_date: 2021-01-01
project_end_date: 2021-08-31
study_section: ZGM1-RCB-6(CI)
subproject_number: 5025
contact_pi_person_id: 10461818
contact_pi: DUNCAN, ELIZABETH MARIE
other_pis: ZHOU, BINHUA P
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:
A major obstacle to achieving long-term cancer remission is the ability of some cancer cells to resist therapy. Strikingly the fundamental cell biology underlying therapy resistance in human tumors is remarkably similar to that which confers incredible regenerative capacity in many planarian species. In these flatworm species even a small piece of excised tissue can recreate an entirely new animal. This remarkable ability relies on the maintenance of a heterogeneous pool of planarian stem cells that bear many similarities to cancer stem cells. For example a subset of these cells can tolerate high doses of -radiation and restore the entire stem cell population. Yet little is known about the mechanisms that confer this tolerance and almost nothing is known about their resistance to chemotherapies. Preliminary research revealed that planarians show resistance to the drug cisplatin. Treatment of planarians with 80-100M cisplatin induced a phenotype that broadly mimicked the development of chemoresistance in human cancers: animals exhibited an initial loss of tissue followed by regeneration. Based on these data and known effects of cisplatin the central hypothesis is that cisplatin differentially affects mitochondrial function across the stem and progenitor populations which differentially alters a conserved chromatin signature that marks tumor suppressor genes i.e. broad H3 lysine 4 trimethylation (H3K4me3) increases cellular heterogeneity and promotes chemoresistance. The goal of this study is to leverage the remarkable functional similarities between human tumors and the planarian stem cell population to uncover fundamental mechanisms that link the development of chemoresistance to metabolic and epigenetic regulation in vivo through the following specific aims: 1) To identify cisplatin-responsive differences in mitochondrial function in stem and progenitor cell populations using mitochondrial probes high resolution imaging and biochemical assays. This study uses state-of the-art approaches to determine the metabolic heterogeneity of stem cells in vivo. 2) To establish mechanistic links between metabolism chromatin state and chemoresistance by perturbing metabolite availability and measuring the impact on H3K4me3 transcriptional heterogeneity and chemoresistance. This study will reveal critical links between metabolic and epigenetic regulation in chemoresistance. 3) To assess the conservation of metabolic H3K4me3 regulatory mechanisms in lung cancer using established airway organoid models. This study will test the hypothesis that resistant lung cancer cells respond to cisplatin-induced ROS by reducing H3K4me3. The proposed research will uncover novel mechanisms and target genes underlying chemoresistance.

project_terms:
Affect;Animals;Biochemical;Biological Assay;Cancer Center;Cancer Remission;Cells;Cellular biology;Chemoresistance;Chromatin;Cisplatin;Data;Development;Dose;Drug resistance;Exhibits;Gamma Rays;Genes;Genetic Transcription;Goals;Heterogeneity;Human;Kentucky;Link;Lysine;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Modeling;Natural regeneration;Organoids;Phenotype;Planarians;Platyhelminths;Population;Regenerative capacity;Research;Resistance;Testing;Tissues;Tumor Suppressor Genes;Universities;Ursidae Family;base;cancer cell;cancer stem cell;cancer therapy;chemotherapy;epigenetic regulation;high resolution imaging;in vivo;lung cancer cell;novel;progenitor;stem;stem cell population;stem cells;tumor;tumor metabolism


application_id: 10310471
project_number: 5R01CA175105-08
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2021-12-01
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;Electron Transport Complex III;Environment;Epigenetic Process;FRAP1 gene;Fostering;Foundations;Funding;Genes;Genetic Transcription;Genetic Translation;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;Phosphotransferases;Polyribosomes;Positioning Attribute;Process;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;base;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;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.


