# projects

application_id: 9809064
project_number: 1R21AG064626-01
project_title: Role of tau circular RNAs in tauopathies
administering_ic: NIA
award_notice_date: 2019-07-26
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AG
serial_number: 064626
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2019-08-01
project_end_date: 2021-04-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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:
Microtubule associated protein tau (encoded by the MAPT gene) is a critical component in the etiology ofAlzheimer's Disease (AD) and other tauopathies in which tau aggregates in neurofibrillary tangles.However the basic regulation of MAPT gene expression is still imperfectly understood. It is not clearwhat causes the formation of neurofibrillary tangles but tauopathic conditions show changes in taumRNA isoforms generated through alternative pre-mRNA processing. Furthermore mutationschanging alternative splicing of MAPT cause frontotemporal dementia underscoring the importance oftau pre-mRNA processing. We have identified human-specific circular RNAs (circRNAs) formed by thetau-encoding mRNA from the MAPT locus generated by backsplicing of exon 10. Backsplicing formingcircRNAs occurs when pre-mRNA forms loops which is aided by primate-specific Alu elements inhumans. The ground-breaking preliminary data demonstrate conclusive evidence of tau circRNAsderived from human brain samples. We hypothesize that Alu elements help forming human specificMAPT circRNAs that likely after RNA methylation could be translated into proteins containingmultimers of microtubule binding sites. We will use (a) minigenes in tissue culture for molecularmechanistic studies to test whether MAPT circRNAs are translated into proteins after RNA methylationand to test tau circRNA's interaction with other RNAs and proteins. These data will be correlated withassessments in human brain tissue across the disease spectrum from pathologically-confirmed normalMCI (mild cognitive impairment) and AD cases. To (b) test tau circRNA's physiological relevance wehave generated zebrafish lines expressing genomic parts of human MAPT that form circular RNAs inneurons and observed abnormal neurons after introduction of FTDP-17 mutants in constructs thatexpress only circRNAs. We will determine the expression of transgenic circRNAs their encodedproteins possible sequestration of other RNAs and proteins changes in neuron morphology taupathology and correlate these data with spatial memory tests that take stress into account. These arethe first reports and studies of human tau circular RNAs. These studies are significant as they couldprovide a novel human-specific molecular mechanism to alter MAPT gene expression and possibly anew mechanism to promote the formation of tau aggregates. Our studies capitalize on the excellentbrain bank at the University of Kentucky headed by Co-I Dr. Nelson and the zebrafish expertise of Co-I Dr. Blackburn.

project_terms:
Adenine;Adenosine;Alternative Splicing;Alu Elements;Alzheimer's Disease;Amino Acids;Animal Model;Antisense Oligonucleotides;Autopsy;Binding;Binding Proteins;Binding Sites;Biological Assay;Biology;Brain;Cells;Cellular Stress;Clinical;Data;Development;Disease;Elements;Epigenetic Process;Etiology;Event;Excision;Exons;FTD with parkinsonism;Fishes;Freezing;Frontotemporal Dementia;Gene Expression;Generations;Genes;Genetic;Genomics;Human;Interdisciplinary Study;Kentucky;Knowledge;Lead;Letters;Link;MAPT gene;Mass Spectrum Analysis;Messenger RNA;Methylation;Microtubules;Modeling;Modification;Molecular;Molecular Weight;Morphology;Motor Neurons;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurons;Open Reading Frames;Pathologic;Pathology;Peptide Initiation Factors;Physiological;Play;Polyadenylation;Polymers;Primates;Protein Isoforms;Proteins;RNA;RNA Processing;RNA methylation;Reader;Regulation;Reporting;Research;Ribosomes;Role;Sampling;Site;Stress;Structure;Tauopathies;Terminator Codon;Testing;Transgenic Organisms;Translating;Translations;Universities;Zebrafish;biobank;brain tissue;circular RNA;mRNA Precursor;mild cognitive impairment;mutant;nervous system disorder;neurochemistry;neurofibrillary tangle formation;neuropathology;novel;novel therapeutics;overexpression;paired helical filament;programs;protein expression;recruit;spatial memory;tRNA Methyltransferases;tau Proteins;tau aggregation;tau function;tissue culture

public_health_relevance:
The microtubule associated protein tau is a protein central for the pathology ofAlzheimer's disease. We unexpectedly discovered that the tau gene generates circularRNAs and will analyze their generation and molecular function in cells and zebrafish.


application_id: 9804746
project_number: 3R21AA025724-02S1
project_title: Gut extracellular vesicles promote alcohol-induced liver injury via TLR4-regulated miRNAs
administering_ic: NIAAA
award_notice_date: 2019-08-25
opportunity_number: PA-18-817
application_type: 3
activity_code: R21
ic: AA
serial_number: 025724
suffix: S1
program_official: WANG, JOE
project_start_date: 2018-08-01
project_end_date: 2020-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
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:
The overarching theme of this supplementary project is to add the new information of parent award that nutritionlead to the changes of extracellular vesicles (EVs) of IECs in alcoholic liver disease (ALD). We will focus on 6PUFAs and gut microbiota-regulated exmiRNAs. Specifically we will examine how 6 PUFAs stimulate theproduction of gut EVs through TLR4/STAT3 signaling and the consequences of these events in the developmentof ALD via gut-liver axis. Novel in vitro and in vivo approaches will be used to address mechanisms of actionwith the goal of identifying new targets for intervention. We propose that 6 PUFAs induce the dysbiosis ofgut microbiota which contribute to the changes in the miRNAs profile of gut-derived EVs. We specificallypropose that TLR4/STAT3-activated extracelluar miRNAs production is the key to the activation ofmacrophages during 6 PUFAs-induced chronic inflammation in ALD. Based on our published work andother preliminary data this proposal will test the hypothesis that 6 PUFAs regulate the production of gutextracellular miRNAs through TLR4/STAT3 signaling which initiates a crosstalk among macrophages andhepatocytes in ALD. Moreover we will determine whether supplement of 3 PUFAs with diet-associatednanoparticles carrying inflammatory miRNAs inhibitor have potential therapeutic implications in ALD. Thesehypotheses will be tested in the following Specific Aims: Aim 1: Determine the role of 6 PUFAs-regulatedgut EVs in alcohol-induced liver inflammation. Aim 2: Determine whether alteration of IEC miRNAs viaTLR4/STAT3 modulation affects the severity of 6 PUFAs-induced liver inflammation and injury in ALD..

project_terms:
Address;Affect;Alcoholic Liver Diseases;Alcohols;Antigens;Attenuated;Automobile Driving;Award;Cells;Chronic;Colon Carcinoma;Consumption;Data;Development;Diet;Distant;Epithelial;Epithelial Cells;Event;Goals;Grant;Hepatic;Hepatocyte;High Fat Diet;Immune;Immune signaling;Immunotherapy;Impairment;In Vitro;Inflammation;Inflammatory;Inflammatory disease of the intestine;Injury;Intervention;Intestinal permeability;Intestines;Kupffer Cells;Lead;Link;Linoleic Acids;Liver;Liver diseases;Macrophage Activation;Mediating;MicroRNAs;Molecular;Outcome;Parents;Pathogenicity;Patients;Play;Polyunsaturated Fatty Acids;Production;Proteins;Publishing;Regulation;Role;STAT3 gene;Severities;Signal Transduction;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Ulcerative Colitis;Work;antimicrobial;base;dysbiosis;exosome;extracellular;extracellular vesicles;fatty acid supplementation;gut microbiota;gut-liver axis;improved;in vivo;inhibitor/antagonist;interest;liver development;liver inflammation;liver injury;macrophage;microbial;migration;nanoparticle;nanovesicle;non-alcoholic fatty liver disease;novel;nutrition;overexpression;prevent;response;therapeutic target;translational study;vesicular release

public_health_relevance:
Project NarrativeThis proposal underscores the importance of investigating n-6 PUFAs-activated extracellular miRNAs as acritical IECs-derived factor for the development of alcoholic liver diseases by regulating the function of hepaticmacrophages. We anticipate that we can abrogate their local and/or distant activities by targeting gutextracellular miRNAs.


application_id: 9799434
project_number: 1R01DA048876-01
administering_ic: NIDA
award_notice_date: 2019-07-25
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: DA
serial_number: 048876
program_official: MULFORD, CARRIE FRIED
project_start_date: 2019-08-01
project_end_date: 2024-05-31
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
project_terms:
Address;Aftercare;Back;Caring;Characteristics;Communities;Continuity of Patient Care;County;Crime;Criminal Justice;Data;Distal;Drug Screening;Drug usage;Economically Deprived Population;Education;Elements;Enrollment;Equipment and supply inventories;Foundations;Future;Geographic Locations;Geography;Goals;Health;Health Services Accessibility;Healthcare;Imprisonment;Individual;Injectable;Intervention;Interview;Kentucky;Knowledge;Literature;Longitudinal cohort study;Measures;Mediating;Medicaid;Mentors;Methods;Naltrexone;National Institute of Drug Abuse;Opiate Addiction;Outcome;Outpatients;Overdose;Persons;Pharmaceutical Preparations;Pilot Projects;Predictive Factor;Prisoner;Prisons;Process;Public Health;Recovery;Relapse;Reproducibility;Research;Resources;Rural;Rural Appalachia;Rural Population;Safety;Sampling;Science;Social Network;Social Work;Structure;Substance abuse problem;Supervision;Support Groups;Surveys;System;Time;Treatment outcome;United States National Institutes of Health;Urban Population;Validation;Variant;Woman;addiction;adverse outcome;base;effective therapy;evidence base;experience;follow-up;geographic difference;improved;interest;offender;opioid epidemic;opioid misuse;opioid use disorder;primary outcome;programs;prospective;recidivism;recruit;relapse risk;response;social;uptake;willingness


application_id: 9795728
project_number: 1R01DK121695-01
project_title: Macrophage Migration Inhibitory Factor mediates bladder pain
administering_ic: NIDDK
award_notice_date: 2019-06-21
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: DK
serial_number: 121695
program_official: KIRKALI, ZIYA
project_start_date: 2019-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZRG1 DKUS-B (90)]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078344581
primary_uei: JCSKALYM8HU6
duns_number: 078344581
uei: JCSKALYM8HU6
fips: US
organization_id: 10030991
organization_name: LEXINGTON BIOMEDICAL RESEARCH INSTITUTE
organization_city: LEXINGTON
organization_state: KY
organization_type: Research Institutes
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Binding;Bladder;Bladder Injury;Cyclophosphamide;Cystitis;Data;Goals;HMGB1 Protein;Human;Hyperalgesia;In Vitro;Infection;Infective cystitis;Inflammation;Inflammatory;Injury;Interstitial Cystitis;Knowledge;Mediating;Microglia;Migration Inhibitory Factor;Organ;Outcome;Pain;Pathology;Patients;Pelvic Pain;Peptides;Peripheral;Production;Proteins;Publishing;Research;Rodent Model;Signal Pathway;Signal Transduction;Spinal;Spinal Cord;Symptoms;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Urothelial Cell;Work;base;bladder pain;chronic pelvic pain;cytokine;inhibitor/antagonist;interstitial;new therapeutic target;novel;prevent;protease-activated receptor 4;radiation cystitis;receptor;targeted treatment;therapeutic target


application_id: 9793998
project_number: 5R01DA047952-02
administering_ic: NIDA
award_notice_date: 2019-07-31
opportunity_number: PA-18-345
application_type: 5
activity_code: R01
ic: DA
serial_number: 047952
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2018-09-30
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-AARR-K(92)S]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
project_terms:
Abstinence;Address;Affect;Aftercare;Age;Antiviral Agents;Appalachian Region;Blood;Caring;Case Management;Centers for Disease Control and Prevention (U.S.);Characteristics;Chronic;Chronic Hepatitis C;Clinical Research;Communities;Community Health;Complement;County;Data;Drug user;Enrollment;Generations;Genotype;Goals;Guidelines;HIV;Health;Health Services Accessibility;Hepatitis C;Hepatitis C Prevalence;Hepatitis C Therapy;Hepatitis C Transmission;Hepatitis C virus;Hepatology;Hospitals;Housing;Improve Access;Incidence;Individual;Infection;Insurance;Intervention;Jail;Kentucky;Letters;Liver diseases;Measures;Medicaid;Modeling;Needle-Exchange Programs;Nurse Practitioners;Opioid;Outcome;Participant;Pharmaceutical Preparations;Pike fish;Policies;Population;Prevalence;Primary carcinoma of the liver cells;Provider;Public Health;RNA;Research;Research Personnel;Resources;Rural;Rural Appalachia;Sampling;Science;Secure;Services;Specialist;Syringes;Tablets;Text;United States;Universities;Viral hepatitis;community intervention;cost;cost effective;cost effectiveness;follow-up;liver injury;mathematical model;medication compliance;medication-assisted treatment;opioid abuse;opioid use disorder;portability;prevent;recruit;research study;response;rural area;rural dwellers;rural setting;side effect;telehealth;treatment services;uptake;viral RNA;virology


application_id: 9792232
project_number: 5U01AA026934-02
project_title: Pilot Trial UO1 DUR-928
administering_ic: NIAAA
award_notice_date: 2019-07-25
opportunity_number: RFA-AA-18-005
application_type: 5
activity_code: U01
ic: AA
serial_number: 026934
program_official: GAO, PETER
project_start_date: 2018-09-25
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
25-hydroxycholesterol;ADD-1 protein;Acute;Acute Alcoholic Hepatitis;Acute Renal Failure with Renal Papillary Necrosis;Adrenal Cortex Hormones;Agonist;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Anorexia;Apoptosis;Biology;Cell Nucleus;Cell Survival;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Clinical Data;Cytoplasm;Data;Development;Diet;Disease;Dose;Drug Kinetics;Enzymes;FDA approved;Failure;Fatty acid glycerol esters;Fibrosis;Glucocorticoids;Glycols;Hepatic;Hepatocyte;Hepatomegaly;Histology;Hospitals;Human;Hydroxylation;Icterus;In Vitro;Infection;Infiltration;Inflammatory;Inflammatory Response;Injury;Intracellular Accumulation of Lipids;Knowledge;Life;Link;Lipids;Liver;Liver Regeneration;Malaise;Malnutrition;Metabolic Diseases;Mitochondria;Morbidity - disease rate;Natural regeneration;Organ;Pathway interactions;Patients;Pentoxifylline;Placebos;Prednisone;Prevalence;Safety;Signal Pathway;Signal Transduction;Sterols;Syndrome;Systemic Inflammatory Response Syndrome;Therapeutic Agents;Unspecified or Sulfate Ion Sulfates;base;effective therapy;high risk;improved;in vivo;lipid biosynthesis;lipid metabolism;liver cell proliferation;macrophage;mortality;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;open label;overexpression;pilot trial;pre-clinical;preclinical study;standard of care;sulfation;sulfotransferase;treatment guidelines


application_id: 9791137
project_number: 5U01AA026936-02
project_title: Lipid metabolites can both potentiate and treat alcoholic hepatitis
administering_ic: NIAAA
award_notice_date: 2019-07-25
opportunity_number: RFA-AA-18-003
application_type: 5
activity_code: U01
ic: AA
serial_number: 026936
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-09-22
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: JOSHI-BARVE, SWATI
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:
Abstinence;Acrolein;Acute Alcoholic Hepatitis;Address;Alcoholic Hepatitis;Alcoholic liver damage;Alcohols;Aldehydes;American diet;Arachidonate 15-Lipoxygenase;Attenuated;Bacteria;Biological Markers;Blood;Butyrates;Cell Death;Cell membrane;Cessation of life;Data;Development;Diet;Diet and Nutrition;Dietary Fats;Disease;Dose;Endotoxemia;Fatty acid glycerol esters;Free Radicals;Funding;Genetic;Health Care Costs;Heavy Drinking;Hepatocyte;Human;Inflammatory disease of the intestine;Injury;Institution;Intake;Intervention;Intestinal permeability;Investigation;Laboratories;Linoleic Acids;Lipid Peroxidation;Lipids;Liver;Liver diseases;Macronutrients Nutrition;Mediating;Membrane Lipids;Metabolism;Morbidity - disease rate;Mus;National Institute on Alcohol Abuse and Alcoholism;Nutritional;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Organ;Oxidative Stress;Oxides;Patient Care;Patients;Play;Polyunsaturated Fatty Acids;Production;Receptor Activation;Recovery;Research;Risk;Rodent;Rodent Model;Role;Sampling;Serum;Severities;Severity of illness;Smoking;Testing;Therapeutic;Tissues;Toll-like receptors;United States;Universities;Urine;Volatile Fatty Acids;adduct;alcohol research;cytokine;dysbiosis;endoplasmic reticulum stress;gut bacteria;gut microbiota;human subject;improved;liver injury;mortality;mouse model;nutrition;oxidation;polyunsaturated fat;pre-clinical;prevent;response;tributyrin


application_id: 9790920
project_number: 5R01AI137324-02
project_title: Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
administering_ic: NIAID
award_notice_date: 2019-08-06
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 137324
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2018-09-24
project_end_date: 2023-08-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 9620088
contact_pi: LI, BING
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:
SummaryPsoriasis is the most prevalent and intractable immune-mediated chronic inflammatory skin disease. It is clearthat dendritic cells (DCs) and keratinocytes in the skin tissues play a central role in the pathogenesis ofpsoriasis. The objectives of this proposal are to determine the role of epidermal fatty acid binding protein (E-FABP) in promoting psoriasis pathogenesis through simultaneously targeting both DCs and keratinocytes andin linking obesity-associated psoriasis development. E-FABP first cloned in psoriatic skin tissues (also knownas psoriasis associated FABP) has been identified as a critical regulator of both metabolic and inflammatorypathways. Our preliminary studies demonstrate that E-FABP is greatly upregulated in the skin tissue frompatients with psoriasis. Intriguingly deficiency of E-FABP confers protection from imiquimod (IMQ) or IL-23-induced psoriasis-like inflammation in mouse models. While obesity is associated with increased severity ofpsoriasis and poor responses to therapy the underlying mechanisms between obesity and psoriasis areunknown. While high fat diet (HFD) increases E-FABP expression in both DCs and keratinocytes and promotesobesity-associated chronic skin inflammation in wild type mice E-FABP deficiency protects mice against HFD-induced effects. All these data suggest that E-FABP may link obesity and psoriasis via regulating metabolismand function of DCs and keratinocytes. Thus we hypothesize that E-FABP as a new link underlying theobesity-psoriasis association promotes psoriasis pathogenesis through enhancing cellular metabolism andfunction of both DCs and keratinocytes. Therefore targeting E-FABP may represent a novel strategy forpsoriasis therapy. We design three specific aims (Figure A) to address our hypotheses. Specific Aim 1 willaddress how E-FABP regulates DC metabolism and function in psoriasis. We hypothesize that E-FABP linksFA metabolism and innate immune signaling in DCs and bridges innate and adaptive immune responses forpsoriasis pathogenesis. Specific Aim 2 will determine how E-FABP promotes keratinocyte aberrantmetabolism and differentiation in psoriasis. We will design experiments to test the hypothesis that E-FABPexpression in keratinocytes mediates innate signal-induced metabolic changes that are critical for abnormalkeratinocyte differentiation. Specific Aim 3 will examine whether E-FABP links the obesity/psoriasisassociation using our unique E-FABP global and conditional knock out mouse models and samples frompsoriasis patients. In summary this proposal will demonstrate a novel mechanism by which E-FABP promotespsoriasis pathogenesis and links obesity-associated psoriasis development. Thus targeting E-FABP may offera novel strategy for treatment of psoriasis and other inflammatory skin disorders.

project_terms:
Abnormal Keratinocyte;Address;Cell physiology;Cellular Metabolic Process;Chronic;Data;Dendritic Cells;Development;High Fat Diet;Human;Imiquimod;Immune;Immune signaling;Inflammation;Inflammatory;Knock-out;Knockout Mice;Link;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Mus;Obese Mice;Obesity;Pathogenesis;Pathway interactions;Patients;Physiological;Play;Protein Deficiency;Psoriasis;Role;Sampling;Severities;Signal Transduction;Skin;Skin Tissue;Testing;Wild Type Mouse;adaptive immune response;chronic inflammatory skin;design;experimental study;fatty acid-binding proteins;immunoregulation;innate immune function;interleukin-23;keratinocyte;keratinocyte differentiation;link protein;mouse model;novel;novel strategies;oxidation;protein expression;response;sensor;skin disorder;treatment strategy

public_health_relevance:
Project NarrativeData from this study are expected to establish E-FABP as a new player in psoriasis pathogenesis. Thisproposal will not only determine the cellular and molecular mechanisms by which E-FABP promotes psoriasispathogenesis but will also establish E-FABP as a new molecular link underlying obesity-associated psoriasisdevelopment.


application_id: 9789796
project_number: 5R21AG058006-02
project_title: Dystrophic functions of aged astrocytes following traumatic brain injury
administering_ic: NIA
award_notice_date: 2019-05-30
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AG
serial_number: 058006
program_official: WISE, BRADLEY C
project_start_date: 2018-09-30
project_end_date: 2021-05-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The broad and long-term goals of this proposal are to form a significant knowledge-basesurrounding the role aged astrocytes in the propogation of neurodegenerative sequelae after TBI.TBI in the aged population represents a significant unmet healthcare challenge as advancedaging is the greatest risk factor for acquiring a TBI and subsequently developingneurodegenerative disease such as dementia Alzheimers- and Parkinsons disease.Cumulatively the research design takes advantage of specific inflammatory hallmarks andfunctional modulators associated with dystrophic astrocytes in an attempt to delineate theirrespective contributions to neuronal pathology and cognitive dysfunction. Ultimately we willdetermine if harnessing astrocytes via novel AAV constructs in aged TBI models is associatedwith improving neuronal and cognitive outcome measures.

project_terms:
Acute;Adult;Affect;Age;Aging;Alzheimer's Disease;Animals;Astrocytes;Behavioral;Biological Response Modifiers;Brain;Brain Injuries;CCL2 gene;Cell Separation;Chemotactic Factors;Chronic;Cognitive;Data;Dementia;Development;Disease;Environment;Environmental Risk Factor;Epidemic;Experimental Designs;Financial Hardship;Flow Cytometry;Gene Expression;Genes;Glial Fibrillary Acidic Protein;Goals;Healthcare;Healthcare Systems;Impaired cognition;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Injections;Injury;Knowledge;Leukocytes;Light;Link;Magnetism;Measures;Mediating;Microglia;Modeling;Molecular;Molecular Profiling;Mus;Myelogenous;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Outcome;Outcome Measure;Parkinson Disease;Pathologic;Pathology;Pathway interactions;Peripheral;Population;Production;Radial;Recovery of Function;Research Design;Resolution;Risk;Risk Factors;Rodent;Role;Severities;Signal Transduction;Stimulus;Survivors;Synapses;Therapeutic;Therapeutic Intervention;Time;Traumatic Brain Injury;Traumatic Brain Injury recovery;United States;age effect;aged;aging brain;aging population;arm;cognitive function;controlled cortical impact;cytokine;demographics;improved;inflammatory milieu;injured;knowledge base;macrophage;monocyte;nano-string;neurotoxic;novel;prevent;recruit;response;response to injury;restoration;targeted treatment;therapeutic target;transcription factor;water maze;young adult

public_health_relevance:
Aging represents a significant healthcare challenge with respect to incidence and functional recovery from TBI. Currently little knowledge exists regarding the role of inflammation in the propagation of diminished functional recovery in aged-TBI models. The salient findings fromthis project will significantly contribute to fundamental the fundamental knowledge-base of the role of inflammation and aging as determinants of outcome following TBI.


application_id: 9789761
project_number: 271201600028C-7-0-2
administering_ic: NIDA
project_start_date: 2016-09-18
project_end_date: 2021-09-17
contact_pi_person_id: 14759366
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF Development & Manufacture of Pharmaceutical Products for the Treatment of Substance Abuse Disorder. NIDA Ref. No. N01DA-16-8926; POP: 09/18/2016 - 09/17/2021.

project_abstract:
Management of New Project Tasks:  As an incumbent contractor MPI offers experience for the management of new project tasks.Preformulation Studies I:  The investigations in this task will identify potential formulation/analytical challenges and/or development strategies.Preformulation Studies II:  The investigations will assist in the selection of appropriate excipients and provide insight into potential incompatibilities for the drug products.Dosage Form Development Studies:  Formulation studies will result in the appropriate design of useful preclinical and clinical formulations.

project_terms:
Clinical;Clinical Research;Communities;Contractor;Cyclic GMP;Development;Disease;Documentation;Dosage Forms;Drug Incompatibility;Ensure;Excipients;Formulation;Investigation;Investigational Drugs;Investigational New Drug Application;Label;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Production;Quality Control;Regulation;Research;Testing;United States Food and Drug Administration;Validation;design;experience;insight;novel therapeutics;pre-clinical;substance abuse treatment


application_id: 9788349
project_number: 5R01DA016718-12
project_title: Licit and Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2019-07-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: ANDERSON, ANN
project_start_date: 2004-07-10
project_end_date: 2023-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
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:
Absence of pain sensation;Alcohols;Alprazolam;Autopsy;Benzodiazepines;Carbon Dioxide;Cessation of life;Characteristics;Clinical;Cognitive;Comparative Study;Crossover Design;Data;Decision Making;Dose;Double-Blind Method;Drug Controls;Drug Interactions;Drug Kinetics;Drug usage;Enrollment;Ensure;Epidemic;Fentanyl;Guidelines;Health;Heroin;Hospitals;Human;Individual;Inpatients;Intervention;Knowledge;Laboratories;Laboratory Study;Measures;Medical;Metabolic Pathway;Morbidity - disease rate;Nature;Opioid;Opioid agonist;Outcome;Overdose;Oxycodone;Pain Disorder;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Physicians;Physiological;Placebos;Polypharmacy;Procedures;Property;Provider;Psychomotor Performance;Randomized;Recording of previous events;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Safety;Sedation procedure;Supervision;Surgeon;Surveys;Testing;Time;Toxicology;United States;Work;benzodiazepine abuse;cognitive performance;design;experience;experimental study;gabapentin;illicit drug use;illicit opioid;indexing;mortality;mortality risk;non-opioid analgesic;off-label use;opioid abuse;opioid misuse;opioid mortality;opioid overdose;opioid use disorder;overdose death;pain model;pain relief;participant safety;prescription opioid;recreational drug use;sedative;statistics;targeted agent;volunteer


application_id: 9787561
project_number: 5R44HL120370-03
project_title: Development of a TransApical to Aorta Double Lumen Cannula for a Neonate LVAD
administering_ic: NHLBI
award_notice_date: 2019-08-08
opportunity_number: PA-17-302
application_type: 5
activity_code: R44
ic: HL
serial_number: 120370
program_official: EVANS, FRANK
project_start_date: 2014-09-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1-CVRS-A(12)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Left ventricular assist device (LVAD) support allows the neonate with congenital heart disease orcardiomyopathy to grow to a larger body weight that is more feasible for complex surgical correction or hearttransplant. The Berlin Heart ExCOR is FDA-approved for pediatric LVAD application. Although this device isoutside the body the outflow graft may still create coronary artery/heart compression. Our ultimate goal is todevelop a less invasive and dependable LVAD system for the neonate as well as older pediatric patients. Theenabling technology is a double lumen cannula (DLC) which is inserted from the apex into the aorta. Coupledwith an existing blood pump this DLC withdraws blood from the LV and delivers blood into the aorta unloadingthe LV. Our DLC-based LVAD only requires a one site less invasive apex cannulation. The advantages are:1) no outflow graft and associated heart/coronary artery compression; 2) no need of cardiopulmonary bypassand associated blood transfusion; 3) reserves more invasive sternotomy for future complex heart surgery. Thistransapical to aorta (TAA) DLC enables a high performance paracorporeal/ extracorporeal LVAD and allowsaddition of a gas exchanger for cyanotic heart disease. Our Phase I study proved that the TAA DLC-basedneonate LVAD system was very easy to implant via a small left thoracotomy and efficiently unloaded the LV for6 hours with no increase in free hemoglobin and no decrease in hemoglobin and platelet counts. Phase IISBIR objective: Based on the Phase I results we will optimize the design and fabricate a final commercialquality TAA DLC prototype for even smaller neonate application and for 5 day survival lamb studies. SpecificAim 1: To design fabricate and bench-test the high efficiency commercial quality TAA DLC prototypefor smaller neonate application and for 5 day survival in vivo lamb studies. The TAA DLC will be made ofone piece reinforced polyurethane. Computational fluid dynamics will be used to optimize the DLC design. ADLC anchoring system will be also developed to secure TAA DLC on apex and chest wall for long-termambulatory use. A 13 Fr/10 Fr TAA DLC will be developed for 2-4 kg neonate lamb acute study and a 19 Fr/15Fr TAA DLC will developed for 4 week old lamb (20 kg) survival study. The final prototype will be tested forperformance reliability and hemolysis. Thirty day durability will be tested in 37% glycerin. Specific Aim 2: Totest new 13/10 Fr TAA DLC-based LVAD in 2- 4 kg neonate lamb (n=5). This 6 hour study is designed toprove TAA DLC suitable for clinical neonate LVAD application. We will investigate ease of TAA deploymentand in vivo performance as well as potential aortic valve obstruction by extension infusion cannula. SpecificAim 3: To test the TAA DLC prototype for 5 days LVAD application in 4 weeks old neonate lamb (n=5).The 4 week old lamb is still considered a neonate but almost fully weaned allowing us to perform 5 daysurvival study. This in vivo study will test performance reliability durability and biocompatibility. Upon thisSBIR grant completion the commercialized TAA DLC will provide a less invasive neonate LVAD.

project_terms:
Acute;Adult;Animals;Aorta;Apical;Berlin;Biotechnology;Blood;Blood Circulation;Blood Transfusion;Body Weight;Cannulas;Cannulations;Carbon Dioxide;Cardiac;Cardiac Surgery procedures;Cardiogenic Shock;Cardiomyopathies;Cardiopulmonary Bypass;Chest;Chest wall structure;Childhood;Clinical;Complex;Coronary artery;Coupled;Development;Devices;Eating;Engineering;Ensure;Enteral Nutrition;Excision;FDA approved;Food;Future;Gases;Glycerol;Goals;Grant;Heart;Heart Diseases;Heart Transplantation;Heart failure;Hemoglobin;Hemolysis;Hemorrhage;Hour;Implant;Incidence;Infection;Infusion procedures;Kentucky;Laboratory Animal Production and Facilities;Left;Liquid substance;Lung;Mediastinal;Milk;Morbidity - disease rate;Neonatal;Newborn Infant;Obstruction;Operative Surgical Procedures;Patients;Pediatrics;Performance;Phase;Platelet Count measurement;Polyurethanes;Positioning Attribute;Publications;Recovery;Research Support;Safety;Savings;Scientist;Secure;Sedation procedure;Site;Small Business Innovation Research Grant;Solid;Sternotomy;Surgeon;System;Technology;Testing;Thoracotomy;Transplantation;Universities;Ventricular;Weaning;Weight;aortic valve;artificial lung;base;biomaterial compatibility;blood pump;congenital heart disorder;design;experience;falls;feeding;implantation;in vivo;left ventricular assist device;mortality;multidisciplinary;neonate;novel;pediatric patients;performance tests;phase 1 study;prototype;research and development;respiratory

public_health_relevance:
We are proposing to develop a simple less invasive double lumen cannula-based left ventricular assist device(LVAD) for the neonate as well as older pediatric patients. The enabling technology is the novel double lumencannula which is coupled with a blood pump to form a LVAD system to provide total left ventricular supportthereby saving the lives of sick neonates and older pediatric patients. This neonate LVAD system will bridgethe patient to recovery transplant or further advanced heart surgery.


application_id: 9786727
project_number: 5K99DE028346-02
project_title: Polymicrobial Synergy between Treponema denticola and Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2019-07-23
opportunity_number: PA-18-398
application_type: 5
activity_code: K99
ic: DE
serial_number: 028346
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-09-17
project_end_date: 2020-03-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11206459
contact_pi: MILLER, DANIEL PATRICK
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPolymicrobial communities that exhibit synergistic pathogenicity cause periodontal disease one of the mostcommon infections of humans. As a model system for the study of polymicrobial synergy we are investigatingthe interactions of Treponema denticola and Porphyromonas gingivalis. Heterotypic communities develop asphysiologically compatible organisms modulate their own and their partners physiology resulting in enhancedfitness and virulence. Synergistic metabolism can reduce the nutrient requirements of the entire communitythereby increasing the pathogenic potential. T. denticola and P. ginigvalis display metabolic cross-feeding toenhance the growth of both bacteria. Additional bacterial members of the subgingival plaque community areknown to cooperate in metabolic exchanges. However the molecular details of metabolic cross-feeding and howit functions to drive pathogenicity are understudied. The overall premise of this study is to characterize themetabolic interactions between T. denticola and P. gingivalis to better understand the pathogenic potential of thecommunity. Aim 1 will evaluate how glycine is acquired and utilized as a carbon and energy source. Aim 2 willcharacterize the response of T. denticola to mutualistic metabolism by enhancing biofilm development andinvasion into gingival epithelial cells. Aim 3 will demonstrate that metabolic cross-feeding enhances thepathogenicity of T. denticola. Our overall long-term goal is to translate these novel molecular mechanisms intothe development of future therapeutic approaches targeting polymicrobial pathogenic communities. Thecandidate Dr. Miller has a longstanding interest in the microbiology of periodontal diseases. After completingthe mentored (K99) phase his goal is to become an assistant professor at a leading research university wherehe plans to continue his research on interbacterial interactions that promote periodontal diseases. This K99/R00proposal is designed to complement Dr. Millers previous research expertise and provide him with the opportunityto develop the necessary skills and experiences to become an independent research scientist. Dr. Miller willreceive additional training under the guidance of the primary mentor Dr. Richard Lamont and co-mentor Dr.David Scott. Both mentors were carefully selected for as they each contribute diverse yet complementaryexpertise for the successful completion of this research program. Additionally Dr. Miller has assembled acommittee of scientists with various backgrounds who will provide oversight and advise his scientific and careerdevelopment during his transition to independence.

project_terms:
Adherence;Alveolar Bone Loss;Bacteria;Biological Models;Carbon;Catabolism;Cell model;Cells;Chemotaxis;Communication;Communities;Community Developments;Complement;Complex;Development;Disease;Disease model;Energy-Generating Resources;Environment;Epithelial Cells;Exhibits;Future;Gingiva;Glycine;Goals;Growth;Human;Immune response;Infection;Inflammatory;Investigation;Link;Mediating;Mentors;Metabolic;Metabolism;Microbial Biofilms;Microbiology;Modeling;Molecular;Movement;Mus;Nutritional Requirements;Organism;Outcome;Pathogenicity;Periodontal Diseases;Periodontitis;Phase;Phenotype;Physiological;Physiological Processes;Physiology;Porphyromonas gingivalis;Research;Rodent Model;Role;Scientist;Signal Transduction;Signal Transduction Pathway;Source;Symbiosis;System;Therapeutic;Training;Translating;Treponema denticola;Universities;Virulence;bone loss;career development;cell motility;design;dysbiosis;experience;feeding;fitness;improved;in vivo;insight;interest;member;microbial community;novel;novel strategies;novel therapeutics;periodontopathogen;polymicrobial disease;prevent;professor;programs;response;skills;synergism;uptake

public_health_relevance:
Project NarrativePeriodontal diseases are one of the most common infections of humans and are the result of several compatiblebacterial species working synergistically to cause more severe disease. The goal of this study is to examinecooperative metabolism between two periodontal pathogens that promotes synergistic pathogenicity.Understanding polymicrobial metabolic communication and signaling is critical to development of noveltherapeutics or approaches to prevent polymicrobial diseases.


application_id: 9786054
project_number: 5F30DE028166-02
project_title: Regulation of ZEB1 by Porphyromonas gingivalis in gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2019-07-18
opportunity_number: PA-18-673
application_type: 5
activity_code: F30
ic: DE
serial_number: 028166
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-09-01
project_end_date: 2022-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14903180
contact_pi: FITZSIMONDS, ZACKARY R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryOral cancer is the 11th most frequently diagnosed cancer in the world and due to its late diagnosis it has anapproximately 50% survival rate after 5 years. Metastasis is meditated through Epithelial to MesenchymalTransition (EMT) which is the process by which epithelial cells lose their tight junctions and apical/basal polarityand shift to a more invasive mesenchymal phenotype giving the cancer cells systemic access through invasionof the bloodstream. EMT is mediated through several transcriptional factors however we will focus on ZEB1.Porphyromonas gingivalis is an oral obligate anaerobe that when present shifts the host/microbe relationshipfrom synergy to a more dysbiotic environment which contributes to periodontal disease. P. gingivalis has beenshown to invade gingival epithelial cells and once inside the cells can inhibit apoptosis ramp up the cell cycleand more recently by our lab has been shown to upregulate ZEB1. Although we are beginning to understand thepotential oncogenic role of P. gingivalis we do not currently know how ZEB1 is regulated by P. gingivalis ingingival epithelial cells. Our preliminary data suggests that this regulation is occurring through SMAD signalingregulation and through the long non-coding RNA ZEB1-AS1. SMAD signaling is a branch of the TGF-b signalingpathway which during embryonic development is responsible for producing mesenchymal cells from the initialepithelium. SMAD signaling occurs by phosphorylation of SMAD2/3 by the TGF-b receptor followed by theformation of a transcriptional regulatory trimer by SMAD2/3 and SMAD4 and finally nuclear localization andupregulation of ZEB1. Additionally ZEB1 can bind to SMAD2/3 and SMAD4 to form a ZEB1/SMAD trimer toregulate ZEB1 transcription. We have found that P. gingivalis upregulates the regulatory SMAD3 which suggestsP. gingivalis is able to intercept this pathway to upregulate ZEB1. We have also found that P. gingivalisupregulates ZEB1-AS1 which has been shown in hepatocarcinoma and esophageal squamous cell carcinomato directly upregulate ZEB1 and our preliminary data supports this as knocking down ZEB1-AS1 leads toabrogation of ZEB1 regulation by P. gingivalis in gingival epithelial cells. We will investigate mechanisms ofregulation by ZEB1-AS1 including direct promotion of gene expression in the nucleus through binding to P300and/or control of ZEB1 mRNA stability. EMT regulation is a complex process that involves integration of severalhost signaling pathways so we also suspect that ZEB1-AS1 will be integrated with SMAD signaling by potentiallyacting as a scaffold for SMAD3. Developing a better understanding of P. gingivalis mediated EMT will lay thefoundation for future studies to target these regulatory mechanisms for diagnosis and treatment and ultimatelyreduce the 50% chance of survival current patients have 5 years after diagnosis.

project_terms:
Amanitins;Anaerobic Bacteria;Apical;Apoptosis;Binding;Biopsy;Blood Circulation;Cancer Patient;Cell Cycle;Cell Cycle Progression;Cell Nucleus;Cells;Co-Immunoprecipitations;Complex;Data;Development;Diagnosis;E-Cadherin;E1A-associated p300 protein;Embryonic Development;Environment;Epidemiology;Epithelial;Epithelial Cells;Epithelium;Esophageal Squamous Cell Carcinoma;Family;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Germ Cells;Gingiva;Homeobox;Human;Immunofluorescence Immunologic;Immunohistochemistry;Immunoprecipitation;Intercept;Invaded;Knowledge;Laboratories;Lead;Literature;Luciferases;MADH2 gene;MADH3 gene;MADH4 gene;MADH6 gene;MADH7 gene;MMP9 gene;Malignant Neoplasms;Measures;Mediating;Mesenchymal;MicroRNAs;Migration Assay;Molecular;N-Cadherin;Neoplasm Metastasis;Nuclear;Oncogenic;Oral;Oral cavity;Pathway interactions;Patients;Periodontal Diseases;Periodontitis;Phenotype;Phosphorylation;Plasmids;Play;Porifera;Porphyromonas gingivalis;Primary carcinoma of the liver cells;Process;Property;Quantitative Reverse Transcriptase PCR;RNA;RNA Synthesis Inhibitors;Ramp;Regulation;Role;Sampling;Signal Pathway;Signal Transduction;Speed;Survival Rate;TGF Beta Signaling Pathway;Testing;Tight Junctions;Time;Tongue Neoplasms;Transcription Coactivator;Transcription Repressor/Corepressor;Transforming Growth Factor beta Receptors;Translating;Untranslated RNA;Up-Regulation;Western Blotting;Zinc Fingers;arm;cancer cell;cancer diagnosis;differential expression;dysbiosis;epithelial to mesenchymal transition;expression vector;host-microbe interactions;human tissue;knock-down;mRNA Expression;mRNA Stability;malignant mouth neoplasm;mouth squamous cell carcinoma;new therapeutic target;novel;novel diagnostics;novel therapeutics;outcome forecast;overexpression;prevent;promoter;recruit;response;scaffold;synergism;transcription factor;tumor

public_health_relevance:
Project NarrativeOral Cancer is the eleventh most frequently diagnosed cancer in the world and has approximately a 50% survivalrate 5 years post diagnosis. In this project we will study the intricate molecular interplay between Porphyromonasgingivalis and gingival epithelial cells and how this can lead to an environment conducive to cancer. This projecthas the potential to identify novel contributors to oral cancer and could potentially lead to novel therapeutics inthe future.


application_id: 9785371
project_number: 5R01AI140195-02
project_title: Innate immunity and inflammatory response of macrophages to Legionella infection
administering_ic: NIAID
award_notice_date: 2019-08-06
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 140195
program_official: ERNST, NANCY L
project_start_date: 2018-09-14
project_end_date: 2023-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adaptor Signaling Protein;Amylases;Animal Model;Anti-inflammatory;Attenuated;Bacterial Infections;Binding;Bypass;Case Study;Communities;Crystallization;Cytosol;Data;Dimensions;Exhibits;Glucose;Glycogen;Glycolysis;Growth;Human;Immune;In Vitro;Infection;Infection Control;Inflammatory;Inflammatory Response;Innate Immune Response;Knowledge;Legionella;Legionella pneumophila;Legionnaires' Disease;Lung;Lysosomes;Macrophage Activation;Mediating;Membrane;Metabolism;Morbidity - disease rate;Mus;Natural Immunity;Pathway interactions;Phenotype;Phosphotyrosine;Pneumonia;Proteins;Role;Side;Signal Transduction;Structure;Surface;Testing;Up-Regulation;Vacuole;aerobic glycolysis;arm;cytokine;diabetic patient;in vivo;macrophage;monocyte;mortality;mutant;novel;pathogen;pathogenic bacteria;response


application_id: 9783774
project_number: 5U01DK074007-14
project_title: University of Louisvilles Clinical Center in Gastroparesis Clinical Research Consortium
administering_ic: NIDDK
award_notice_date: 2019-08-23
opportunity_number: RFA-DK-16-010
application_type: 5
activity_code: U01
ic: DK
serial_number: 074007
program_official: SERRANO, JOSE
project_start_date: 2006-04-15
project_end_date: 2021-08-31
study_section: ZDK1-GRB-8(O2)S
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
project_abstract:
Gastroparesis is a disorder of gastric function characterized by delay in gastric emptying frequently associatedwith chronic nausea and vomiting early satiety postprandial fullness abdominal pain and malnutrition thatmay require nutritional support. Gastroparesis has a devastating impact on quality of life and predominantlyaffects younger women. In the past 5 years the Gastroparesis Clinical Research Consortium (GpCRC) hasmade a series of important contributions (see below) to improve our understanding of this disorder andadvancing the goals of patients physicians and the NIH for management of gastroparesis. Yet much remainsto be learned about its etiology natural history treatment strategies and clinical course whichis the rationale behind our response to the Continuation of the Gastroparesis Consortium RFA-DK-10-502. Thebiggest barrier to effective therapeutic approaches to gastroparesis is our lack of knowledge about either itspathogenesis or its pathophysiology. Further the correlation between the major symptoms such as nauseavomiting pain and current methods to measure change in gastric function (electrical motor activity mealemptying times) is poor at best. Finally we do not understand the long-term outcomes of these patients andwhether outcomes differ on the basis of etiology symptom severity and degree of emptying abnormalities.Consequently our approach to these patients is erratic and treatment has been empirical and only partiallyeffective if at all in relieving the major symptoms. The mission of the GpCRC is completely aligned with therecommendations of the National Commission on Digestive Diseases;5 specifically Research Goal 2.6 relatesto gastroparesis and states: "Understand the noxious visceral signaling causing nausea and vomiting related togastric neuro-electrical and/or motor dysfunction and the bi-directional brain-gut interactions. Gastroparesisprovides an archetypal disease for investigative inquiry. Chronic vomiting a debilitating and socially isolatingdigestive symptom creates potentially life-threatening disruptions in fluid and electrolyte homeostasis andcompromises nutritional status. Chronic nausea remains a significant hidden disability. Nausea and vomitingusually occur in tandem and overlay with other Gl symptoms as well as presenting in numerous digestivediseases. More effective treatments for nausea and vomiting would improve quality of life and physicalfunctioning in a vast array of illnesses. A paucity of research exists for defining peripheral noxious signaling ofnausea and vomiting related to primary Gl motor/sensory disturbances."The Specific Aims of this proposal are to: 1. Complete the current GpCRC registry; 2. To continue the GpCRCcore lab responsible for anatomic and related studies on tissue sample of patients with Gp syndromes; 3.Continue pharmacologic studies on patients with Gp syndromes; 4. Continue device studies for patients withthe Gp syndromes; and 5. A new multicenter study based on several GpCRC ancillary studies and other pilotdata.

project_terms:
Abdominal Pain;Affect;Anatomy;Ancillary Study;Area;Chronic;Clinical;Clinical Research;Complex;Data;Databases;Devices;Digestive System Disorders;Disease;Effectiveness;Electric Stimulation;Electrolytes;Electrophysiology (science);Enteral;Etiology;Functional disorder;Gastric Emptying;Gastroparesis;Goals;Grant;Health;Homeostasis;Inflammatory;Insulin Infusion Systems;Knowledge;Life;Liquid substance;Malnutrition;Measures;Methods;Mission;Motor;Motor Activity;Multicenter Studies;Natural History;Nausea;Nausea and Vomiting;Nortriptyline;Nutritional Support;Nutritional status;Outcome;Pain;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmacology Study;Physical Function;Physicians;Psychological Impact;Publications;Publishing;Quality of life;Recommendation;Registries;Research;Safety;Sensory;Series;Severities;Signal Transduction;Stomach;Symptoms;Syndrome;Time;Tissue Sample;Treatment Efficacy;United States National Institutes of Health;Universities;Visceral;Vomiting;Work;aprepitant;base;disability;early satiety;effective therapy;glucose monitor;gut-brain axis;improved;motor disorder;novel strategies;recruit;response;social;treatment strategy;young woman

public_health_relevance:
This proposal aims to gather a better understanding of gastroparesis which is a devastating disorder inpredominantaly younger women. This is a continuation of the Gastroparesis Clinical Research Consortium(GpCRC). The GpCRC has made a series of important contributions to improve our understanding of thisdisorder and advancing the goals of patients physicians and the NIH for management of gastroparesis. Thisproposal continues the mission of the GpCRC to better understand and treat this disorder.


application_id: 9783687
project_number: 261201300013I-4-26100007-1
project_title: SEER LINKED VIRTUAL TISSUE REPOSITORY (VTR)
administering_ic: NCI
project_start_date: 2015-09-11
project_end_date: 2019-03-31
contact_pi_person_id: 14259412
contact_pi: TUCKER, THOMAS
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
funding_mechanism: R and D Contracts
project_abstract:
The National Cancer Institute Surveillance Epidemiology and End Results (SEER) Program is interested in developing a SEER-linked Virtual Tissue Repository (VTR). A SEER VTR with its population representativeness and large sampling frame would be a unique resource for assembling robust collections of biospecimens even for rare tumors and outcomes. SEER demographic and clinical data can be augmented with custom annotation of data including detailed chemotherapy time to recurrence and body mass index.The objectives of the VTR Pilot Study are to assess the ability of SEER RegistriesTo serve as a resource for biospecimen researchTo locate cases with biospecimens in pathology laboratories and determine the requirements to retrieve those biospecimensTo provide custom annotation of specified data itemsThe VTR Pilot will also capture costs to identify and annotate these biospecimens.

project_terms:
Body mass index;Clinical Data;Collection;Custom;Data;Laboratories;Link;National Cancer Institute;Outcome;Pathology;Pilot Projects;Population;Recurrence;Registries;Research;Resources;SEER Program;Sampling;Specific qualifier value;Time;Tissues;chemotherapy;cost;interest;rare cancer;repository;virtual


application_id: 9783186
project_number: 1R56AG060608-01
administering_ic: NIA
award_notice_date: 2018-09-13
opportunity_number: PAR-17-314
application_type: 1
activity_code: R56
ic: AG
serial_number: 060608
program_official: ANDERSON, DALLAS
project_start_date: 2018-09-15
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-N(55)R]
contact_pi_person_id: 7875188
contact_pi: JIANG, YANG
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-09-15
project_title:
Predictive Neurophysiological Biomarkers for Risk of Alzheimers Disease (AD) and Related Dementia (ADRD) Induced Cognitive Impairment in Sino-US Cohorts

project_abstract:
ABSTRACTAlzheimers disease (AD) and related dementia (ADRD) are irreversible progressive brain disorders thatslowly destroy memory thinking and other neuro-cognitive skills in older adults. More people die from ADRDin the US than breast and prostate cancer combined. Medical care for about 50 million ADRD cases worldwideis an enormous financial burden equivalent to the 18th largest economy in the world. A major challenge forcountries like China is that with industrialization and rapid growth of the economy the prevalence of unhealthylifestyle and metabolic factors has increased which contributes to an increased rate of ADRD. Chinese have amuch higher risk of stroke and diabetes than Americans and these traits have not been well-studied inconnection with ADRD. Predictive and affordable biomarkers for ADRD risk are needed to tackle dementia in inlow- and middle-income regions. The goal of this Sino-US study is to validate neurophysiological biomarkersfor individualized prediction of MCI in Kentucky and Beijing cohorts using an ultimate clinical outcomemeasure conversion to mild cognitive impairment (MCI) an early stage of ADRD. The cross-national researchteam will test the central hypothesis that healthy older individuals who have MCI-like neurophysiological brainsignatures have high-risk of MCI conversion induced by ADRD. The hypothesis is based on promising resultsfrom our longitudinal pilot study i.e. individuals who convert to MCI have MCI-like brainwave signatures about5 years before conversion. The team has previously identified unique brainwaves during the Bluegrassmemory task in patients with amnestic MCI (aMCI; memory-related impairment) using the Kentucky cohort.Here matching standardized protocols will be applied in the two Sino & US cohorts. The NIA-funded Universityof Kentucky Alzheimers Disease Center has been following a cohort of 500 cognitively intact older adults toautopsy for the past 35 years along with multiple ADRD biomarker banks. The Beijing cohort is part of anational longitudinal cohort for ADRD early detection. Specifically Aim 1 will determine whether individualbaseline memory-related neuromarkers are predictors for MCI conversion. Neurocognitive measures will becollected at the baseline and 3-year follow-up in both healthy cohorts to test the hypothesis that the convertersto MCI already show abnormality of brain activity patterns at the baseline. Aim 2 will determine whether theneuromarkers differentiate between amnestic versus non-amnestic MCI. The hypothesis that the distinctneurophysiological responses are associated with vascular diseases induced MCI will be tested. Aim 3 willvalidate the neuromarkers by correlating them with established ADRD biomarkers and neuropsychologicalscores from baseline to follow-up. Using gold-standard AD biomarkers the hypothesis that individuals who areA-positive have an increased rate of longitudinal change in neurophysiological biomarkers. Thesenoninvasive and affordable risk markers once validated and replicated will be suitable for large-scale use. Thepropose study will build a base for research networking that can be used for future prevention and treatment.

project_terms:
Age;Alzheimer disease detection;Alzheimer's Disease;Alzheimer's disease risk;American;Amyloid beta-Protein;Appointment;Autopsy;Biological Markers;Blood Vessels;Brain;Brain Diseases;Caring;Cerebrospinal Fluid;China;Chinese People;Clinical;Clinical assessments;Cognitive;Cognitive aging;Country;Data Collection;Dementia;Diabetes Mellitus;Diagnosis;Dyslipidemias;Early Diagnosis;Early Intervention;Elderly;Electrophysiology (science);Frequencies;Funding;Future;Goals;Gold;Health;Hypertension;Impaired cognition;Impairment;Income;Individual;Industrialization;Kentucky;Life Style;Ligands;Longitudinal Studies;Longitudinal cohort;Malignant neoplasm of prostate;Measures;Medical;Medical Care Costs;Memory;Mental disorders;Metabolic;Methods;Modeling;Neurocognitive;Neuropsychology;Obesity;Outcome Measure;Patients;Pattern;Pilot Projects;Poa plant;Positron-Emission Tomography;Prevalence;Prevention;Protocols documentation;Radioactive;Reporting;Research;Research Design;Risk;Risk Factors;Risk Marker;Screening procedure;Site;Specificity;Spinal Puncture;Standardization;Stroke;System;Testing;Thinking;Time;Universities;Vascular Dementia;Vascular Diseases;World Health Organization;Yang;amnestic mild cognitive impairment;base;brain abnormalities;care costs;cohort;common treatment;early detection biomarkers;effective therapy;follow-up;high risk;low and middle-income countries;malignant breast neoplasm;mild cognitive impairment;nerve injury;neurophysiology;personalized predictions;rapid growth;response;rural area;skills;social;stroke risk;tau Proteins;trait;trend;unhealthy lifestyle

public_health_relevance:
PROJECT NARRATIVEMedical care cost for about 50 million people with Alzheimers disease and related dementia worldwide is anenormous financial burden equivalent to the 18th largest economy in the world and we have developed newpredictive and noninvasive memory-related brain signatures for dementia risk in cognitively normal olderadults which is critical for early intervention before diagnosis. Once validated in the US cohort and replicatedin a Chinese cohort the personalized and affordable screening tools will be suitable for large-scale useworldwide. The propose study will build a base for research networking that can be used for future preventionand treatment.


application_id: 9783096
project_number: 1R56AG057589-01A1
administering_ic: NIA
award_notice_date: 2018-09-19
opportunity_number: PAR-15-358
application_type: 1
activity_code: R56
ic: AG
serial_number: 057589
suffix: A1
program_official: PETANCESKA, SUZANA
project_start_date: 2018-09-30
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-E(56)R]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
The surprising impact of APOE alleles on gut microbiome: does altering the microbiome reduce AD risk?

project_abstract:
This application focuses on the interface between Alzheimer's disease (AD) genetics inflammation and thegut microbiome. APOE alleles are the most impactful AD genetic risk factor and modulate several pathwaysincluding inflammation. Microglial function itself is clearly linked to AD risk by TREM2 and CD33 singlenucleotide polymorphisms (SNP)s. Hence agents that modulate microglial function are excellentcandidates to modulate AD risk. Recently a gut microbiome metabolite short chain fatty acids (SCFA)shave emerged as promoting microglial function. The possibility that the microbiome may modulate AD issupported by findings that AD-related phenotypes are reduced in APP mice treated with antibiotics ormaintained in a gnotobiotic environment. Here we propose a novel link between AD genetics and the gutmicrobiome. This study resulted from a serendipitous meeting at an APOE conference with RichardGuerrant who described his studies showing that gut health in humans and mice is associated with APOEgenotype; when humans in a third world environment suffer from diarrheal outbreaks APOE4 carriers haveless severe disease and better outcomes relative to APOE3 individuals. Similar findings were found in thewidely used APOE targeted replacement (TR) murine model wherein APOE4 was associated with animproved response to gastrointestinal infection and undernourishment compared to APOE3. The possibilitythat APOE alters the gut microbiome is also supported by a report of microbiome variation between wild-type and APOE deficient mice. Considering these findings we propose the global hypothesis that APOEalleles modulate the gut microbiome and that this contributes to APOE allelic effects on AD risk. Asa corollary we further hypothesize that changing the microbiome to that of APOE2 individuals willreduce AD risk. To evaluate this scientific premise we submit the following Specific Aims: 1. Test thehypothesis that the gut microbiome is associated with APOE genotype in a murine model. Ourpreliminary results show a striking stepwise pattern in microbiome profiles from APOE2 to APOE3 toAPOE4 with Ruminococcaceae highest in APOE2. 2. Test the hypothesis that the gut microbiome isassociated with APOE genotype in humans. 3. Test the hypothesis that the gut microbiomesassociated with APOE2 and APOE4 have opposing effects on AD-related phenotypes. If successfulwe expect this interdisciplinary proposal to demonstrate (i) an APOE2-associated microbiome amelioratesAD-related phenotypes and (ii) dietary resistant starch mimics APOE2 effects on the microbiome SCFAlevels microglial activation amyloid burden and cognition in a murine model. Since resistant starch hasbeen shown to increase Ruminococcaceae and SCFAs in humans such results may be directly translatableto human trials.

project_terms:
APP-PS1;Alleles;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Amyloid;Antibiotics;Bacteria;Behavior;Biological;Blood;Cerebrovascular Circulation;Cognition;Communities;Data;Diet;Disease;Disease Outbreaks;Elderly;Environment;Family;Genetic Diseases;Genotype;Gnotobiotic;Health;Human;Individual;Inflammation;Intestines;Lactobacillaceae;Link;Metabolism;Mus;Neurologic;Outcome;Pathology;Pathway interactions;Pattern;Peripheral;Phenotype;Plasma;Production;Reporting;Resistance;Single Nucleotide Polymorphism;Starch;TREM2 gene;Testing;Variant;Volatile Fatty Acids;amyloid pathology;base;cohort;gastrointestinal infection;genetic risk factor;gut microbiome;improved;indexing;inflammatory marker;meetings;microbiome;microbiome alteration;microbiota transplantation;mouse model;novel;operational taxonomic units;response;symposium;volunteer

public_health_relevance:
This project will evaluate whether APOE alleles the primary genetic risk factor for Alzheimer's disease (AD)modulate the gut microbiome in mice and humans. In turn we will evaluate whether these microbiomedifferences impact cognition inflammation and AD associated pathology in a murine model of AD.


application_id: 9783064
project_number: 3R01CA193220-04S2
project_title: Ubiquilin1 regulates EMT and metastasis of human lung adenocarcinoma
administering_ic: NCI
award_notice_date: 2018-09-19
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: CA
serial_number: 193220
suffix: S2
program_official: LIN, ALISON J
project_start_date: 2015-08-07
project_end_date: 2020-07-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9743542
contact_pi: BEVERLY, LEVI J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality worldwide causing more than 1.3 million deaths each year. Over ~700000 of these victims succumb to lung cancers that have alterations in one of the genes encoding members of the Ubiquilin family (UBQLN). The UBQLN family of proteins consists of 5 family members (UBQLN1-4 and UBQLNL) which all contain ubiquitin-like (UBL) and ubiquitin-associated domains (UBA). There is very limited data on biological processes regulated by UBQLN proteins. A direct role for UBQLN proteins in human cancer has not previously been examined. The goal of this proposal is to understand how disruption of UBQLN1 or UBQLN2 contributes to the metastatic progression of human lung adenocarcinoma. The ultimate goal of this project is to identify the cellular processes altered specifically in cancers that harbor loss of UBQLN function. The preliminary data in this proposal are the first to suggest that UBQLN loss is capable of directly altering processes involved in metastatic progression of human lung cancer. We demonstrate that loss of UBQLN1 or UBQLN2 increases EMT migration and invasion of transformed and non-transformed lung epithelial cells and that UBQLN1 regulates multiple pathways known to be critical in human lung cancer including IGF1R mTOR MYC and ERK. We propose to examine in detail how UBQLN1 and UBQLN2 regulate key steps of metastatic progression in vitro as well as determine if UBQLN1 loss alters the in vivo kinetics of metastatictumor progression. Importantly we have observed that one allele of UBQLN1 or UBQLN2 is lost in over 50% of human lung adenocarcinomas. The data gained from this application will determine if cancers harboring altered UBQLN function represent a novel subset of lung cancers and if the expression of UBQLN family members can be used as a predictive biomarker to determine which patients are more likely to succumb to metastatic lung cancer. By understanding how alterations in UBQLN1 signaling contributes to metastatic progression we may be able to target these downstream pathways specifically in tumors with altered UBQLN1 function to block metastasis thus potentially affecting millions of lung cancer patients in the coming decades.

project_terms:
Adenocarcinoma;Adenocarcinoma Cell;Affect;Alleles;Amino Acids;Back;Biochemical;Biological;Biological Assay;Biological Process;CRISPR/Cas technology;Cancer Etiology;Cancer Patient;Cancer cell line;Cell Line;Cell physiology;Cells;Cessation of life;Client;Data;Diagnosis;Disease;Disseminated Malignant Neoplasm;Engineering;Epithelial Cells;FRAP1 gene;Family;Family member;Future;Genes;Genetic Engineering;Goals;Growth;Human;Human body;IGF1R gene;In Vitro;Individual;Kinetics;Laboratories;Link;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metastatic Neoplasm to the Lung;Metastatic to;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Pathway interactions;Patients;Phenotype;Play;Primary Neoplasm;Process;Property;Protein Family;Proteins;Recurrence;Role;Sampling;Signal Pathway;Signal Transduction;Site;Staging;Therapeutic;Transgenic Mice;Tumor Burden;UBA Domain;UBQLN1 gene;Ubiquitin;Xenograft Model;Xenograft procedure;base;cancer cell;cell motility;epithelial to mesenchymal transition;experimental study;in vivo;in vivo Model;insight;member;metastatic process;migration;mortality;mouse model;mutant;neoplastic cell;novel;predictive marker;protein function;public health relevance;small hairpin RNA;success;therapeutic target;tumor;tumor progression;tumorigenesis;ubiquilin

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Lung cancer is a leading cause of cancer mortality throughout the world and adenocarcinoma sub-type of non-small cell lung cancer (NSCLC) now accounts for nearly 40% of all diagnosed lung cancer cases. This proposal seeks to advance our understanding of human lung cancer by examining how the novel family of proteins the Ubiquilins (UBQLN) contributes to (NSCLC) in vitro and in vivo. Using cultured human adenocarcinoma cell lines human lung adenocarcinoma cell lines primary human lung cancer samples and oncogene-driven mouse models of NSCLC we propose to characterize the role that UBQLN proteins plays in the genesis of human NSCLC.


application_id: 9782341
project_number: 4R00NS097638-03
administering_ic: NINDS
award_notice_date: 2018-11-30
opportunity_number: PA-15-083
application_type: 4
activity_code: R00
ic: NS
serial_number: 097638
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-15
project_end_date: 2021-11-30
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 9428270
contact_pi: CHERRA, SALVATORE JAMES
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-12-01
project_title:
Understanding the molecular mechanisms that maintain excitation-inhibition balance in neural circuits

project_abstract:
Many neurological disorders are associated with an imbalance between excitatory and inhibitory (E/I) neuronal signaling. The nervous system normally maintains an E/I balance by regulating the number or strength of synaptic connections between neurons. Neurons in the human brain are outnumbered nearly ten to one by non-neuronal glial cells which provide support for neuronal function. While maintaining the richness of neuronal signaling the reduced cellular complexity of the roundworm Caenorhabditis elegans (C. elegans) makes it an excellent model system to study E/I balance. The overall goal of this proposal is to elucidate how non-neuronal cells and neurons interact to regulate E/I balance. By understanding how glial cells and neurons interact this project will provide novel insights into the treatment and management of neurological disorders such as epilepsy autism spectrum or schizophrenia. C. elegans will be used as a model for thisproject for the following reasons: 1) its nervous system has been fully mapped 2) it's been widely used to study how neuronal networks are formed and maintained 3) the genes and molecular mechanisms that regulate nervous system function are conserved with humans and 4) it is easy to manipulate through genetic techniques. For these reasons C. elegans provides a simple model to study the molecular mechanisms that underlie neurological disorders associated with E/I imbalance. The goals of this study will be accomplished through the following specific aims: Aim 1: Determine how the two immunoglobulin domain transmembrane protein ZIG-10 regulates the phagocytosis pathway to balance excitatory and inhibitory neurotransmission using electron microscopy and electrophysiology. Aim 2: Elucidate the ZIG-10 signaling pathway in maintaining synaptic connections using genetic cell biologic and biochemical approaches. Aim 3: Determine how a novel transporter regulates neuronal activity and E/I balance in vivo. The completion of this proposal will provide a deeper understanding of how neurons and non-neuronal glia cooperate to regulate E/I balance. Additionally this study will uncover the mechanism(s) affecting aberrant neuronal activity associated with neurological disorders. Finally this project will identify potential therapeutic targets for novel treatments of autism spectrum disorders epilepsy schizophrenia and related neurological diseases.The mentored portion of this award will take place at the University of California San Diego under the mentorship of Dr. Yishi Jin. UCSD and the superb neuroscience faculty provide an excellent environment for the proposed research which employs electron microscopy and electrophysiology under the guidance of Dr. Mark Ellisman and Dr. Darwin Berg leaders in their respective fields. Dr. Jin a world-renowned geneticist and neurobiologist will provide both the resources and guidance to accomplish the research proposed during the mentored phase. Through hands-on training and formal meetings with Dr. Ellisman and Dr. Berg I will learn how to use new techniques to dissect the structure-function relationship of the nervous system. This will allow me to understand how neurons and non-neuronal cells interact to regulate E/I balance in the short-term. During the independent phase applying these new techniques with my expertise in molecular and cellular biology andbiochemistry will allow me to decipher how the E/I balance is regulated during normal and disrupted during disease states. Overall the research and career development proposed during this award will enable me to uncover the mechanisms that regulate E/I balance that is disrupted in many neurological disorders including epilepsy schizophrenia and autism spectrum.

project_terms:
Affect;Award;Behavior;Behavioral;Biochemical;Biochemistry and Cellular Biology;Biological;Biological Assay;Biological Models;Brain;CRISPR/Cas technology;Caenorhabditis elegans;California;Cells;Cholinergic Receptors;Cholinesterase Inhibitors;Convulsions;Data;Disease;Electron Microscopy;Electrophysiology (science);Environment;Epidermis;Epilepsy;Equilibrium;Faculty;Frequencies;Future;Genes;Genetic;Genetic Screening;Genetic Techniques;Genomics;Glutamates;Goals;Human;Immunoglobulin Domain;Immunoglobulins;In Vitro;Integral Membrane Protein;Investigation;Laboratories;Learning;Mammals;Maps;Mediating;Mentors;Mentorship;Modeling;Molecular;Molecular and Cellular Biology;Mutation;Nematoda;Nervous System Physiology;Nervous system structure;Neuroglia;Neurons;Neurosciences;Neurotransmitters;Pathway interactions;Patients;Phagocytosis;Phase;Phenotype;Physiological;Process;Protein Binding Domain;Proteins;RNA interference screen;Regulation;Research;Resistance;Resources;Schizophrenia;Seizures;Signal Pathway;Signal Transduction;Singlet Oxygen;Structure-Activity Relationship;Symptoms;Synapses;System;Techniques;Testing;Training;Universities;Use of New Techniques;autism spectrum disorder;career development;cholinergic;density;gain of function mutation;in vivo;insight;meetings;member;mutant;nervous system disorder;neural circuit;neurotransmission;new therapeutic target;novel;research and development;synaptic function;synaptogenesis;transmission process

public_health_relevance:
Neurological disorders such as autism spectrum epilepsy and schizophrenia are associated with imbalances in neuronal activity within the brain. There are currently no cures or long-term therapies to assuage the symptoms. This project will uncover mechanisms that regulate how neuronal activity is balanced and will provide novel therapeutic targets for future treatments.


application_id: 9781860
project_number: 1R56AG055596-01A1
project_title: mTOR activation and the pathogenesis of Alzheimer disease in Down syndrome
administering_ic: NIA
award_notice_date: 2018-09-19
opportunity_number: PA-16-160
application_type: 1
activity_code: R56
ic: AG
serial_number: 055596
suffix: A1
program_official: OPANASHUK, LISA A
project_start_date: 2018-09-30
project_end_date: 2020-08-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: HEAD, ELIZABETH
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
7. Project Summary/AbstractDown syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over300000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficientneuropathology for a diagnosis of Alzheimer disease (AD) in their 40th year. However dementia may notdevelop until up to a decade later and some people remain cognitively intact. We hypothesize that mTORsignaling is a key component to aging in DS and may be targeted with an appropriate intervention. First wewill compare brain samples from people with DS over a wide range of ages to controls for changes in themTOR pathway and downstream sequelae. Second we will isolate exosomes from plasma samples from acohort of people with DS that are being followed longitudinally to measure mTOR associated pathways and linkthese changes to cognitive decline and brain magnetic spectroscopy. These studies have the potential toidentify novel biomarkers and clinical outcome measures for AD in people with DS. Identifying a role for themTOR pathway in the pathogenesis of AD in DS may provide novel targets for a preventative approach to slowor halt the development of AD neuropathology and significantly improve the quality of life of DS individuals aswell as provides insights into AD itself.

project_terms:
Adult;Age;Age of Onset;Aging;Alzheimer's Disease;American;Amyloid beta-Protein;Autophagocytosis;Autopsy;Biological Markers;Blood specimen;Brain;Brain imaging;Chromosomes Human Pair 21;Clinical;Clinical Research;Clinical Trials;Cognition;Cognitive;Data;Dementia;Dependence;Development;Diagnosis;Disease;Down Syndrome;Event;FDA approved;FRAP1 gene;Functional disorder;Future;Genetic Diseases;Goals;Human;Impaired cognition;Individual;Intellectual functioning disability;Intervention;Intervention Studies;Knowledge;Link;Longevity;Longitudinal Studies;Magnetic Resonance Spectroscopy;Magnetism;Measures;Memory;Memory impairment;Metformin;Molecular;Nerve Degeneration;Neurobiology;Neurons;Outcome;Outcome Measure;Oxidation-Reduction;Pathogenesis;Pathologic;Pathway interactions;Peripheral;Persons;Pharmaceutical Preparations;Plasma;Play;Proteins;Proteomics;Quality of life;Role;Sampling;Signal Transduction;Sirolimus;Spectrum Analysis;Synapses;Testing;United States;Western Blotting;age related;brain metabolism;brain tissue;cohort;exosome;glucose metabolism;improved;insight;insulin signaling;neurochemistry;neuropathology;novel;novel marker;optimal treatments;overexpression;prevent;virtual

public_health_relevance:
8. Project NarrativeThe proposed study will identify early changes in mTOR activation that may signal changes in cognition andbrain metabolism reflecting Alzheimer disease (AD) in adults with Down syndrome (DS). Studies of braintissues and exosomes isolated from blood samples from people with DS will be combined with brain imagingdata. The combined studies will provide novel opportunities to implement DS appropriate preventativeapproaches to slow or halt the development of AD neuropathology and significantly improve the quality of lifeof DS individuals who are vulnerable to neurodegeneration..


application_id: 9779524
project_number: 3R01EY012354-17A1S1
project_title: Isolation of Congenital Stationary Night Blindness Genes
administering_ic: NEI
award_notice_date: 2018-09-17
opportunity_number: PA-16-160
application_type: 3
activity_code: R01
ic: EY
serial_number: 012354
suffix: A1S1
program_official: GREENWELL, THOMAS
project_start_date: 1999-02-01
project_end_date: 2022-01-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
other_pis: HASAN, NAZARUL ;MCCALL, MAUREEN A
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decreaserelease of the neurotransmitter glutamate from cone and rod photoreceptor terminals and decreases in lightincrease its release. These changes in synaptic glutamate concentration are detected by two classes of bipolarcells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitterchanges also are detected by horizontal cells that provide lateral transmission in the form of feedback andfeedforward inhibition.There are two classes of bipolar cells hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilizeionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropicglutamate receptor mGluR6 that signals to TRPM1 depolarizing in response to a light flash. Defects intransmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6NYX TRPM1 GPR179 and LRIT3 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largelyunknown. The long term goal of this project is study the molecular interactions between LRIT3 and known andknown components DBC signal transduction components. The specific aims are: 1) determine the function ofLRIT3 domains on rod and cone DBC mGluR6 signalplex assembly and signaling and 2) Define proteininteractions required for DBC assembly and synaptic function and 3) determine the function of LRFN1 and 2on cone synapse function.At the completion of this project we will have characterized the function of LRIT3 and how it interacts withcurrently unknown presynaptic partners. Further we will have identified new candidate genes for congenitalstationary night blindness.

project_terms:
Binding;Biological Assay;Brain;CRISPR/Cas technology;Candidate Disease Gene;Cells;Complex;Cone;Defect;Disease;Electroretinography;Elements;Feedback;Future;GNB5 gene;Gene Proteins;Genes;Glutamate Receptor;Glutamates;Goals;Immunohistochemistry;Kainic Acid Receptors;Knockout Mice;Label;Lateral;Leucine-Rich Repeat;Light;Mediating;Metabotropic Glutamate Receptors;Methods;Morphology;Mus;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Pathway interactions;Photoreceptors;Proteins;Research;Retina;Retinal;Retinal Cone;Role;Side;Signal Transduction;Structure;Synapses;Synaptic Transmission;TRPM1 gene;Testing;Therapeutic;Vertebrate Photoreceptors;Vision;cell assembly;ganglion cell;horizontal cell;human disease;in vivo;light intensity;member;mutant;neurotransmitter release;novel;patch clamp;postsynaptic;postsynaptic neurons;presynaptic;receptor;response;retinal rods;synaptic function;transmission process;visual coding

public_health_relevance:
Vision requires a light signal be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The diseases being studied are referred to as congenital stationary night blindness. The studies in this proposal will characterize the nature of the defects and determine the function of newly identified proteins critical for normal vision which will set the stage of therapeutic approaches in the future.


application_id: 9778990
project_number: 3P42ES007380-21S3
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2018-09-10
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S3
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2020-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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
project_abstract:
DESCRIPTION (provided by applicant) Due to their relative chemical stability and ubiquity in the environment chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) and trichloroethylene (TCE) pose significant health risks and enduring remediation challenges. For example extensive PCB contamination at the Paducah Gaseous Diffusion Plant the largest Superfund site in Kentucky is of major concern for its health consequences. The University of Kentucky Superfund Research Center (UK-SRC) provides a focused transdisciplinary research training and translation environment to address human health challenges associated with such exposures. Preliminary findings suggest that nutrition-based concepts and exercise can markedly influence the mechanisms of toxicity of chlorinated organics. Indeed healthful nutrition/nutritional components may provide a platform to develop primary prevention strategies for diseases associated with environmental toxic insults while also providing the basis for new risk assessment paradigms. Further novel iron-based nano-structured capture/sensing and remediation systems based on biomimetic binding domains and functionalized/responsive membrane platforms offer potential for sustainable advances in technical capability for site remediation. The UK-SRC proposes to reduce risk by: 1) developing lifestyle-related modulators of environmental disease and elucidating relevant protective mechanisms and 2) developing technologically effective and economically efficient methods for capture/sensing and remediation of PCBs. Three biomedical and two environmental science projects a Research Support Core and Administrative Research Translation Community Engagement and Training Cores collectively advance understanding of toxicant-induced mechanisms of disease introduce sustainable approaches for remediation and enhance stakeholder and community capacity to act. Biomedical projects focus on models of inflammation and associated changes in redox status and inflammatory cytokines in vascular (Project 1) fetal (Project 2) and adipose (Project 3) tissues with relevance to atherosclerosis insulin resistance/diabetes and obesity. Environmental science projects employ nanomaterials to create selective PCB-binding domains with high affinity and selectivity for PCBs (Project 4) and a functionalized polymer immobilized membrane platform to support PCB dechlorination (Project 5). All Projects focus on common PCB toxicants. Biomedical scientists with the Research Support Core also evaluate byproducts of environmental science projects for unintended effects. Use of PCBs as a model contaminant will advance understanding of inflammatory diseases associated with exposure to persistent chlorinated organic pollutants. Research results will lead to evidence-based multidirectional information/education technology transfer training policy and translational activities via UK-SRC cores. Expected outcomes include positive lifestyle interventions across the lifespan for populations at risk and advanced technical capacity to reduce public health risks.

project_terms:
Address;Adipose tissue;Affinity;Atherosclerosis;Binding;Biological;Biological Markers;Biology;Biomedical Research;Biomimetics;Blood Vessels;Chemicals;Collaborations;Communities;Coupled;Detection;Diabetes Mellitus;Diet;Diffusion;Disease;Drug Metabolic Detoxication;Ecology;Education;Environment;Environmental Health;Exercise;Exposure to;Health;Human;Immobilization;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Iron;Kentucky;Lead;Learning;Life Style;Longevity;Mass Spectrum Analysis;Mediator of activation protein;Membrane;Mentorship;Methods;Modeling;Monitor;National Institute of Environmental Health Sciences;Nutritional;Obesity;Outcome;Oxidation-Reduction;Oxidative Stress;Pigments;Plants;Policies;Policy Developments;Polychlorinated Biphenyls;Polymers;Population;Populations at Risk;Prevention strategy;Primary Prevention;Process;Production;Public Health;Recommendation;Research;Research Design;Research Project Grants;Research Support;Research Training;Risk;Risk Assessment;Risk Management;Role;Rotation;Scientist;Site;Statutes and Laws;Students;Superfund;System;Techniques;Technology;Technology Transfer;Tissues;Toxic effect;Toxin;Training;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;Work;base;biomedical scientist;chemical stability;computer infrastructure;cytokine;data management;dechlorination;development policy;evidence base;experience;fetal;global environment;improved;in vivo Model;innovative technologies;insight;lifestyle intervention;manufacturing process;nanomaterials;nanostructured;novel;nutrition;organic contaminant;particle;pollutant;programs;public health relevance;remediation;science education;sensor technology;superfund chemical;superfund site;technology development;tool;toxicant;translational engagement

public_health_relevance:
Public Health Relevance: The proposed research may lead to novel dietary and exercise recommendations contaminant detection and remediation technology development and policy recommendations for populations at risk to improve the health of people residing near Superfund sites. Outcomes should provide important technology tools and insights for primary stakeholders to use in improving Superfund site risk assessment and management specifically related to the class of compounds known as chlorinated organics.


application_id: 9778135
project_number: 1R43GM133247-01
project_title: Enhancing transgenic laboratory animal genotyping
administering_ic: NIGMS
award_notice_date: 2019-03-21
opportunity_number: PA-18-574
application_type: 1
activity_code: R43
ic: GM
serial_number: 133247
program_official: WANG, FEI
project_start_date: 2019-04-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-H (15)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYParaTechs mission is to develop innovative technologies and bring to market novel products to enablediscovery and development in the area of biotechnology. Our expertise with laboratory animal models providesthe basis for a new genotyping process for use in the biomedical industry starting with a 3Rs alternative forrodent genotyping. Ultimately our vision is to expand the technology to personalized genotyping so that anindividual can test for the presence or absence of a gene in the privacy of their home.This new system is called structured nucleotide-nanoparticle advanced genotyping or SNNAG. SNNAG is anovel analytical method based upon the properties of nucleic acid hybridization to detect specific gene(s) andultra-sensitive detection enabled by fluorescent mesoporous silica nanoparticles (mSNPs). This does not relyon existing techniques (PCR and DNA sequencing) but utilizes the selective properties of nucleic acidhybridization between tissue DNA samples and fluorescent oligonucleotide labeled mSNPs to support directgenotypic detection. The SNNAG system will be coupled with a new system for oral sampling of tissue inrodents. This novel device the LolliswabTM entices rodents to deposit tissue on the device eliminating theneed for toe tail or ear samples for genotyping.Genotyping workflows entail tissue collection DNA isolation signal amplification (by PCR and/or sequencing)and detection. The Lolliswab collection device and SNNAG detection system will provide fast easy and morehumane genotyping to laboratory animal research. This novel system will provide an alternative to painfultissue sampling procedures in rodents and pair it with an easy and ultra-sensitive detection system. Our short-term project goal of improving laboratory animal genotyping is both a significant research and commercial goaland a key step toward validating and reaching the ultimate goal of this research and commercialization effort:establishing personalized genotype detection.

project_terms:
Address;Animal Experimentation;Animals;Area;Binding;Biological Assay;Biotechnology;Clip;Collection;Complex;Consumption;Coupled;DNA;DNA sequencing;Data;Deposition;Detection;Development;Devices;Double-Stranded RNA;Ear;Elements;Equilibrium;Genes;Genotype;Goals;Growth;Home environment;Hour;Human;Hybrids;Individual;Industry;Insecta;Label;Laboratory Animal Models;Laboratory Animals;Laboratory Research;Link;Methods;Microscope;Mission;Names;Nucleic Acid Hybridization;Nucleotides;Oligonucleotides;Oral;Pain;Phase;Pregnancy Tests;Privacy;Procedures;Process;Property;Research;Research Personnel;Respondent;Rodent;Sampling;Scourge;Signal Transduction;Silicon Dioxide;Solid;Speed;Structure;Surveys;Swab;System;Tail;Techniques;Technology;Testing;Time;Tissue Banks;Tissue Sample;Tissues;Toes;Transgenic Organisms;United States National Institutes of Health;Vision;analytical method;animal care;base;commercialization;design;experience;improved;innovation;innovative technologies;insight;nanoparticle;new technology;novel;oral tissue;sensor

public_health_relevance:
Narrative.The genotyping market is undergoing explosive growth with annual increases in excess of 22% with revenuesof 6.12 B in 2015 and projected at 17.0 B by 2020. However there are privacy concerns that are not welladdressed by industry as well as opportunities to improve its speed and accessibility. Our long-term goal is todevelop a personalize genotyping system so that individuals can test for presence or absence of a specific genein their homes.!


application_id: 9775557
project_number: 2R44NS084701-03A1
project_title: Catheter for Large Volume Intraparenchymal Brain Therapies
administering_ic: NINDS
award_notice_date: 2019-08-31
opportunity_number: PA-18-574
application_type: 2
activity_code: R44
ic: NS
serial_number: 084701
suffix: A1
program_official: TRZCINSKI, NATALIE KATHERINE
project_start_date: 2014-09-30
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
contact_pi_person_id: 12334483
contact_pi: ABRAMOV, VASILIY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 786659719
primary_uei: CBL5M5DKH3K7
duns_number: 786659719
uei: CBL5M5DKH3K7
fips: US
organization_id: 10021015
organization_name: CREOSALUS, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402046033
organization_country: UNITED STATES
project_abstract:
Project AbstractSignificance: Neurodegenerative and malignant diseases along with injury of the central nervous system(CNS) affect millions of Americans. These injuries and diseases are often devastating and difficult to treat andeffective drug delivery remains a significant challenge. Infusion of drugs into the brain parenchyma usingconvection-enhanced delivery (CED) allows direct treatment of lesions circumventing the blood brain barrier.In particular new treatments and diseases call for large regions of brain to be subjected to therapeutic doses.Multiple clinical trials have been conducted using CED to deliver large volumes of chemotherapy andimmunotoxins in patients with gliomas but actual drug delivery to the tumor has been poor for several reasonsincluding the unpredictable dispersion of the drug in the tissue. These adverse events result in reducedefficacy and increased toxicity. To overcome the limitations associated with conventional CED catheters inheterogeneous tissue the Applicants have developed a Porous Brain Infusion Catheter (PBIC) for improvedCNS drug delivery. Hypothesis: The Applicant proposes that Phase II research will create a multi-capabilityPBIC optimized for small to large volume distribution and short to long durations for multiple (small to large)neurological therapeutics. Phase I Results: Applicant has developed a PBIC that met Aim 1 designrequirements as demonstrated in Aim 3 design verification testing that has been passed. In Aim 2 in vivoporcine testing the PBIC demonstrated superior large volume distribution (p=.03) compared to a standard endport brain infusion catheter such that the PBIC is expected to be used in brain tumor human studies by aleading brain tumor center. Specific Aims: With the proposed Phase II PBIC research the Applicants expectto verify and validate an optimized PBIC design that provides broad CED performance capabilities to CNSincluding chronic delivery to enhance commercialization potential. Aim 1: The PBIC design will be optimizedfor small to large volume distribution for multiple therapeutics and short to long durations. The resulting PBICdesign verification and performance characterization testing in vitro and in vivo will be completed to allow forhuman use and product approvals. Aim 2: The PBIC design will be validated for human use with therapeuticsin non-clinical models including chronic delivery with the infusion of a chemotherapeutic in companion dogbrain tumor patients demonstrating the IND enabling capabilities of the PBIC for a broad range of therapeuticadministration protocols. These Aim 2 studies will reduce PBIC clinical risk and are expected to acceleratecustomer human study adoption.

project_terms:
Acute;Address;Adoption;Adverse event;Affect;American;Animals;Anti-Mullerian Hormone Receptor Type II;Award;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Brain region;Canis familiaris;Catheters;Central Nervous System Agents;Chronic;Clinical Research;Clinical Trials;Companions;Convection;Data;Disease;Dose;Drug Delivery Systems;Elements;Evaluation;Experimental Models;FDA approved;Family suidae;Glioma;Human;Immunotoxins;Implant;Implantable Pump;In Vitro;Infusion procedures;Injury;Investigation;Kentucky;Lesion;Letters;Malignant - descriptor;Mechanics;Medical center;Minnesota;Modeling;Nerve Degeneration;Neuraxis;Neurologic;Neurosciences;Patients;Performance;Pharmaceutical Preparations;Phase;Preparation;Primary Brain Neoplasms;Product Approvals;Protocols documentation;Research;Research Personnel;Small Business Innovation Research Grant;Sterility;Study Section;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Tracer;Treatment Efficacy;Universities;Virginia;biomaterial compatibility;brain parenchyma;central nervous system injury;chemotherapy;clinical efficacy;clinical risk;commercial application;commercialization;design;human model;human study;improved;in vivo;interest;novel;safety study;standard of care;technological innovation;tumor

public_health_relevance:
Project NarrativeEffective drug delivery of large volumes of solutions containing therapeutic agents into the brain remains asignificant obstacle to achieving clinical efficacy of therapies for injuries neurodegenerative and malignantdiseases affecting the central nervous system (CNS). The Applicant has developed novel porous brain infusioncatheters which demonstrate more uniform and better distribution of infusates into CNS tissue as compared tostandard of care catheters. In this project bench and animal studies will be conducted including designverification testing to generate data for product and clinical study approvals.


application_id: 9775083
project_number: 9R44MH122117-02A1
administering_ic: NIMH
award_notice_date: 2019-07-29
opportunity_number: PA-18-574
application_type: 9
activity_code: R44
ic: MH
serial_number: 122117
suffix: A1
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2016-04-15
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZRG1 IMST-B (12)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_title:
An Innovative Device Integrating Cryopreservation Storage and Artificial Insemination of Mouse Sperm

project_abstract:
SUMMARYParaTechs Corporation aims to provide researchers with advanced technology and methods to simplifyprocedures for laboratory animal models. While actively supporting efforts to reduce replace and refine animaluse ParaTechs provides safe and efficient alternatives for surgical procedures. We have already brought tomarket a nonsurgical embryo transfer device (NSETTM) which replaces surgical embryo transfers with anonsurgical method that takes only seconds and does not require anesthesia. We have developed a newprotocol for non-surgical artificial insemination (AI) of mice which replaces existing protocols for surgical AI andis a technical advancement for existing nonsurgical AI protocols. We plan to use this newly developed protocolto revolutionize the process of archiving and global distribution of mouse models through a novel spermcryopreservation and strain recovery system.The use of mouse strains in research is one of the most important tools used to study mammalian gene function.While hundreds of thousands of mouse strains have been catalogued and cryopreserved sharing of strains isbecoming increasingly difficult as regulatory constraints and the cost of shipping live animals increase. We cansolve this problem and provide a technically superior alternative with the cryopreservation and insemination (C&I)device. This system will integrate storage and shipment of cryopreserved sperm with non-surgical AI. The devicewill be suitable for storage of cryopreserved sperm will be shippable will allow viable sperm recovery uponthawing and then will be used directly for non-surgical AI. This device will eliminate the need to perform in vitrofertilization (IVF) upon thawing of cryopreserved sperm; greatly reducing the number of mice required for theprocedure and replacing a surgical method of artificial insemination both of which promote animal health andwelfare.Therefore the goals of this project are to develop protocols for the C&I device to optimize efficiency and ease ofuse to test the parameters required for storage and shipping and expand utility of the device to embryo storageand transfer. This new technological breakthrough will provide an alternative to cryorecovery of mouse strainsby in vitro fertilization methods the currently preferred but technically challenging and labor intensive strainrecovery method. In doing so the C&I device will provide a substantial cost savings to researchers and aconvenient method for shipping and strain recovery. The C&I device will replace a technically challenging andlabor intensive recovery method culminating in a fast and easy way to share research models betweeninstitutions around the world.

project_terms:
Address;Age;Anesthesia procedures;Animal Experimentation;Animal Model;Animal Welfare;Animals;Archives;Artificial Insemination;Biotechnology;Breeding;Businesses;Catalogs;Cohort Studies;Collaborations;Communities;Consumption;Core Facility;Cost Savings;Cryopreservation;Development;Devices;Disease;Dry Ice;Embryo;Embryo Transfer;Fertilization in Vitro;Funding Opportunities;Genetic Drift;Goals;Health;Individual;Insemination;Institution;Laboratories;Laboratory Animal Models;Laboratory Animal Production and Facilities;Laboratory Animals;Laboratory Procedures;Laboratory Research;Laboratory mice;Liquid substance;Methods;Missouri;Modeling;Mouse Strains;Mus;Natural Disasters;Nitrogen;One-Step dentin bonding system;Operative Surgical Procedures;Phase;Pregnancy Rate;Price;Problem Solving;Procedures;Process;Protocols documentation;Recovery;Research;Research Personnel;Resources;Services;Shipping;Ships;Small Business Innovation Research Grant;Sperm Transport;System;Technology;Testing;Time;Transgenic Organisms;United States National Institutes of Health;Universities;Uterus;Workload;animal care;animal colony;animal facility;biobehavior;cost;design;falls;gene function;human disease;improved;innovation;mouse model;novel;preservation;pup;repository;sperm cell;sperm cryopreservation;sperm viability;tool;welfare

public_health_relevance:
NARRATIVEThe ability to genetically modify the laboratory mouse is now producing an ever-rising number of increasinglyvaluable and unique strains to investigate human disease. While maintaining these mouse strains has becomea significant budgetary commitment cryopreservation of strains in sperm repositories has proven successful asa means to permanently and economically preserve them. ParaTechs is developing a cryopreservation andinsemination (C&I) device for the purpose of integrating cryopreservation storage shipping and strain recoveryby non-surgical artificial insemination; providing a fast convenient and easy to use method in mice at aconsiderably reduced cost.


application_id: 9774640
project_number: 3R01HL139047-01A1S1
project_title: Remote Hind Limb Ischemia Mechanism of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2019-05-17
opportunity_number: PA-18-586
application_type: 3
activity_code: R01
ic: HL
serial_number: 139047
suffix: A1S1
program_official: SCHWARTZ, LISA
project_start_date: 2018-07-01
project_end_date: 2022-06-30
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anti-inflammatory;Antioxidants;Apoptotic;Attenuated;Biochemical;Biology;Blood;Bone Marrow Stem Cell;Cardiac;Cardiac health;Coronary heart disease;Cystathionine;DNA;Data;Diabetes Mellitus;Endocrine;Enzymes;Epigenetic Process;Exercise;Functional disorder;Future;Gases;Genes;Goals;Heart;Hematopoietic Stem Cell Mobilization;Hindlimb;Homocysteine;Hormones;Hydrogen Sulfide;Hyperhomocysteinemia;Hypermethylation;Incidence;Injury;Ischemia;Knowledge;Laboratories;Ligation;Limb structure;Lyase;Manuscripts;Measures;Mitochondria;Modification;Molecular Genetics;Muscle;Muscle function;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Oxygen Consumption;Physiological;Production;Protocols documentation;Recovery;Research;Resources;Risk;Site;Skeletal Muscle;Stress;Techniques;Testing;Translational Research;Work;Writing;cardioprotection;diabetic;effective therapy;exosome;experience;femoral artery;gene induction;heart function;improved;in vivo;ischemic conditioning;meetings;mitochondrial metabolism;peer;skeletal;symposium


application_id: 9774540
project_number: 3R01EY026158-03S1
project_title: Cone Rescue in Retinitis Pigmentosa
administering_ic: NEI
award_notice_date: 2018-09-19
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: EY
serial_number: 026158
suffix: S1
program_official: NEUHOLD, LISA
project_start_date: 2016-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(04)S]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: MCCALL, MAUREEN A
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractA major cause of blindness in North America is hereditary retinal degeneration and RetinitisPigmentosa (RP) is the leading cause. RP is a group of inherited diseases characterized bythe onset of night blindness the early loss of the peripheral visual field and ultimately theloss of central vision. The most common form of autosomal dominant form of RP is causedby a Pro23His mutation in rhodopsin that results in retinal degeneration  i.e. P23Hretinopathy. We have created and characterized a miniature pig model of P23H retinopathyto investigate therapeutic options to prevent or delay the onset of visual loss.Multiple therapeutic approaches have been or are being considered to prevent/delay theprogression of RP including cell-based gene and drug therapies. Gene transfer in Leber'sCongenital Amaurosis (LCA) a small subset of RP patients shows very strong therapeuticpromise. That said gene therapy for other forms of RP faces several challenges includingthe wide variety of mutations associated with the disease. Cellbased transplantation of rodphotoreceptors derived from a number of sources seeks to reverse the progression of RP.Although the early stage of RP is marked by the onset of rod degeneration in mid-peripheral retina only in the late stages of the disease when retinal degenerationapproaches the macula and cone degeneration ensues do most patients find themselveswith a severe visual handicap. It also is well established that in RP cone survival dependson normal rods. We have preliminarily observed that transplanted rod photoreceptorsderived from pig induced Pluripotent Stem Cells (iPSCs) injected beneath the retina in ourpig model of P23H retinopathy will rescue cones morphologically and functionally in the areacentralis (analogous to the macula in man). We will confirm this observation explore thesynergistic effect of neuroprotection with rod derived cone viability factor (RdCVF) andfurther investigate the mechanism of cone loss in our model. Our studies have the potentialto prevent the onset of functional blindness in the majority of patients with RP not onlythose with the P23H mutation.

project_terms:
ARHGEF5 gene;Adult;Animal Model;Area;Binding;Birth;Blindness;Cell Differentiation process;Cell Transplants;Cells;Color Visions;Cone;Disabled Persons;Disease;Electrophysiology (science);Endoplasmic Reticulum;Evaluation;Face;Family member;Family suidae;Gene Transfer;Genes;Glucose;Hereditary Disease;Inherited;Label;Leber's amaurosis;Light;Mitochondria;Modeling;Molecular Conformation;Morphology;Mus;Mutation;Neuroprotective Agents;Night Blindness;North America;Opsin;Patients;Peripheral;Pharmacotherapy;Population;Prevention;Process;Reading;Resolution;Retina;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinal Pigments;Retinitis Pigmentosa;Rhodopsin;Rod Outer Segments;Series;Source;Starvation;Stem cell transplant;Symptoms;TXN gene;Therapeutic;Time;Transplantation;Vertebrate Photoreceptors;Vision;Visual;Visual Fields;base;fetal;gene therapy;glucose transport;glucose uptake;hereditary blindness;in vivo;induced pluripotent stem cell;macula;man;mutant;neuroprotection;overexpression;prevent;restoration;retinal rods;sensor;synergism

public_health_relevance:
Project NarrativeFunctional blindness in Retinitis Pigmentosa (RP) the most common form of hereditaryblindness is ultimately caused by the loss of central vision late in the course of disease from theloss of cone photoreceptors. We propose to transplant rod precursors derived from iPSC(induced Pluripotent Stem Cells) as well as a neuroprotective factor (rod-derived cone viabilityfactor  RdCVF) in our pig model of the most common form of RP to preserve/rescue conesfrom dying. Our ultimate aim is to prevent functional blindness accompanying the late stages ofRP in man.0925-0001/0002 (Rev. 08/12) Page Continuation Format Page


application_id: 9773116
project_number: 5R25GM125680-02
project_title: Interactive Mentoring to Enhance Research Skills (IMERS)
administering_ic: NIGMS
award_notice_date: 2019-07-19
opportunity_number: PAR-17-070
application_type: 5
activity_code: R25
ic: GM
serial_number: 125680
program_official: SESMA, MICHAEL A
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: ZGM1-TWD-7(IP)
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
other_pis: SPEAR, BRETT
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Active Learning;Address;Award;BRAIN initiative;Behavior;Biomedical Research;Communities;Consultations;Coupled;Development;Discipline;Diverse Workforce;Educational workshop;Enrollment;Event;Extramural Activities;Faculty;Foundations;Funding;Future;Goals;Grant;Health;Human;Individual;Institution;Kentucky;Laboratories;Malignant Neoplasms;Mentors;Mentorship;Minority;Minority-Serving Institution;Mission;Modeling;Motivation;Outcome;Participant;Personal Satisfaction;Productivity;Research;Research Personnel;Research Project Grants;Research Support;Research Training;Resource Development;Role;Running;Science;Scientific Advances and Accomplishments;Series;Site;Statistical Data Interpretation;Students;Teacher Professional Development;Time;Training;Training and Education;Underrepresented Minority;Underrepresented Students;United States;United States National Institutes of Health;Universities;Writing;base;career;cohort;data management;demographics;design;education research;experience;faculty research;innovation;interest;minority scientist;minority undergraduate;next generation;outreach;post-doctoral training;precision medicine;programs;research and development;skill acquisition;skills;skills training;student mentoring;student training;success;symposium;therapy development;training opportunity


application_id: 9773114
project_number: 5R01GM126181-03
project_title: Chronic muscle weakness in sepsis survivors
administering_ic: NIGMS
award_notice_date: 2019-08-16
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 126181
program_official: ZHAO, XIAOLI
project_start_date: 2017-09-15
project_end_date: 2021-08-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this project is to identify sub-cellular and molecular mechanisms of skeletal muscledysfunction that are responsible for chronic weakness in sepsis survivors. Using the knowledge obtained thisproject will elucidate potential therapeutic interventions targeting post-sepsis chronic muscle weakness. Over 1million sepsis survivors are now discharged from the hospital every year and a majority of these survivorsreport reduced quality of life due to considerable muscle weakness lasting for years after hospital discharge.However the lack of an appropriate animal model has been a critical barrier to identifying the changes whichpersist long after recovery from sepsis. We recently developed a new mouse model that has enabled us toevaluate long-term muscle quality and function in severe sepsis survivors. Our preliminary studies demonstratethat sepsis-surviving mice exhibit significant skeletal muscle weakness even after bacterial infection andinflammation are resolved and muscle mass is recovered giving us the unique opportunity to evaluatemolecular mechanisms of muscle weakness beyond the muscle wasting phenotype. Skeletal muscles fromthese sepsis-surviving mice also show histological abnormalities significant nitro-oxidative damage andprofound structural and functional defects in mitochondria. These preliminary results support our centralhypothesis that sepsis-induced oxidative damage causes mitochondrial dysfunction and sarcomeric proteindamage both of which remain long after sepsis recovery and these are the major contributors to the sustainedskeletal muscle weakness in sepsis survivors. Specific Aims to test the hypothesis are: (1) To determinemitochondrial damage and dysfunction in sepsis-surviving mice; (2) To investigate sarcomeric protein damageand its causal mechanisms in sepsis-surviving mice; and (3) To formulate therapeutic strategies to amelioratepost-sepsis chronic muscle weakness.

project_terms:
Acute;Animal Model;Antibiotics;Antioxidants;Atrophic;Bacterial Infections;Chronic;Defect;Development;Electron Microscopy;Exhibits;Functional disorder;Goals;Histologic;Hospitals;Incidence;Individual;Infection;Inflammation;Innate Immune Response;Kinetics;Knowledge;Life;Life Style;Liquid substance;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Multienzyme Complexes;Mus;Muscle;Muscle Proteins;Muscle Weakness;Muscular Atrophy;Mutant Strains Mice;Oxidative Stress;Oxygen Consumption;Pathology;Patients;Phase;Phenotype;Proteins;Protocols documentation;Public Health;Quality of life;Recovery;Reporting;Resuscitation;SOD2 gene;Sepsis;Skeletal Muscle;Structure;Survivors;Testing;Therapeutic;Therapeutic Intervention;Transgenic Mice;clinically relevant;effective therapy;mitochondrial dysfunction;mortality;mouse model;muscle form;novel therapeutics;oxidative damage;septic patients;skeletal muscle weakness

public_health_relevance:
PROJECT NARRATIVEThis project is relevant to public health because it will enhance our understanding of the mechanisms for post-sepsis chronic muscle weakness and allow us to elucidate a novel therapeutic strategy which would helpsepsis patients to return to a more productive and fulfilling lifestyle.


application_id: 9772994
project_number: 5R01CA196634-05
project_title: Improving chemotherapy of castration-resistant prostate cancer
administering_ic: NCI
award_notice_date: 2019-07-05
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 196634
program_official: FORRY, SUZANNE L
project_start_date: 2019-01-15
project_end_date: 2021-07-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Improving chemotherapy of castration-resistant prostate cancerAbstractBecause prostate cancer (PCa) requires androgen for development androgen ablation (castration) is theprimary treatment for patients with late stage PCa. However recurrent tumors arise within 2 years whereasandrogen receptor (AR) signaling has been inappropriately restored and the disease enters a stage calledcastration-resistant prostate cancer (CRPC). Docetaxel is the standard treatment for CRPC patients withlimited success. Therefore it is urgent to understand mechanisms of docetaxel so novel avenues can bedeveloped to increase its efficacy. It was recently found that the nuclear localization of AR is microtubuledynamics dependent and that the anti-tumor effect of docetaxel in CRPC is largely due to its inhibition of ARnuclear import. However the detailed molecular mechanisms behind these intriguing observations are stillelusive. The long-term goals of this study are to provide novel approaches to overcome docetaxel resistanceof CRPC. Polo-like kinase 1 (Plk1) a critical regulator in many cell cycle events is elevated in PCa and linkedto tumor grades. The objective here is to define the role of Plk1 in activating AR signaling and to examinewhether its inhibition can enhance the efficacy of docetaxel in CRPC. Clip-170 and p150Glued two regulators ofmicrotubule dynamics were recently identified as novel Plk1 substrates. The central hypothesis of the proposalis that Plk1-associated activity towards Clip-170 and p150Glued increases microtubule dynamics resulting inconstitutive activation of AR signaling and development of docetaxel resistance. This hypothesis will be testedby pursuing three specific aims  (1) to test how Plk1 phosphorylation of Clip-170 and p150Glued contributes todocetaxel resistance in CRPC cells; (2) to analyze whether Plk1-associated kinase activity contributes todocetaxel resistance in CRPC in mice; and (3) to ask whether a combination of Plk1 inhibition and docetaxelis a novel avenue for treatment of CRPC. These complementary aims will be accomplished using biochemicalanalyses of signaling intermediates and employing genetic strategies with inducible PCa mouse modelsculture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first toprobe the importance of Plk1 to the AR signaling and to examine how Plk1 induces docetaxel resistance inCRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1activates AR; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1as a critical therapeutic target to enhance the efficacy of docetaxel. The research is innovative as it approachesthe disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely toregulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies byidentifying the key regulator of the AR signaling that is critical for generating and maintaining the CRPCphenotype.

project_terms:
Ablation;Affect;Agreement;Androgen Receptor;Androgens;Apoptosis;Binding;Biochemical;Cancer Patient;Castration;Cell Cycle;Cell Nucleus;Cells;Clinical;Clinical Research;Clip;Cytoplasm;Data;Development;Disease;Event;Fostering;Genetic;Genetically Engineered Mouse;Goals;Health;Human;In Vitro;Interphase;Investigation;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Microtubule Depolymerization;Microtubule Stabilization;Microtubules;Mission;Mitotic;Molecular;Mus;Nuclear;Nuclear Import;Nuclear Receptors;Outcome;PLK1 gene;PTEN gene;Patient-Focused Outcomes;Patients;Pharmacology;Phenotype;Phosphorylation;Phosphorylation Site;Phosphotransferases;Public Health;RNA Splicing;Receptor Activation;Receptor Signaling;Recurrent tumor;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Time;Transactivation;Tumor-Derived;Variant;Work;Xenograft Model;Xenograft procedure;antitumor effect;beta Tubulin;cancer cell;castration resistant prostate cancer;chemotherapy;design;docetaxel;event cycle;improved;innovation;mouse model;mutant;novel;novel strategies;overexpression;predictive marker;prevent;prostate cancer cell;prostate cancer progression;receptor function;response;standard care;success;therapeutic target;tumor


application_id: 9772771
project_number: 3OT2OD024898-01S1
administering_ic: OD
award_notice_date: 2018-09-12
opportunity_number: RFA-RM-15-018
application_type: 3
activity_code: OT2
ic: OD
serial_number: 024898
suffix: S1
program_official: QASHU, FELICIA M
project_start_date: 2017-09-20
project_end_date: 2020-08-31
study_section: Anatomical and Functional Mapping of the Innervation of Marjor Internal Organs[AFMI(53)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adverse effects;Affect;Animal Model;Animals;Anodes;Anti-Cholinergics;Anus;Autonomic Dysreflexia;Bladder;Bladder Control;Bladder Dysfunction;Body Weight;Cardiovascular system;Caregivers;Caring;Catheterization;Catheters;Cathodes;Chronic;Clinic;Clinical;Collaborations;Country;Data;Dependence;Development;Devices;Disease;Electric Stimulation;Electrodes;Family suidae;Feasibility Studies;Female;Foundations;Frequencies;Future;Gender;Goals;Health;Healthcare Systems;Human;Impairment;Implant;Increased frequency of micturition;Individual;Injury;Intervention;Intestines;Kentucky;Knowledge;Lead;Lesion;Life;Location;Locomotor training;Long-Term Effects;Lower urinary tract;Manometry;Manuals;Maps;Measurable;Measurement;Measures;Modeling;Morbidity - disease rate;Motor;Movement;Neuronal Plasticity;Operative Surgical Procedures;Organ;Paralysed;Participant;Patients;Peripheral;Pharmaceutical Preparations;Pharmacology;Phase;Physiologic pulse;Pilot Projects;Predisposition;Publications;Quality of life;Questionnaires;Rattus;Rehabilitation therapy;Research;Residual volume;Risk;Rodent;Safety;Scientific Advances and Accomplishments;Scientist;Sensory;Severities;Sex Functioning;Societies;Source;Specific qualifier value;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Stents;Techniques;Technology;Testing;Therapeutic;Time;Training;Translating;Translations;United States;Urethra;Urinalysis;Urinary tract infection;Urination;Urologic Diseases;Width;base;clinical application;clinically relevant;cohort;cost;diaries;dosage;experience;experimental study;functional gain;improved;innovation;life time cost;male;multidisciplinary;neural circuit;neuroregulation;novel;pressure;prevent;programs;rehabilitation engineering;restoration;statistics;symptom treatment;treadmill;urinary;urologic;voltage;white matter


application_id: 9771490
project_number: 5R00ES026653-04
project_title: Mechanisms of mismatch repair mediated cell death after alkylating agent exposure
administering_ic: NIEHS
award_notice_date: 2019-07-02
opportunity_number: PA-15-083
application_type: 5
activity_code: R00
ic: ES
serial_number: 026653
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2018-09-01
project_end_date: 2021-07-31
study_section: NSS
contact_pi_person_id: 9458652
contact_pi: GOELLNER, EVA MARIE
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:
DESCRIPTION (provided by applicant)       Dr. Eva Goellner received her bachelor's degree in Chemical Engineering and Biomedical Engineering from Carnegie Mellon University in 2006. She did her Ph.D. research at the University of Pittsburgh School of Medicine in the Laboratory of Dr. Robert Sobol. Her work primarily focused on the mechanisms behind the toxicity of repair intermediates that are generated when the DNA base excision repair (BER) pathway cannot complete repair. Her work helped elucidate the interaction of BER repair intermediates with cellular metabolism. Her graduate work resulted in a first author manuscript in Cancer Research two co-first author manuscripts a first author review and several co-author works and provided a strong background in cellular and molecular biology mammalian cell culture pharmacology and measurements of cellular metabolism. Dr. Goellner joined the laboratory of Dr. Richard Kolodner in October of 2011 working on a separate DNA repair pathway DNA mismatch repair (MMR) that repairs mispairs formed during normal replication. Mismatch repair requires an excision step to remove the DNA up to and including the mispair however deletion of the only known exonuclease involved Exo1 does not have the strong mutator phenotype expected of a required MMR component. This lead to the hypothesis that Exo1-independent and Exo1-dependent subpathways exist.  Dr. Goellner received an NIH NRSA Ruth L. Kirschstein F32 postdoctoral fellowship to perform a screen for mutations in the loading clamp PCNA that specifically disrupted Exo1-independent MMR. Using Saccharomyces cerevisiae Dr. Goellner identified a number of the desired mutations and through the study of them provided a model of how Exo1-independent MMR is carried out. This work was published in a first author manuscript in Molecular Cell a first author review and a co-author paper currently under revision. Her postdoctoral work provided her with a new model system and technical expertise in yeast genetic screens and biochemistry. Dr. Goellner's postdoctoral work and the mentored portion of this award will be carried at the Ludwig Institute for Cancer Research at the University of California School of Medicine Campus. The Ludwig Institute is a diverse group of researchers in nine research laboratories spanning topics of genetics genome integrity proteomics structural biology chromosome biology cell biology and cell signaling. The San Diego branch is part of a worldwide community of Ludwig Institute Centers and is characterized by its excellence in research. These nine laboratories work together to provide a highly collaborative environment in which almost any biological problem can be answered through an in-house collaboration and it provides a high quality research environment with each laboratory regularly publishing in the highest impact journals. The Ludwig Institute has an excellent track record in producing postdoctoral fellows that go on to tenure track positions at top tier universities and is stronglydevoted to the training and success of its postdoctoral fellows. Additionally as part of the Ludwig Institute Dr. Goellner has access to a number of shared UCSD seminar series resources and Core Facilities as well as the opportunity to interact with the large number of research institutes in San Diego. The K99/R00 pathway to independence proposal focuses on answering long-standing questions into the mechanisms of MMR-dependent cell death after alkylating agent exposure. By using separation-of-function mutations in multiple MMR genes she will be able to systematically evaluate this process at a level of mechanistic detail not previously available. Dr. Goellner will combine her unique background in human cell biology molecular pharmacology Saccharomyces cerevisiae genetics and biochemistry to approach this question with a wide variety of techniques and multiple model systems. During the K99 mentored portion of the award Dr. Goellner will identify mutations that specifically disrupt the Exo1-dependent pathway of MMR and will investigate their genetic and biochemical consequences on repair of replication induced mispairs. This will also generate additional important mutations to use in the evaluation of MMR sub-pathways in the response to alkylating agent sensitivity. It will also provide training in new techniques such as biophysical interaction assays and super resolution imaging. During the R00 independent portion a collection of separation of function mutations will be used to study which MMR protein functions are required to induce cell death after DNA alkylation damage. This proposal will also test if downstream repair processing and excision are required for this response and if so what roles the Exo1- independent and Exo1-dependent MMR sub-pathways play. This work will be translated into human cell culture in order to better comprehend the human health consequences of mutations in MMR genes and how they interact with environmental agents. This will provide training in recent advances in genome editing such as CRISPR/Cas9 techniques. This pathway to independence award will provide additional training not only in critical techniques but also in theskills required to be a successful independent researcher and achieve her goal of a tenure track position. This work is a clear departure from Dr. Kolodner or Dr. Sobol's areas of research and will provide Dr. Goellner a unique research program based on her particular interests and training.

project_terms:
ATP phosphohydrolase;ATR gene;Alkylating Agents;Alkylation;Apoptosis;Area;Award;Bachelor's Degree;Base Excision Repairs;Binding;Binding Proteins;Biochemical;Biochemistry;Biological;Biological Assay;Biological Models;Biology;Biomedical Engineering;Biophysics;CRISPR/Cas technology;California;Cell Culture Techniques;Cell Cycle;Cell Cycle Arrest;Cell Death;Cell Line;Cell Survival;Cell model;Cells;Cellular Assay;Cellular Metabolic Process;Cellular biology;Cessation of life;Chemical Engineering;Chromosomes;Closure by clamp;Collaborations;Collection;Communities;Complex;Core Facility;DNA;DNA Alkylation;DNA Damage;DNA Repair Pathway;DNA lesion;Data;Dependence;Development;Doctor of Philosophy;EXO1 gene;Eating;Engineering;Environment;Environmental Tobacco Smoke;Evaluation;Excision;Exonuclease;Exposure to;Fellowship;Food;Futile Cycling;G2/M Arrest;Genetic;Genetic Screening;Genome;Goals;Health;Human;Image;In Vitro;Industrialization;Institutes;Journals;Kinetics;Laboratories;Laboratory Research;Lead;Libraries;MGMT gene;Malignant Neoplasms;Mammalian Cell;Manuscripts;Measurement;Measures;Mediating;Mentors;Metabolism;Methyltransferase;Mismatch Repair;Modeling;Molecular;Molecular Conformation;Molecular and Cellular Biology;Mutation;National Research Service Awards;Nitroso Compounds;Nuclear Extract;Paper;Pathway interactions;Pharmacology;Phase;Phenotype;Phosphotransferases;Plasmids;Play;Positioning Attribute;Postdoctoral Fellow;Process;Proteins;Proteomics;Publishing;Reaction;Reporter;Research;Research Institute;Research Personnel;Resolution;Resources;Role;S-Adenosylmethionine;Saccharomyces cerevisiae;Series;Signal Transduction;Structure;TEL1 Gene;Technical Expertise;Techniques;Technology;Testing;Thymidine;Toxic effect;Training;Translating;United States National Institutes of Health;Universities;Work;Yeasts;anticancer research;base;collaborative environment;endonuclease;environmental agent;exposed human population;gene repair;genome editing;genome integrity;genotoxicity;insight;interest;medical schools;mutant;mutation screening;programs;protein function;public health relevance;reconstitution;recruit;repaired;response;skills;structural biology;success;tenure track;tool;yeast genetics

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Humans are exposed to alkylating agents through second hand smoke the food we eat and exposure to industrial processes. Alkylating agents can damage our DNA resulting in either toxicity or the accumulation of mutations in our genome that can eventually lead to cancer development. However the cell has a number of DNA repair pathways to remove this damage and this study will focus on how one particular DNA repair pathway mismatch repair recognizes DNA damaged by alkylating agents and signals for a cell death response.


application_id: 9769121
project_number: 5P01HL078825-13
project_title: Project 4 - Metabolic Regulation of Myocardial Repair
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6153
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
budget_start_date: 2019-09-01
project_abstract:
ABSTRACTResults of several preclinical studies and clinical trials suggest that cell therapy improves cardiac function aftermyocardial infarction; however high variability marginal efficacy and our poor understanding of themechanisms by which cell therapy works have precluded its clinical translation. One major knowledge gap is alack of understanding of how host metabolism impinges on the efficacy of cell therapy. This is importantbecause a pervasive feature of heart failure is insulin resistance a condition known to affect glucose transportin the myocardium as well as the function of circulating and tissue-resident stem cells. This dysfunction isfurther exacerbated by frank diabetes a condition inordinately common in HF patients. Therefore identificationof the metabolic factors that determine the efficacy of cell therapy is required to optimize cell therapy for HFpatients. In this project we will examine how diabetes affects cardiac repair induced by transplantation ofcardiac mesenchymal cells (CMCs) or paracrine factors derived therefrom. Our preliminary data indicate thatin contrast to CMCs isolated from non-diabetic mice CMCs isolated from diabetic mice fail to improve thefunction of the infarcted heart. The diabetic CMCs show elevated rates of glycolysis associated with expressionof Pfkfb3 which in cardiac progenitor cells increases glycolysis by augmenting phosphofructokinase activityand appears to diminish their proliferation and survival. In addition we find that these changes involve not onlyglycolytic mediators such as PFKFB3 but mitochondrial effectors such as sirtuin 1 (Sirt1) as well. Building onthese observations we propose to test the hypothesis that diabetes compromises the therapeutic efficacy ofCMCs by chronically increasing glycolysis which alters paracrine mechanisms that mediate cardiac repair andthat Sirt1 improves the repair capacity of CMCs by augmenting mitochondrial activity and thereby decreasingglycolysis. To test this hypothesis we will i) determine how diabetes affects CMC-mediated myocardial repairii) elucidate how glycolysis affects CMC repair competence and iii) develop strategies to improve CMC therapyin diabetes. This project will provide fundamental knowledge regarding how metabolic disease affects celltherapy and how mesenchymal cells adapt to nutrient stress. In addition these studies will illuminatemechanisms by which metabolism regulates paracrine factor secretion thereby generating novel biologicalunderstanding of cell-cell communication. Collectively the knowledge garnered from this project will facilitatethe optimization of cell therapy protocols and provide critical direction to ongoing clinical trials.

project_terms:
Affect;Autologous;Biological;Cardiac;Cause of Death;Cell Communication;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplantation;Cell Transplants;Cell secretion;Cells;Characteristics;Chronic;Clinical;Clinical Trials;Collaborations;Comorbidity;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Family suidae;Functional disorder;Glucose;Glycolysis;Heart;Heart Transplantation;Heart failure;Hyperglycemia;Immune;Impairment;In Vitro;Insulin Resistance;Intervention;Knowledge;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nutrient;Outcome;Paracrine Communication;Patients;Pharmacology;Process;Property;Protocols documentation;Recovery of Function;Regulation;Role;SIRT1 gene;Stem cells;Stress;Testing;Tissues;Treatment Efficacy;Up-Regulation;Work;cardiac repair;clinical translation;cytokine;diabetic;diabetic patient;glucose metabolism;glucose transport;heart function;improved;improved functioning;improved outcome;in vivo;insight;ischemic cardiomyopathy;loss of function;negative affect;non-diabetic;novel;overexpression;paracrine;pre-clinical;preclinical study;repaired;response;senescence

public_health_relevance:
PROJECT NARRATIVEHeart failure is a prevalent cause of death and a large proportion of heart failure patients are diabetic. In thisproject we will examine how diabetes impairs cardiac mesenchymal cell therapy and delineate ways toimprove cell therapy for diabetic patients with heart failure.


application_id: 9769120
project_number: 5P01HL078825-13
project_title: Project 3 - Cell Therapy and Remodeling
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6152
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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: 2019-09-01
project_abstract:
Despite the dearth of mechanistic insights into precisely how cell therapy works preclinical studies commonlyreport a reduction in fibrosis. Thus to understand how cell therapy limits remodeling we must first appreciatehow reparative cells interact with the stromal compartment. In the normal heart fibroblasts are essential inmaintaining the extracellular matrix. Following infarction fibroblasts assume an active role in acute woundhealing. Although this phenotypic activation is necessary for the acute post-ischemic injury responsefibroblasts become chronically activated which contributes to post-ischemic pathology. Project 3 will elucidatewhether and how cardiac mesenchymal cells (CMCs) interact with the recipient heart and will identify CMC-mediated changes in fibroblast activation. Because the post-MI heart is characterized by a shift in the balanceof hyaluronan (HA) metabolism in which more HA is produced than is degraded HA accumulation maycontribute to persistent fibroblast activation and support unresolved inflammation. Furthermore we reason thatcell therapy effects myocardial repair by restoring balance to dysregulated HA metabolism which is largelypropagated by activated fibroblasts. We will perform proof-of-concept studies to show whether and how HAmetabolizing enzymes in reparative cells may regulate their competence in in vivo models of post-ischemicmyocardial repair. We will identify specific receptor-ligand interactions that confer reparative competence totherapeutic cells. Although the aforementioned goals are worthy of pursuit on their own we argue they shouldbe examined further through a translational lens because preclinical studies of reparative cells use healthyanimals as cell donors; however clinical trials of autologous cells use heart failure (HF) patients as bothdonors and recipients. This preclinical/clinical dichotomy creates a sizeable translational barrier. Becausesignificant changes occur in the stromal compartment following infarction reparative cells derived therefromlikely differ from nave reparative cells. Indeed our preliminary data indicate that heart failure-derived CMCslack reparative competence which may stem from their inability to properly metabolize post-MI stromalcomponents such as HA. We will identify and correct defects in incompetent heart failure-derived CMCs.Thus our central hypothesis holds that reparative cells attenuate ventricular remodeling through recognition ofand response to specific stromal components which are lost in CMCs derived from failing hearts. We will testthis hypothesis through these synergistic aims: 1) Elucidate the impact of CMCs on fibroblast activation; 2)Determine how CMCs interact with the recipient heart to limit maladaptive remodeling; 3) Identify and rescuedefective mechanisms in heart failure-derived reparative cells. Thus we will show for the first time how CMCsshape the post-MI stroma to limit fibroblast activation. We will also identify reasons for reparativeincompetence in heart failure-derived CMCs and restore their competence by rescuing their capacity tometabolize HA. Collective insights from Project 3 will fundamentally change future cell therapy studies.

project_terms:
Acute;Address;Affect;Animals;Attenuated;Autologous;Binding;CD44 Antigens;CD44 gene;Cardiac;Cell Shape;Cell Therapy;Cell Transplantation;Cell Transplants;Cells;Chronic;Clinical;Clinical Trials;Collaborations;Competence;Data;Defect;Environment;Enzymes;Equilibrium;Event;Extracellular Matrix;Extravasation;Family suidae;Fibroblasts;Fibrosis;Future;Goals;Heart;Heart failure;Hyaluronan;Hyaluronidase;Infarction;Inflammation;Inflammatory;Injections;Leukocytes;Ligands;Logic;Mediating;Mesenchymal;Metabolism;Modeling;Mus;Muscle;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myofibroblast;Pathology;Patients;Phenotype;Positioning Attribute;Process;Production;Recording of previous events;Reporting;Response Elements;Role;Severities;Signal Transduction;Source;Stromal Cells;Testing;Therapeutic;Time;Ventricular Function;Ventricular Remodeling;Work;Wound Healing;clinical translation;effective intervention;gain of function;improved;in vivo Model;innovation;insight;interest;lens;novel;paracrine;pre-clinical;preclinical study;programs;receptor;repaired;response;response to injury;stem;synergism;transdifferentiation

public_health_relevance:
Cell therapy is a promising approach to limit the severity of heart failure. Unfortunately we have limitedunderstanding of precisely how cell therapy works to limit heart failure. This project will test new ideas related tohow cell therapy interacts with the failing heart to bring about repair of the muscle.


application_id: 9769116
project_number: 5P01HL078825-13
project_title: Project 1 - Repeated Cell Therapy for Heart Failure: A New Paradigm
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6150
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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: 2019-09-01
project_abstract:
The therapeutic benefits of cell-based treatments have often been regarded as modest borderline or nil. As aresult clinical translation has not occurred and considerable uncertainty and skepticism surround the conceptof cell therapy. A major factor limiting the benefits of cell therapy (regardless of cell type) is the poorengraftment of the cells which disappear rapidly after transplantation; because of this we propose thatadministering one dose of cells cannot be considered an adequate test of efficacy. However almost allpreclinical and clinical studies of cell therapy performed heretofore have based their assessment of efficacy onthe outcome of one cell administration. Our work in the current PPG has shown that 3 doses of c-kitPOScardiac progenitor cells (CPCs) are strikingly (~3 times) more effective than 1 dose in improving LV function.Building on this prior work we will test the idea that the problem of poor engraftment can be overcome byrepeated cell administrations. We have recently discovered a new population of cells cardiac mesenchymalcells (CMCs) that appear to be more suitable for widespread use and to have greater therapeutic potentialthan CPCs. Consequently we will focus this proposal on CMCs. The overall goal of Project 1 is tothoroughly evaluate the therapeutic effectiveness and mechanism of action of repeated doses ofCMCs. Our central hypothesis is that repeated administrations of CMCs dramatically increase the beneficialeffects of cell therapy not only in mice but also in large preclinical animal models (pigs) and in the presence ofmajor co-morbidities (diabetes) via mechanisms that involve the cumulative effects elicited by repetitive burstsof extracellular vesicle (EV) release resulting in cumulative favorable modulation of the inflammatory andfibrotic response to CMC transplantation. The specific Aims are: 1) To establish the most effective protocols foradministering repeated doses of CMCs or CMC-derived EVs. We will determine how the effects of repeateddoses can be maximized by varying the number of doses and the interval between doses and the impact ofdiabetes. 2) To generate data necessary for Phase I clinical trials of repeated CMC or EV therapy in patientswith heart failure. Using a preclinical porcine model we will assess the effects of repeated administrations ofCMCs or EVs and identify the optimal doses. 3) To elucidate the mechanism of action of repeated doses ofCMCs and EVs including their effect on the inflammatory and fibroblast response to infarction. Throughoutthese studies the effects of EVs will be compared with those of CMCs to determine whether cell-free EVtherapy recapitulates the benefits of CMC therapy. This Project will test two potentially disruptive ideas: i) theconcept that the full effects of cell or EV therapy require repeated doses would constitute a major paradigmshift with potentially vast implications for the entire field of reparative medicine; ii) the concept that theeffects of cell therapy can be reproduced with cell-free administration of EVs would revolutionize the field.These studies will lay the groundwork necessary for first-in-human trials of repeated CMC/EV administration.

project_terms:
Ablation;Advocate;Animal Model;Cardiac;Cell Therapy;Cell Transplantation;Cell Transplants;Cells;Chronic;Clinical Research;Clinical Trials;Collaborations;Comorbidity;Data;Diabetes Mellitus;Diabetic mouse;Dose;Engraftment;Family suidae;Fibroblasts;Genetic;Goals;Heart;Heart Transplantation;Heart failure;Immune response;Infarction;Inflammatory;Left Ventricular Remodeling;Mesenchymal;Metabolic;Modeling;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardium;Outcome;Patients;Phase I Clinical Trials;Population;Proteins;Protocols documentation;Research;Research Design;Route;Stem cells;Testing;Therapeutic;Therapeutic Effect;Time;Transplantation;Treatment Efficacy;Uncertainty;Vesicle;Work;base;cell type;clinical translation;clinically relevant;efficacy testing;extracellular vesicles;first-in-human;heme oxygenase-1;improved;in vivo;inflammatory modulation;ischemic cardiomyopathy;mouse model;novel;overexpression;pre-clinical;preclinical study;reparative medicine;response;therapeutic effectiveness;transcriptome;vesicular release

public_health_relevance:
Project 1 will determine whether repeated doses of cardiac mesenchymal cells exert cumulativebeneficial effects that make them much more effective than a single dose. It will also determinewhether cell-free administration of vesicles secreted by the cells can reproduce the effects ofthese cells. These studies will lay the groundwork necessary for first-in-human trials; if either ofthese ideas proves correct it would constitute a major paradigm shift with potentially vastimplications that would revolutionize the entire field of reparative medicine.


application_id: 9769115
project_number: 5P01HL078825-13
project_title: Core D - Pathology and Flow Cytometry Core
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6149
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-09-01
project_abstract:
The function of the Flow Cytometry and Pathology (Core D) is to provide each Project with the expertiseequipment and facilities required for the flow cytometric analyses cell sorting and pathological analyses thatare needed for studies of cardiac mesenchymal cells (CMCs) and extracellular vesicles (EVs). Accurateidentification characterization and quantitation of cells in a complex heterogeneous population are technicallydemanding and require specialized and expensive equipment and personnel. One of the major advantages ofthis Program Project is that it will make available to all four Projects the facilities and techniques of flowcytometry and cell sorting which otherwise would not be affordable to any Project in isolation. Flow cytometry-based analysis for the identification of specific cell populations changes in cell commitment or phenotype andcharacterization of cell functions such as cell cycle viability or signal transduction will be crucial to allProjects. A central common facility that performs these technically challenging analyses is thereforeindispensable to achieve the goals of the Program Project. Besides the obvious advantages of efficiency andcost savings the Core will also enable four investigators with diverse and complementary backgrounds (Drs.OToole Moore Li and Ratajczak) to combine their technical and biological expertise in order to ensure thatthe proposed work is successfully executed. The Core will offer the Program Project investigators the ability toidentify and characterize specific cell types from complex populations. It will also offer the facilities andexpertise necessary to perform the comprehensive histopathologic/immunohistochemical analyses required forthis Program. The uniform histopathologic analyses conducted by the Core in a blinded and rigorouslystandardized fashion will make it possible to compare results of different experiments within the same Projectand among different Projects.Core D will be the continuation of the Flow Cytometry Core in the current funding cycle (led by Dr. OToole)and of the intense and productive ongoing collaboration in flow cytometry and pathology between Dr. OTooleand the other PPG investigators. The function of Core D is to provide all four Projects with the expertiseequipment facilities reagents procedures and analyses needed for flow cytometry sorting and pathologywork. Specifically the Core will i) perform the flow cytometric analyses and cell sorting procedures required forstudies of CMCs and EVs ii) perform tissue processing histopathology and immunohistochemistry of cardiacsamples and iii) make available to the four Projects the tremendous experience and expertise of the Corepersonnel.

project_terms:
American Heart Association;Antibodies;Biochemistry;Biography;Biological;Blinded;Bone Marrow;Budgets;Calibration;Cardiac;Cell Culture Techniques;Cell Cycle;Cell Separation;Cell Therapy;Cell physiology;Cells;Centers of Research Excellence;Collaborations;Collection;Complex;Computer software;Confocal Microscopy;Core Facility;Cost Savings;Data Analyses;Diabetes Mellitus;Doctor of Medicine;Doctor of Philosophy;Ensure;Equipment;Experimental Designs;Financial compensation;Flow Cytometry;Funding;Goals;Heart;Heart failure;Histology;Histopathology;Human Resources;Immunofluorescence Microscopy;Immunohistochemistry;Inflammatory;Institutes;International;Investigation;Laboratories;Maintenance;Mesenchymal;Molecular Biology Techniques;Myocardial Ischemia;Myocardial tissue;Obesity;Pathologic;Pathology;Phenotype;Population;Population Heterogeneity;Procedures;Protocols documentation;Reagent;Regulation;Research Personnel;Rodent Model;Running;Sampling;Signal Transduction;Sorting - Cell Movement;Stains;Standardization;Stem cells;Supervision;Techniques;Tissue Sample;Tissues;Tobacco;Training;United States National Institutes of Health;Universities;Work;addiction;analytical tool;base;cell type;experience;experimental study;extracellular vesicles;instrument;light microscopy;member;operation;programs;skills;stem;stem cell biology;tissue processing

public_health_relevance:
The Flow Cytometry and Pathology Core will provide each Project with the expertiseequipment and facilities required for the study and separation of cells by flow cytometry and forthe pathological analyses of tissue samples obtained from the heart after cell therapy. The Corewill ensure that the analyses of cells and tissues are done expertly efficiently and consistently


application_id: 9769113
project_number: 5P01HL078825-13
project_title: Core C - Cell Biology Core
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6148
contact_pi_person_id: 8307878
contact_pi: LI, QIANHONG
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: 2019-09-01
project_abstract:
The Cell Biology Core will be a critical resource to this PPG. It will provide the four Projects with access to awide array of reagents procedures and analyses including fully characterized cardiac mesenchymal cells(CMCs) and CMC-derived extracellular vesicles (CMC-EVs hereafter referred to as EVs) isolated from miceand pigs assays of CMC function in vitro and characterization of EVs (e.g. arrays of EV-related non-codingRNAs particle size analysis protein assays). Specifically the Core will i) isolate CMCs from mouse and pighearts; ii) perform comprehensive CMC characterization including proliferation population doubling timemorphometric analysis (cell length and area) clonogenicity analysis of marker expression secretomeanalysis and gene profiling; iii) isolate EVs from mouse and pig CMCs; iv) perform characterization of EVsincluding particle size analysis validation of markers expression and RNA and protein profiling; v) isolate cellsutilizing multiple markers; vi) assess cell viability; vii) determine changes in cell signaling; and viii) quantify cellsat each phase of the cell cycle. The individual Projects do not have the facilities or expertise needed to isolateand characterize CMCs consistently or to perform the extensive EV characterizations. Consolidation of allCMC/EV work into a Core facility will decrease the costs of supplies and equipment because the Core willmake bulk purchases of supplies (thereby reducing expenses) and because waste and unnecessaryduplication of supplies reagents and equipment will be eliminated with the maintenance of centralized stocksand inventories. Consolidating CMC/EV work into a Core facility is also time-effective because the techniquesinvolved in this work are very labor intensive and require dedicated skilled personnel. Core C will makeavailable to the four Projects the tremendous experience and expertise of the Core personnel in thepreparation and analysis of CMCs and EVs. The Core staff a strong team of dedicated individuals under theimmediate supervision of the Core Leader will provide consistency and reproducibility of analysis. This iscrucial because it will ensure that all four Projects will use CMCs isolated and expanded the same waythereby making the results comparable. A single source of CMCs and EVs with rigorous standardization toensure consistency will result in transplantation of uniform CMC and EV populations in all four Projects andthus is extremely important for the integration and comparison of results from each of the Projects. This willmake it possible to compare results of different experiments within the same Project and among differentProjects. In summary the Core will ensure quality control and by eliminating duplication of effort and maximizingthe use of personnel and supplies will enable an efficient use of resources.

project_terms:
Area;Biochemical;Biography;Bioinformatics;Biological Assay;Biological Markers;Biology;Bone Marrow;Budgets;Cardiac;Cell Culture Techniques;Cell Cycle;Cell Survival;Cell Therapy;Cell physiology;Cells;Cellular biology;Collaborations;Core Facility;Data Analyses;Data Set;Databases;Disease;Doctor of Medicine;Doctor of Philosophy;Ensure;Equipment;Equipment and Supplies;Equipment and supply inventories;Experimental Designs;Family suidae;Foundations;Funding;Gene Expression;Gene Expression Regulation;Gene Transfer;Genes;Grant;Heart;Human;Human Resources;Immunology;In Vitro;Individual;Institutes;International;Leadership;Length;Maintenance;Mesenchymal;Methods;MicroRNAs;Molecular;Molecular Biology;Molecular and Cellular Biology;Mus;Myocardial Ischemia;Particle Size;Pathway Analysis;Phase;Population;Preparation;Procedures;Production;Proteins;Protocols documentation;Quality Control;RNA;Rattus;Reagent;Reproducibility;Research;Research Personnel;Resources;Role;Signal Transduction;Solid;Source;Span 20;Standardization;Stem cells;Structure of thyroid parafollicular cell;Supervision;Techniques;Time;Training;Transplantation;United States National Institutes of Health;Universities;Untranslated RNA;Work;biomarker validation;cost;experience;experimental study;extracellular vesicles;progenitor;protein profiling;skills;stem;stem cell biology;success;vector;wasting

public_health_relevance:
The Cell Biology Core will provide the four Projects with a uniform source of cardiacmesenchymal cells (CMCs) and CMC-derived extracellular vesicles. It will provide uniformassays of CMC function in vitro and characterization of EVs.


application_id: 9769112
project_number: 5P01HL078825-13
project_title: Core B - Mouse Surgery and Physiology
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 6147
contact_pi_person_id: 8251726
contact_pi: GUO, YIRU
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: 2019-09-01
project_abstract:
The function of the Surgery and Physiology Core (Core B) is to provide the expertise equipment and facilitiesneeded for all of the in vivo murine and porcine studies. Specifically Core B will be responsible for all surgicaland cardiac catheterization procedures (coronary artery occlusion/reperfusion delivery of cardiacmesenchymal cells [CMCs] delivery of CMC-derived extracellular vesicles [EVs] and endomyocardialbiopsies) echocardiographic analyses invasive hemodynamic studies magnetic resonance imaging studiesand maintenance and genotyping of transgenic and knockout mouse lines. Accurate physiologicalmeasurements and surgical procedures in mice represent technically demanding tasks that cannot and shouldnot be attempted in every laboratory but rather should be performed by a group of dedicated investigatorswho focus on studies in mice and thereby acquire extensive experience with this difficult model. Similarlystudies in large animals such as the pig are complex expensive and technically challenging and requireexperienced and skilled investigators and staff. One of the main advantages of this Program Project is that itprovides all four Projects with access to complex and technically challenging in vivo mouse and pig models ofmyocardial infarction (MI) and cell therapy expert physiology and surgery and state-of-the-art techniques thatotherwise would not be available to these investigators. This is a major benefit to all investigators. Core Bconsists of a team of skilled highly-experienced investigators who have worked together cohesively for manyyears focusing exclusively on murine and porcine studies (Dr. Guo has performed >31000 surgical proceduresin mice and Dr. Tang >600 procedures in pigs) have developed and perfected murine and porcine models ofMI and cell therapy utilizing state-of-the-art facilities and equipment and have collaborated extensively with theother investigators in this PPG. An important feature of Core B is that it will use a new technique for deliveringCMCs  percutaneous intraventricular infusion in the mouse which was recently developed in our lab.Compared with standard intramyocardial injection percutaneous intraventricular infusion offers the advantageof enabling repeated cell administrations in the same mouse with very low mortality. Another feature is that allechocardiographic hemodynamic and MRI analyses will be performed off-line by blinded observers. Thecapacity of the Core has been tested during the current funding cycle. In the past 5 years the Core hassuccessfully assisted all four Projects resulting in a total of 27 full-length original papers and has performed atotal of 4654 procedures in 5029 mice (including 2964 transgenic/knockout mice provided by our transgenicfacility). These procedures include 2029 coronary occlusion/reperfusion protocols 1060 injections of cells orvehicle 333 implantations of minipumps for BrdU/IdU delivery 1396 echocardiograms and 291 invasivehemodynamic studies. These numbers eloquently illustrate the research output that the Core can produce.

project_terms:
Animal Disease Models;Animals;Biography;Biopsy;Blinded;Breeding;Bromodeoxyuridine;Budgets;Cardiac;Cardiac Catheterization Procedures;Cardiovascular Physiology;Cardiovascular system;Catheterization;Catheters;Cell Therapy;Cells;Collaborations;Complex;Coronary Occlusions;Data Analyses;Data Collection;Development;Doctor of Medicine;Doctor of Philosophy;Echocardiography;Equipment;Family suidae;Funding;Future;Genotype;Heart failure;Human Resources;Image Analysis;Injections;Intraventricular Infusion;Knock-out;Knockout Mice;Laboratories;Left Ventricular Function;Left Ventricular Remodeling;Length;Magnetic Resonance Imaging;Maintenance;Measurement;Mesenchymal;Modeling;Mus;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Output;Paper;Physiological;Physiology;Pressure Transducers;Procedures;Protocols documentation;Quality Control;Radiology Specialty;Reperfusion Therapy;Research;Research Personnel;Study of magnetics;Supervision;Techniques;Testing;Transgenic Mice;Transgenic Organisms;Translational Research;Universities;Work;cohesion;coronary artery occlusion;experience;experimental study;extracellular vesicles;heart function;heart imaging;hemodynamics;imaging program;imaging scientist;imaging study;implantation;in vivo;molecular imaging;mortality;mouse model;pressure;programs

public_health_relevance:
The function of the Surgery and Physiology Core is to provide the expertise equipment andfacilities needed for all of the in vivo studies in mice and pigs. Specifically Core B will beresponsible for all surgical and cardiac catheterization procedures and all echocardiographichemodynamic (catheterization) and magnetic resonance imaging studies in these animalmodels of disease.


application_id: 9769108
project_number: 5P01HL078825-13
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-16-402
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2004-12-01
project_end_date: 2022-08-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP(JH)]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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:
Clinical translation of cell therapy has been hindered by i) lack of understanding of basic mechanisms and ii)borderline or inconsistent results in clinical trials. The overarching objective of this renewal application is todirectly address these two problems; specifically to advance our understanding of the mechanism of action ofcell therapy and to develop strategies that optimize its therapeutic efficacy. We will focus on cardiacmesenchymal cells (CMCs) a promising new population of heart-derived cells that we have recentlydiscovered and that appears to be particularly suitable for clinical translation. Four closely inter-related andinter-dependent Projects will address different facets of this theme. Project 1 (Bolli) will carefully evaluate theuse of repeated treatments to maximize therapeutic benefit including translational studies in a preclinicalporcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase thebeneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. Project 2(Wysoczynski) will elucidate the role of immune cells in mediating the beneficial effects of cell therapy and testthe hypothesis that CMCs and EVs facilitate recruitment of monocytes and activation of reparativemacrophages which are endogenous mediators of repair. Project 3 (Jones) will illuminate the role of thestromal compartment (including fibroblast activation and hyaluronan metabolism) in the reparative actions ofCMCs and EVs and identify and correct defects in CMCs rendered incompetent by heart failure (HF). Theoverarching hypothesis is that CMCs attenuate remodeling by favorably enhancing hyaluronan metabolismwhich is defective in HF. Project 4 (Bhatnagar) will determine how diabetes affects CMC-mediated myocardialrepair and how CMC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetescompromises the therapeutic efficacy of CMCs by increasing glycolysis which alters paracrine mechanismsand that Sirt1 improves CMC repair capacity by decreasing glycolysis. Thus all four Projects focus cohesivelyon CMCs. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgerycell transplantation CMC culture and phenotyping pathology flow cytometry and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long historyof collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. Throughout thefour Projects the effects of CMCs will be systematically compared with those of EVs. These will be the firststudies to systematically examine the effects of repeated doses and the role of immune and stromal cellsglycolysis and Sirt1 in the salubrious effects of cell therapy; thus the results will be entirely new. The pigstudies (3 Projects) will lay the groundwork for translational investigations of CMC therapy in patients with HF.This PPG may generate disruptive new knowledge including two new therapeutic paradigms (repeatedtreatments and use of cell-free EV products) either of which in itself would revolutionize cell therapy.

project_terms:
Address;Affect;Animal Model;Animals;Attenuated;Autologous;Cardiac;Catabolism;Cell Culture Techniques;Cell Separation;Cell Therapy;Cell Transplantation;Cell Transplants;Cells;Chronic;Clinical Trials;Collaborations;Comorbidity;Competence;Data;Defect;Diabetes Mellitus;Diabetic mouse;Dose;Engraftment;Event;Family suidae;Fibroblasts;Flow Cytometry;Funding;Glycolysis;Goals;Heart;Heart failure;Hyaluronan;Immune;Immune response;Infarction;Inflammation;Injury;Intervention;Investigation;Knowledge;Left Ventricular Remodeling;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Operative Surgical Procedures;Paracrine Communication;Pathology;Patients;Phenotype;Population;Property;Recording of previous events;Regulation;Research Design;Research Personnel;Role;SIRT1 gene;Stromal Cells;Study models;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Translations;Treatment Efficacy;Treatment Protocols;cardiac repair;cell type;clinical application;clinical translation;cohesion;diabetic;effective therapy;extracellular vesicles;first-in-human;heart function;immunoregulation;improved;improved outcome;inflammatory modulation;insight;macrophage;monocyte;non-diabetic;novel;novel therapeutics;paracrine;pre-clinical;preclinical study;programs;recruit;repaired;reparative medicine;response;stem;tool;translational study;vesicular release;virtual

public_health_relevance:
The goal of this application is to study cardiac mesenchymal cells (CMCs) a promising newpopulation of heart-derived cells that we have recently discovered and that appears to beparticularly suitable for clinical application. The overall objective of this renewal application is toadvance our understanding of the mechanism of action of CMCs and to develop strategies thatoptimize their efficacy for treating heart failure caused by a heart attack (myocardial infarction).The results of these studies will lay the groundwork for first-in-human clinical trials of CMCs.


application_id: 9769083
project_number: 5R01GM129532-02
project_title: Visceral fat gamma delta T cells in sepsis pathogenesis
administering_ic: NIGMS
award_notice_date: 2019-05-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 129532
program_official: ZHAO, XIAOLI
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adipose tissue;Affect;Anti-inflammatory;Bioinformatics;Cells;Cellular biology;Clinical;Collaborations;Complex;Creatinine;Critical Care;Critical Illness;Data;Development;Endocrine Glands;Evaluation;Excision;Failure;Fatty acid glycerol esters;Flow Cytometry;Functional disorder;Future;Genes;Goals;Immune;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-17;Kidney;Knock-out;Knockout Mice;Link;Mediating;Mediator of activation protein;Metabolic Pathway;Molecular Biology;Mouse Strains;Mus;Operative Surgical Procedures;Organ;Pathogenesis;Pathologic;Patients;Physiology;Plasma;Plasminogen Activator Inhibitor 1;Play;Procedures;Production;Renal function;Role;Sampling;Sepsis;Series;Serum;Severities;Signal Transduction;Source;Specimen;T-Lymphocyte;Testing;Therapeutic;Thrombosis;Tissues;Transgenic Mice;Transplantation;Visceral;Visceral fat;Wild Type Mouse;aged;clinically relevant;cytokine;design;experimental study;innovation;liver injury;lung injury;mortality;mouse model;multidisciplinary;multiorgan injury;novel;organ growth;patient population;pre-clinical;public health relevance;second transplant;statistics;success;therapeutic target; T cells


application_id: 9768891
project_number: 5U01AA026225-03
project_title: 2/2 Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV)
administering_ic: NIAAA
award_notice_date: 2019-08-28
opportunity_number: RFA-AA-17-014
application_type: 5
activity_code: U01
ic: AA
serial_number: 026225
program_official: WANG, JOE
project_start_date: 2017-09-22
project_end_date: 2022-08-31
study_section: ZAA1-DD(14)V
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: COOK, ROBERT L
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:
Heavy alcohol drinking and HIV-1 infection are independently associated with the development ofabnormalities in the brain function and cognition and increasing evidence indicates that the combinatorialeffects of HIV infection and alcohol are likely to worsen these abnormalities. Significantly both HIV- 1 infectionand chronic alcohol abuse cause alterations in gut microbiome (dysbiosis) and increase intestinal permeabilityand microbial translocation (MT) which are major pathogenic factors driving local and systemic inflammation.The dysbiosis is characterized by loss of gut bacterial biodiversity a reduction in beneficial bacteria and/or anexpansion of harmful or pro-inflammatory bacteria. However there is limited understanding of (i) the interactiveeffects of heavy alcohol drinking and HIV-1 infection on gut dysbiosis and (ii) the longitudinal qualitative(microbial membership) and quantitative (relevant abundance) determinants of dysbiosis. The current proposaladdresses these gaps with an overall goal to promote the development of rational therapies targeting gutdysbiosis. Accordingly we pursue a unifying hypothesis that in HIV-infected individuals heavy alcohol usecompounds gut dysbiosis and consequent peripheral immune inflammation leading to exacerbation of neuro-inflammation and cognitive dysfunction. To test these hypotheses we will enroll 100 HIV+ participants from30-to-90-day challenge Florida SHARC study (AA020797). This is a funded prospective cohort study in whichenrolled heavy drinkers are challenged to stop drinking for 30 to 90 days assisted by contingencymanagement (CM) payments and motivational interviewing. This application Alcohol associatedComorbidities and Microbiome Evaluation in HIV (ACME HIV 2/2) leverages the existing resources of30-to-90-day challenge Florida SHARC study: participant recruitment measures of alcohol consumptionbiospecimen and biomarker collection; expertise in alcohol HIV and neuroimaging. New data include:longitudinal changes in gut dysbiosis correlative changes in peripheral inflammation and measures ofcognition and neuroinflammation. In response to RFA-AA-17-014 we will partner with the St. PETER HIVstudy (ACME HIV 1/2) to corroborate our findings in Aims 1 and 2 and to conduct combined cross-cohortanalyses. We will complete the following Specific Aims among HIV+ heavy drinkers: AIM 1: To assesslongitudinal qualitative and quantitative changes in the gut microbiome (dysbiosis) associated with very heavyalcohol consumption. AIM 2: To determine the impact of HIV infection and alcohol abuse induced gut dysbiosison intestinal permeability microbial translocation (MT) and resultant peripheral endotoxemia immuneactivation and inflammation. AIM 3: To investigate the impact of dysbiosis and peripheral inflammation ondevelopment of neuro-inflammation and cognitive function. Completion of these aims will lay groundwork for anintervention targeting alcohol-associated dysbiosis which could profoundly reduce inflammation and improvecognitive functions in HIV+ heavy drinkers.

project_terms:
16S ribosomal RNA sequencing;Address;Adverse effects;Alcohol abuse;Alcohol consumption;Alcoholic beverage heavy drinker;Alcohols;Automobile Driving;Bacteria;Bacterial Genes;Behavior assessment;Biodiversity;Biological Markers;Brain;Chronic;Clinical Research;Cognition;Cognitive;Cohort Analysis;Cohort Studies;Collection;Comorbidity;Data;Development;Endotoxemia;Enrollment;Evaluation;Evaluation Studies;Florida;Functional disorder;Funding;Goals;HIV;HIV Infections;HIV-1;Heavy Drinking;Immune;Impaired cognition;Impairment;Individual;Infection;Inflammation;Inflammatory;Intervention;Intestinal permeability;Link;Longitudinal Studies;Measures;Neurobiology;Neurocognitive;Neurocognitive Deficit;Outcome;Participant;Pathogenesis;Pathogenicity;Pathologic;Patient Recruitments;Peripheral;Phylogeny;Prospective cohort study;Research;Resolution;Resources;Role;Sample Size;Shotguns;Structure;Taxonomy;Testing;Virulence Factors;alcohol effect;alcohol measurement;alcohol research;clinically relevant;cognitive function;cognitive performance;cognitive testing;combinatorial;contingency management;cooking;drinking;dysbiosis;gut microbiome;gut microbiota;gut-brain axis;immune activation;improved;metagenomic sequencing;microbial;microbial community;microbiome;microbiome alteration;microbiota;motivational enhancement therapy;neuroimaging;neuroinflammation;outcome prediction;payment;preclinical study;prospective;relating to nervous system;response;targeted treatment;whole genome

public_health_relevance:
The goal of this proposal is to investigate the effects of heavy alcohol drinking on intestinal microbiota and gutbarrier dysfunction with consequent peripheral inflammation which ultimately worsen neurocognitive functionsin HIV-1 infected individuals.


application_id: 9768418
project_number: 5R21CA229057-02
project_title: A microreactor chip platform for quantitative analysis of unsaturated aldehydes in exhaled breath
administering_ic: NCI
award_notice_date: 2019-07-22
opportunity_number: RFA-CA-17-010
application_type: 5
activity_code: R21
ic: CA
serial_number: 229057
program_official: KRUEGER, KARL E
project_start_date: 2018-08-22
project_end_date: 2021-07-31
study_section: ZCA1-TCRB-W(M1)
contact_pi_person_id: 10807170
contact_pi: FU, XIAO-AN
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Title:A microreactor chip platform for quantitative analysis of unsaturated aldehydes in exhaled breath7. Project Summary/Abstract Lung cancer has the highest mortality of all types of cancer. Early lung cancer detection is a key factor forincreasing survival rates of lung cancer patients. The analysis of exhaled breath samples has great potential tobecome a powerful non-invasive screening and diagnostic tool for early lung cancer detection. A number ofrecent publications have indicated that certain volatile organic compounds (VOCs) in exhaled breath may belung cancer metabolic output. However there are some critical challenges for the analysis of breath VOCs thathinder the use of breath analysis technology for clinical applications. These challenges include trace levels ofVOCs in breath much lower than the detection limits of most current analytical instruments; the complexity ofsorting a large number of VOCs; and matrix interferences imparted by abundant and/or structurally similarVOCs unrelated to cancers. These challenges make it very difficult to identify true metabolic markers of lungcancers. We have developed a microreactor approach that uses a quaternary aminooxy coating for chemoselectivecapture of carbonyl compounds in exhaled breath. Four carbonyl compounds have been identified to havesignificantly higher concentrations in the breath of lung cancer patients than in the breath of healthy controlsubjects. However the slow reaction kinetics of the quaternary aminooxy coating with unsaturated aldehydesand unstable nature of these compounds make the microreactor technology inadequate for quantification ofkey unsaturated aldehydes in exhaled breath. Many unsaturated aldehydes in exhaled breath are related tolung cancer dysfunction-induced oxidative stress. Unfortunately there is no current technology that can beused to adequately measure unsaturated aldehydes in exhaled breath. The goal of this project is to develop a microreactor chip platform technology for quantitative analysis ofunsaturated aldehydes in exhaled breath for differentiation of early lung cancer from benign pulmonarynodules. The technology will overcome all critical challenges of current breath analysis technologies andenable quantitative analysis of unsaturated aldehydes. The goal will be fulfilled by the following two specificaims: Specific Aim 1. Develop a novel microreactor platform for accurate measurement of unsaturatedaldehydes in exhaled breath; Specific Aim 2. Establish novel algorithms for diagnosis of lung cancer by breathanalysis. The proposed microreactor chip platform for quantitative analysis of unsaturated aldehydes will betransformative because it will enable measurement and identification of lung cancer metabolic aldehydes andestablish a non-invasive tool for differentiation of lung cancer from benign pulmonary nodules. Themicroreactor chip enabled quantitative analysis of unsaturated aldehydes in breath can also be used with lowdose CT screening for detection of early lung cancer and differentiation of lung cancer from benign pulmonarynodules. The proposed technology will be superior to current breath analysis approaches because of fourcritical innovations: (1) diagnosis of lung cancer by quantitative measurement of cancer metabolic unsaturatedaldehydes in exhaled breath; (2) a novel microreactor for decreasing sample evacuation time; (3) optimizedchemoselective coatings for efficient capture of unsaturated aldehydes; and (4) separation of analyte adductsand quantitation by UHPLC-MS.

project_terms:
2-butenal;4 hydroxynonenal;Acrolein;Adult;Affect;Aldehydes;Algorithms;Ammonium;Benign;Breath Tests;Cancer Patient;Centers for Disease Control and Prevention (U.S.);Charge;Cigarette;Detection;Diagnosis;Diagnostic;Diagnostic Sensitivity;Early Diagnosis;Exhalation;Functional disorder;Goals;Hexenal;High Pressure Liquid Chromatography;Human;Ketones;Kinetics;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Measurement;Measures;Metabolic;Metabolic Marker;Modality;Nature;Non-Malignant;Output;Oxidative Stress;Patients;Phase;Process;Publications;Reaction;Sampling;Scanning;Sensitivity and Specificity;Silicon;Smoker;Smoking;Sodium Chloride;Sorting - Cell Movement;Specificity;Statistical Data Interpretation;Structure;Survival Rate;Technology;Time;X-Ray Computed Tomography;adduct;base;cancer type;carbonyl compound;clinical application;computed tomography screening;cost effective;diagnostic accuracy;innovation;innovative technologies;instrument;low-dose spiral CT;lung cancer screening;lung imaging;mortality;non-smoking;noninvasive diagnosis;novel;novel diagnostics;screening;success;tool;volatile organic compound

public_health_relevance:
8. Project Narrative Quantitative analysis of volatile organic compounds in exhaled breath has great potential to bedeveloped as a powerful noninvasive diagnostic tool for differentiation of lung cancer from benign pulmonarynodules. This project proposes to develop an innovative technology for quantitative analysis of unsaturatedaldehydes in exhaled breath for diagnosis of lung cancer. The approach is to investigate novel microreactorwith new quaternary aminooxy compound phase for chemoselective capture and preconcentration ofunsaturated aldehydes in exhaled breath.


application_id: 9768251
project_number: 5UH3NS100606-04
project_title: Small vessel disease biomarkers in a longitudinally-followed "stroke-belt" cohort
administering_ic: NINDS
award_notice_date: 2019-08-08
opportunity_number: RFA-NS-16-020
application_type: 5
activity_code: UH3
ic: NS
serial_number: 100606
program_official: MCGAVERN, LINDA
project_start_date: 2016-09-30
project_end_date: 2021-07-31
study_section: ZNS1-SRB-T(19)
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: JICHA, GREGORY A
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:
Abstract Vascular contributions to cognitive impairment and dementia (VCID) describes cognitive impairmentresulting from cerebrovascular disease or dysfunction. VCID is a frequent co-morbidity with Alzheimer'sdisease (AD) as well as a single dementia-causing entity. The most common vasculopathy associated withcognitive impairment is cerebral small vessel disease (SVD). It is highly likely that SVD significantly contributesto the clinical manifestation of dementia and therefore is a viable target for disease-modifying therapieswhether alone or in combination with AD-targeting therapies. One major obstacle for therapeutic developmentis the lack of biomarkers that are predictive of the presence and course of SVD-VCID. In this proposal wepresent candidate biomarkers for SV-VCID that will contribute to the consortium. We have identified MRI imaging modalities of 3D FLAIR ASL and DTI as our imaging candidatebiomarkers. We have also identified IL-12 p70 TNF PIGF and VEGFD as our candidate fluid biomarkers thatdiscriminate SVD well in the subset of our cohort that we have analyzed. In this application we have a plan fordeveloping our candidate biomarkers and validating them through the UH2 phase an individual research groupand also through the UH3 part as a member of the consortium. In addition we bring significant strengths thatwill help synergize and move the consortium as a whole forward in our collective goal of developing biomarkersthat are ready for large scale clinical trials and FDA qualification in years 6-7 of the consortium. Thesestrengths include a well characterized longitudinal cohort supported through our ADC and other NIH initiativesour long history of active participation in consortia providing the experience and infrastructure needed toensure success in this UH2/UH3 mechanism our history of data sharing resource sharing including samplesrecruitment of research participants for longitudinal studies and our foundation in basic and translationalscience.

project_terms:
3-Dimensional;ABCC9 gene;Address;Affect;Alzheimer's Disease;Alzheimers disease biomarker;Amyloid beta-Protein;Angiogenic Proteins;Applications Grants;Basic Science;Biological Markers;Biometry;Brain;Brain Diseases;Brain Pathology;Cerebral small vessel disease;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognition;Comorbidity;Data;Dementia;Diagnosis;Diffusion;Disease;Disease Progression;Elderly;Ensure;Foundations;Genetic Polymorphism;Genotype;Goals;Image;Impaired cognition;Individual;Inflammatory;Infrastructure;Injury;Interleukin-12;Kentucky;Liquid substance;Longitudinal Studies;Longitudinal cohort;Magnetic Resonance Imaging;Measures;Microvascular Dysfunction;Monitor;Neurofilament-M;Neuropsychology;Participant;Pathology;Patients;Perfusion;Phase;Plasma;Population;Process;Proteins;Public Health;Recording of previous events;Research;Research Personnel;Resource Sharing;Risk;Sampling;Severities;Spatial Distribution;Spin Labels;Stroke Belt;Subcategory;TNF gene;Therapeutic Intervention;Time;Translational Research;United States National Institutes of Health;Universities;Vascular Diseases;White Matter Hyperintensity;Work;accurate diagnosis;biomarker development;candidate marker;cerebrovascular pathology;cohort;data sharing;effective intervention;experience;imaging biomarker;imaging modality;medical specialties;member;multidisciplinary;pre-clinical;predictive marker;prognostic value;recruit;response;success;targeted treatment;tau Proteins;therapeutic development;vascular cognitive impairment and dementia;vascular contributions

public_health_relevance:
Project Narrative Vascular cognitive impairment and dementia (VCID) is second only to Alzheimer's disease (AD) as aleading cause of dementia in Western populations. In addition VCID is a frequent co-morbidity with ADcomplicating the diagnosis and treatment of AD for an important proportion of patients. One major obstacle forthe advancement of VCID studies is accurate diagnosis at a preclinical state or at a time early in the diseaseprocess to allow for effective intervention. We have identified candidate biomarkers that we propose to validateas part of a consortium to establish biomarkers for VCID.


application_id: 9767782
project_number: 5R21DK118954-02
project_title: Peripheral Blood Exosome Lipids as Biomarkers of Disease Activity in Crohns Disease
administering_ic: NIDDK
award_notice_date: 2019-08-22
opportunity_number: PA-15-317
application_type: 5
activity_code: R21
ic: DK
serial_number: 118954
program_official: UNALP-ARIDA, AYNUR
project_start_date: 2018-09-01
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1-DKUS-H(04)]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractManagement of inflammatory bowel disease (IBD) patients requires knowledge of disease status to informtreatment decisions. Commonly used biomarkers such as clinical disease activity indices C reactive protein(CRP) and fecal calprotectin achieve suboptimal sensitivity and specificity for intestinal inflammation1. Dataprovided indicate that peripheral blood exosome (PBE) lipid composition distinguishes active IBD fromnormal patients (Fig. 1). We contend that PBE lipid compositions will provide clinicians with a highly sensitiveand specific biomarker to assess disease activity without invasive testing. The need to identify subtle diseasederives from the consensus conclusion that deep remission should be the endpoint of therapy. Thusmonitoring of patients with intent to suppress subclinical inflammation has emerged as a treatmentgoal3. Exosomes are lipid-encased subcellular (60-80 nm) structures released into the peripheral blood atfrom intestinal epithelial cells (IEC) activated leukocytes (e.g. neutrophils macrophages dendritic cells etc.)and mesenchymal cells during inflammation3. We used an ultrahigh resolution Orbitrap mass spectrometer toanalyze lipid compositions of PBEs from patients (>25/group). Principal component analysis (PCA) of PBE lipidintensities showed a wide separation of datapoints between active IBD and normal controls and a heatmapanalysis of differential abundance revealed high within-group correlations and low between-group correlationssuggesting that distinct lipids can be resolved that correlate with disease activity. In this two year project wepropose to collect plasma from 1) moderate-severe 2) mildly-active and 3) quiescent Crohns disease (CD)patients as well as inflammatory (C. difficile-infected) and 4) normal controls. Using CD allows us to testwhether PBE composition detects levels of mild (in many cases subclinical) disease activity as this identifiespatients not in deep remission a goal of medical therapy. In Aim 1 PBE lipid-based classifiers will bedeveloped to discriminate mildly-active from severely-active CD and controls. In Aim 2 PBE lipids will beexamined longitudinally within individual patients before and after therapy to identify lipids correlate with clinicalresponse. Such information will also be passed to Aim 1 to develop more robust classifiers. Testing patterns ofPBE lipids in responsive and refractory patients is intended to improve the robustness of the classifiers.Studies in Aim 1 and 2 are greatly enhanced by the inclusion of a second clinical site (Baylor University) toprovide samples to validate (or not) data from University of Kentucky. The long-term goal will be to justifystudies to identify a exosomal lipid signature panel that provide a novel set of biomarkers for discriminatinglevels of CD disease activity and informing treatment decisions. We post that the creation of a CD exosomelipid biomarker test will obviate the need for follow-up endoscopy in the majority of patients.

project_terms:
Address;Biological Markers;C-reactive protein;Cells;Charge;Clinical;Clinical assessments;Clostridium difficile;Consensus;Control Groups;Crohn's disease;Data;Data Set;Dendritic Cells;Development;Diagnostic;Disease;Disease remission;Endoscopy;Epithelial Cells;Goals;Image;Individual;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Intestines;Kentucky;Knowledge;Leukocyte L1 Antigen Complex;Leukocytes;Link;Lipids;Longitudinal Studies;Mass Spectrum Analysis;Medical;Mesenchymal;Newly Diagnosed;Pathology;Patient Monitoring;Patients;Pattern;Plasma;Principal Component Analysis;Process;Public Health;Refractory;Research;Resolution;Sampling;Sensitivity and Specificity;Speed;Structure;Testing;Tissues;Universities;Work;base;clinical research site;design;disorder control;exosome;follow-up;improved;indexing;individual patient;macrophage;mass spectrometer;neutrophil;novel;novel therapeutics;peripheral blood;response;sample collection;specific biomarkers;tool

public_health_relevance:
Project NarrativeThis proposal is designed to test the novel idea that the lipid composition of peripheral blood exosomes (PBE)provides useful biomarkers of disease activity in Crohns Disease (CD). Our research is relevant to publichealth because it will provide new means for assessing disease activity in CD. This information will greatlyfacilitate the speed of discovery of new therapies as well as improve clinical assessment of CD patients.


application_id: 9767766
project_number: 5R01ES026446-05
project_title: Developmental Effects of Manganese Exposure in Rural Adolescents: The CARES Cohort Comes of Age
administering_ic: NIEHS
award_notice_date: 2020-09-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026446
program_official: MARTIN, LINDSEY ANN
project_start_date: 2016-09-30
project_end_date: 2022-08-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: CECIL, KIM M
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Manganese (Mn) plays an essential role in normal growth and development; howeveroverexposure to Mn can result in neurotoxicity. This dual role of Mn as essential mineral andneurotoxicant appears as a biphasic dose-response curve for neurodevelopmental healthoutcomes in children. Children may be particularly susceptible to the neurotoxic effects ofambient Mn exposure as their brains are undergoing a dynamic process of growthdifferentiation pathway direction and apoptosis all of which can be influenced byenvironmental factors. Recent developments in magnetic resonance imaging (MRI) andspectroscopy (MRS) can provide novel quantitative information about the effects of Mn on brainanatomy and physiology; yet these imaging methods have never been applied to an adolescentpopulation exposed to chronic ambient Mn. Given the role of Mn as both nutrient andneurotoxicant we anticipate that biomarkers of Mn exposure will exhibit a biphasic dose-response association with adolescent neurobehavior neuromotor function brainanatomy and physiology and hypothesize that both low (1st quartile) and high (4thquartile) levels of exposure will be significantly associated with deficits in thesedomains. This overarching hypothesis will be addressed through two specific aims.Specific Aim 1: Evaluate neurodevelopment with historic and current biomarkers of Mn in acohort of rural adolescents in order to evaluate the impact of Mn from essential to excess onexecutive function attention and reaction time cognition achievement behavior andneuromotor status. Specific Aim 2: Conduct a sub-study of adolescents based on previouslydetermined Mn biomarkers using quantitative MRI/S in order to evaluate the effects of Mnexposure from essential to excess on neuroanatomy metabolism organization function andconnectivity. Neuroimaging outcomes (volume metabolite concentrations metrics for diffusiontensor functional activation and network connectivity) will be compared with historic andcurrent biomarkers of Mn. This well-characterized longitudinal cohort study of adolescents willadvance our understanding of the impact of Mn on neurodevelopment and brain anatomy andphysiology using innovative MRI methodologies. These patterns may be useful in defining thelines of essential benefit and neurotoxicological harm from Mn. The findings from this study willhave regional national and global implications for advancement of neuroscience and will beused to inform policy related to Mn in gasoline and ambient air standards. This proposalleverages the only cohort available in the United States that can directly address these aims.

project_terms:
Achievement;Address;Adolescence;Adolescent;Air;Anatomy;Apoptosis;Attention;Axonal Transport;Basal Ganglia;Behavior;Biliary;Biological Markers;Blood;Brain;Bypass;Cerebellum;Child;Chronic;Cognition;Cohort Studies;Communities;Deposition;Development;Diagnosis;Diffusion;Dose;Elements;Emotional;Environmental Risk Factor;Event;Excretory function;Exhibits;Exposure to;Follow-Up Studies;Gait;Gasoline;Globus Pallidus;Growth;Growth and Development function;Health;Infant;Ingestion;Inhalation;Lead;Longitudinal cohort study;Magnetic Resonance Imaging;Manganese;Measures;Metabolism;Methodology;Methods;Minerals;Motor;Multimodal Imaging;Musculoskeletal Equilibrium;Neuraxis;Neuroanatomy;Neuropsychology;Neurosciences;Neurotoxins;Nose;Nutrient;Ohio;Outcome;Parkinson Disease;Pathway interactions;Pattern;Pediatric cohort;Physicians;Physiology;Play;Policies;Population;Prefrontal Cortex;Process;Protocols documentation;Psyche structure;Reaction Time;Research;Risk;Risk-Taking;Role;Rural;Rural Appalachia;Source;Structure;Structure of subthalamic nucleus;Substantia nigra structure;United States;Work;adverse outcome;base;cognitive function;cohort;environmental tobacco smoke;executive function;frontal lobe;high risk;imaging modality;innovation;myelination;nervous system development;neurobehavior;neurodevelopment;neuroimaging;neurotoxic;neurotoxicity;novel;olfactory bulb;putamen;relating to nervous system;response;spectroscopic imaging;synaptogenesis;white matter

public_health_relevance:
Narrative: This study will innovatively examine the impact of manganese exposure along withother known neurotoxicants including lead and environmental tobacco smoke in a follow-upstudy of a rural Appalachian cohort. We will examine the impact of these exposures onneurobehavior postural balance and gait brain anatomy and physiology.


application_id: 9767236
project_number: 5R44HL132649-03
project_title: A Novel Lipotherapy to Reduce Infarct Size Following Myocardial Infarction
administering_ic: NHLBI
award_notice_date: 2019-08-08
opportunity_number: PA-17-302
application_type: 5
activity_code: R44
ic: HL
serial_number: 132649
program_official: DESVIGNE-NICKENS, PATRICE
project_start_date: 2016-07-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1-CVRS-A(12)]
contact_pi_person_id: 10119089
contact_pi: BAUER, PHILIP
other_pis: MALDONADO, CLAUDIO ;TANG, XIAN-LIANG
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
According to the CDC in 2013 ischemic heart disease is the leading cause of death worldwide and in theUS approximately 450000 patients died of ischemic heart disease. It is well established in clinical practicethat recanalization of the infarct related artery (IRA) using percutaneous coronary intervention (PCI)enhances myocardial salvage and outcomes in patients with ST-segment elevation myocardial infarction(STEMI). When the duration of ischemia exceeds 1 h from onset of symptoms reperfusion injury followingPCI often leads to infarct expansion due to the no-reflow phenomenon in the microvasculature of thearea at risk. Multiple mechanisms are thought to contribute to no-reflow and no effective treatment toameliorate no-reflow and infarct expansion during reperfusion has been identified in large randomizedclinical trials following STEMI and PCI. EndoProtech Inc. has developed a novel therapeutic approachthat alters the lipid content of endothelial cells (ECs) during PCI which has a stabilizing effect on themicrovascular endothelium and ameliorates no-reflow in the area at risk during reperfusion. The overallgoal of this project is to demonstrate the safety and efficacy of our therapy in enhancing myocardialsalvage following STEMI and PCI. The aims of this Phase II proposal are: 1. Evaluate efficacy of therapyin reducing no-reflow and infarct size; 2. Characterize the effect of the therapy on regenerative/reparativecells involved in early post-MI remodeling; 3. Perform pharmacokinetic studies of therapy; and 4.Determine stability of therapy under various storage conditions. Successful completion of these aims willdetermine: a) the effective dose of our therapy when delivered during PCI b) the effect of the therapy onno-reflow in the area at risk and c) protocols for optimal production and longer shelf life of the therapy.Aims are consistent with studies that will provide partial support for a new drug application to the FDA.

project_terms:
Adverse effects;Area;Arteries;Biological;Blood flow;Cause of Death;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Coronary;Coronary Occlusions;Coronary artery;Data;Dose;Drug Kinetics;Edema;Endothelial Cells;Endothelium;Family suidae;Fibrinolysis;Functional disorder;Glycocalyx;Goals;Heart;Hemorrhage;Histopathology;Infarction;Infiltration;Inflammation;Infusion procedures;Ischemia;Lead;Left ventricular structure;Leukocytes;Life;Lipids;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Oryctolagus cuniculus;Outcome;Patients;Perfusion;Phase;Plug-in;Production;Protocols documentation;Randomized Clinical Trials;Reperfusion Injury;Reperfusion Therapy;Risk;Safety;Swelling;Symptoms;Testing;Therapeutic;Therapeutic Embolization;Thioflavin S;Time;Toxic effect;Treatment Efficacy;Vesicle;base;cell type;clinical practice;effective therapy;endothelial dysfunction;novel;novel therapeutic intervention;novel therapeutics;percutaneous coronary intervention;phase 1 study;recruit;regenerative;sex

public_health_relevance:
Percutaneous coronary intervention (PCI) to reopen blocked coronary arteries enhances myocardialsalvage and outcomes but when blood flow is re-established (reperfusion) it can lead to infarct expansion.This infarct expansion is caused in part by the no-reflow phenomenon that occurs in the microvasculatureof the area at risk during reperfusion. To reduce infarct expansion during reperfusion Endoprotech Inc.has developed a lipid-based treatment that protects the endothelium in the microvasculature from the no-reflow phenomenon and enhances myocardial salvage following PCI.!


application_id: 9766984
project_number: 5R01AA023190-05
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2019-08-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 023190
program_official: WANG, JOE
project_start_date: 2015-09-15
project_end_date: 2020-08-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Severe alcoholic liver disease (ALD) has a high morbidity and mortality. Recent studies demonstrated that probiotics reversed alcohol-induced hepatic steatosis and inflammation and improved liver enzymes in animal models and in patients. Our laboratory showed that administration of a probiotic strain Lactobacillus rhamnosus Gorbach-Goldin (LGG) significantly improved liver enzymes and histology in alcohol treated mice. However the beneficial mechanisms of action of LGG either in viable bacteria form or in culture supernatant form are not clear. Our overall hypothesis is that LGG increases intestinal cathelicidin-related antimicrobial peptide (CRAMP) intestinal trefoil factor (ITF) expression and intestinal short chain fatty acids (SCFAs) leading to improved gut microbiota homeostasis intestinal barrier integrity and hepatic fat metabolism and these are likely the mechanisms by which LGG supplementation attenuates alcohol induced liver injury. We evaluate mechanisms of LGG action with 4 specific aims: Aim 1 will determine the role of CRAMP in the alcohol-mediated changes in gut microbiota and the role of CRAMP in the beneficial effects of LGG in experimental ALD. We will use CRAMP knockout mouse model of ALD to determine the role of CRAMP and LGG in alcohol-induced changes in gut microbiota using a metagenomic approach. Aim 2 will determine the role of LGG in promoting ITF expression and evaluate whether ITF positively modulates intestinal tight junctions as a mechanism for improved intestinal barrier integrity in experimental ALD. We will use an ITF-secreting goblet cell line to evaluate the role of LGG in the production of ITF and the role of ITFin the modulation of intestinal tight junctions in an epithelial cell line. We will also examine th strategy that oral administration of recombinant human ITF attenuates alcohol-induced intestinal barrier and liver injury. Aim 3 will determine the role and mechanisms of butyric acid in the beneficial effects of LGG on intestinal tight junctions in experimental ALD. A metabolomics approach will be used to analyze the changes in SCFAs induced by alcohol and LGG intervention in the intestinal lumen. We will explore the potential mechanisms underlying the role of butyric acid in the regulation of occludin expression involving intestinal histone deacetylases (HDACs) miR122a and HIF--mediated signaling in vitro and in vivo. Aim 4 will evaluate and compare the effectiveness of LGG supernatant (LGGs) with viable LGG (vLGG) and heat-inactivated LGG (hiLGG) in the prevention/therapy of ALD in mouse models. These three LGG preparations will be tested for the effectiveness in the prevention/therapy of ALD in three experimental models of ALD of steatosis steatohepatitis and fibrosis. This study will have a major impact on the development of probiotic-based new therapeutic strategy for the prevention and treatment of ALD.

project_terms:
Acute;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Bacterial Translocation;Butyric Acids;Carbohydrates;Cell Line;Chronic;Cirrhosis;Data;Development;Disease Progression;Effectiveness;Endotoxins;Enzymes;Epithelial;Epithelial Cells;Etiology;Experimental Models;Fatty Liver;Fibrosis;Functional disorder;Goals;Goblet Cells;Health;Hepatic;Histology;Histone Deacetylase;Homeostasis;Human;Hypoxia Inducible Factor;Immune response;Impairment;In Vitro;Inflammation;Injury;Intervention;Intestinal Diseases;Intestinal permeability;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Leaky Gut;Liver;Mediating;Metagenomics;Morbidity - disease rate;Mucous Membrane;Mucous body substance;Mus;Oral Administration;Outcome;Pathologic;Patients;Pilot Projects;Plasma;Play;Preparation;Prevention strategy;Prevention therapy;Probiotics;Process;Production;Proteins;Recombinants;Regulation;Reporting;Role;Sampling;Signal Transduction;Steatohepatitis;Supplementation;Testing;Tight Junctions;Volatile Fatty Acids;alcohol exposure;antimicrobial peptide;bacterial metabolism;base;cathelicidin;cathelicidin antimicrobial peptide;comparative efficacy;compare effectiveness;dysbiosis;gastrointestinal epithelium;gut microbiota;improved;in vivo;lipid metabolism;liver inflammation;liver injury;metabolomics;mortality;mouse model;novel therapeutic intervention;occludin;prevent;protective effect;public health relevance;repaired;transcription factor;trefoil factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goals of this project are to investigate the mechanisms of probiotic action on alcohol-induced liver injury. This study will have a major impact on the development of a probiotics-based new therapeutic strategy for the prevention and treatment of alcoholic liver disease.


application_id: 9766291
project_number: 5R01ES026657-03
project_title: Microenvironment and Arsenic Lung Tumorigenesis
administering_ic: NIEHS
award_notice_date: 2019-08-05
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026657
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-09-30
project_end_date: 2022-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Chronic exposure of environmental arsenic promotes skin bladder liver and lung cancers. Howeverthe mechanism underlying arsenic lung carcinogenesis is unclear. Evidence from animal models and studies incancer patients indicate that the immune system monitors the host body recognizing and reacting againstnewly arising transformed/tumor cells to stop/control tumor formation. The encounter between the immunesystem and transformed/tumor cells initiates a process termed immunoediting that can bring about threeoutcomes: elimination equilibrium or escape of transformed/tumor cells from immune control. Host immunitysuppresses tumor development whereas tumor formation implies the successful escape of transformed/tumorcells from the surveillance of the immune system. Effector T cells particularly cytotoxic T (Tc) cells representa major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cell antitumoreffector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cell antitumorfunction through the activation of immune checkpoint pathways (e.g. PD-1/PD-L1 pathway) has been shown topromote tumor cell immune escape and tumor formation. In addition previous reports indicate that the aberrantactivation of STAT3 occurs in many human tumors and STAT3-mediated PD-L1 up-regulation impedes T cellantitumor function. Our previous in vitro study showed that the IL-6/STAT3 axis plays a critical role in arsenic-induced transformation in human bronchial epithelial cells. Using a lung tumor mouse model our newpreliminary data show that long-term arsenic exposure increased lung tumor incidence rate and multiplicity ofA/J mice. In addition arsenic exposure dose-dependently activated STAT3 increased the binding of STAT3 tothe promoter of the PD-L1 gene and up-regulated PD-L1 in mouse lungs. Flow cytometry data further indicatedthat arsenic increased PD-1+ T cell numbers and decreased CD8+/CD4+ T cell ratio in the lungs while injectionof PD-1 or PD-L1 antibodies reversed the decreased CD8+/CD4+ ratio. Since PD-1/PD-L1 up-regulation mayinhibit T cell antitumor function and promote escape of transformed cells from host immunosurveillance andeventually lead to tumor formation we hypothesize that arsenic promotes lung tumor formation throughSTAT3/PD-1/PD-L1-mediated inhibition of T cell antitumor function. Three specific aims are proposed:Aim 1: To determine if chronic arsenic exposure inhibits T cell antitumor function and the types of cells inwhich PD-1 or PD-L1 is up-regulated by arsenic in the lungs of A/J mice.Aim 2: To determine if inhibition of the PD-1/PD-L1 pathway ameliorates arsenic-promoted T cell dysfunctionand tumor formation in the lungs of A/J mice.Aim 3: To determine if activation of STAT3 is the mechanism underlying arsenic-enhanced PD-L1 up-regulation T cell dysfunction and tumor formation in the lungs of A/J mice.

project_terms:
A/J Mouse;Animal Model;Animals;Antibodies;Arsenic;Binding;CD4 Positive T Lymphocytes;CD4/CD8 ratio procedure;CD8B1 gene;Cancer Patient;Cell Count;Cell membrane;Cells;Cellular Structures;Chronic;Data;Development;Dose;Environmental Exposure;Environmental Risk Factor;Epithelial Cells;Equilibrium;Flow Cytometry;Functional disorder;Genes;Human;Immune;Immune system;Immunity;Immunologic Monitoring;Immunologic Surveillance;In Vitro;Incidence;Injections;Interleukin-6;Investigation;Knock-out;Lead;Lung;Lung Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mediating;Modeling;Monitor;Mus;Outcome;PD-1/PD-L1;PDCD1LG1 gene;Pathway interactions;Pharmacologic Substance;Play;Process;Receptor Inhibition;Regulation;Reporting;Role;SLEB2 gene;STAT3 gene;Skin Cancer;T-Lymphocyte;T-Lymphocyte Subsets;Tumor Escape;Tumor Immunity;Up-Regulation;cell transformation;cell type;cytotoxic;effector T cell;genetic approach;immune activation;immune checkpoint;in vivo;inhibiting antibody;inhibitor/antagonist;innovation;lung carcinogenesis;lung tumorigenesis;mouse model;neoplastic cell;novel;novel strategies;prevent;promoter;tumor;tumor initiation;tumorigenesis

public_health_relevance:
This proposed study aims to investigate a mechanism for lung tumor initiation by using an arsenic-promotedlung tumor formation mouse model. We hypothesize that chronic arsenic exposure compromises hostimmune system which in turn promotes an immune escape of tumor cells from the surveillance of immunesystem. The idea has never been investigated before and will provide valuable information for thedevelopment of new approaches/strategies to prevent and treat lung cancer promoted not only by arsenicbut by other environmental factors as well.


application_id: 9766184
project_number: 5R01AR067667-05
project_title: Mitigating mitochondrial epigenetics in bone remodeling by hydrogen sulfide
administering_ic: NIAMS
award_notice_date: 2019-09-09
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 067667
program_official: CHEN, FAYE H
project_start_date: 2015-09-01
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-U(90)S]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Clinical studies report that children born with severe hyperhomocysteinemia (HHcy) due to deficiency in cystathionine--synthase (CBS) gene resulting in an elevation in plasma homocysteine (Hcy) levels develop skeletal malformations with weaker bone. Although mitochondrial dysfunction has been involved in bone pathology altered mitochondrial (Mito) epigenetics and dynamics contributing to frailer bone have not been studied. The long term goal of this project is to understand the mechanisms of mito-epigenetic remodeling and changes in bone structure/function during genetic HHcy. Alterations in mitochondrial dynamics disturb bone cell (osteoclast/ osteoblast) differentiation and matrix metabolism. Studies have confirmed that type-I collagen (coll-1) a dominant protein of the organic bone matrix is homocysteinylated (N-Hcy-coll-1) during HHcy. Our preliminary data suggest that genetic HHcy affects mito-epigenetic remodeling by altering mito-redox stress mito-DNA methylation / hydroxymethylation fission-fusion and cause N-Hcy-coll-1 cross linking. These processes cumulatively disrupt bone matrix bone density bone blood flow and lead to mitophagy accompanying with significant bone loss. Interestingly hydrogen sulfide (H2S an anti-redox stress and Hcy lowering agent) mitigates bone damage. The central hypothesis of this proposal is that HHcy contributes to bone-matrix inferiority through N-Hcy-coll-1 in part byincreasing mito- epigenetic remodeling and altering mitochondrial dynamics. However treatment with H2S ameliorates HHcy-induced bone abnormalities. We will test this hypothesis by following three specific Aims: Specific Aim # 1: To determine whether the HHcy instigates mito-epigenetic remodeling and DNA methylation in part by altering mitochondrial fission and fusion and whether H2S mitigates mito-epigenetic remodeling. Specific Aim # 2: To determine whether the HHcy homocysteinylates bone type-I collagen activates MMP-1-3-13 disrupts bone matrix (MMP/TIMP axis; collagen/elastin ratio) and H2S ameliorates these changes. Specific Aim # 3: To determine whether the HHcy alters bone mineral density bone mineral content biomechanical load-bearing capacity bone blood flow and disrupts osteoblast/osteoclast differentiation and whether H2S alleviates these alterations.

project_terms:
Affect;Alkaline Phosphatase;Antibodies;Architecture;Attenuated;Azacitidine;Biomechanics;Blood Vessels;Blood flow;Bone Density;Bone Diseases;Bone Matrix;Bone Mineral Contents;Bone Resorption;Bone remodeling;Bone structure;C-terminal;Child;Chimeric Proteins;Clinical Research;Co-Immunoprecipitations;Collagen;Collagen Type I;Consumption;Cyclophosphamide;Cystathionine;DNA Methylation;Data;Deformity;Elastin;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Event;Gel;Gelatin;Gelatinase B;Generations;Genes;Genetic;Goals;Homocysteine;Hydrogen Sulfide;Hyperhomocysteinemia;Immunohistochemistry;Impairment;In Situ;Inferior;Interstitial Collagenase;Knock-out;Knockout Mice;Lasers;MMP9 gene;MTHFR gene;Matrix Metalloproteinases;Measures;Mechanics;Metabolism;Mitochondria;Mitochondrial DNA;Molecular;Mus;N-terminal;Osteoblasts;Osteocalcin;Osteoclasts;Osteocytes;Osteogenesis;Oxidation-Reduction;Oxidative Stress;Pathologic;Pathology;Pathway interactions;Peptides;Plasma;Process;Proteins;Proteome;Pyridoxal Phosphate;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Role;Stains;Stress;Structure;Testing;Therapeutic;Therapeutic Agents;Weight-Bearing state;Western Blotting;blood lead;bone;bone cell;bone loss;bone strength;bone turnover;cortical bone;crosslink;density;femoral artery;inhibitor/antagonist;innovation;malformation;microCT;mitochondrial dysfunction;novel;osteoblast differentiation;public health relevance;skeletal;substantia spongiosa;tibia

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed project will delineate the novel molecular pathological and functional mechanisms for bone deformity by incorporating mitochondrial epigenetics and dynamics studies during hyperhomocysteinemia. The involvement of knockout (MMP9- /-) gene deficient (CBS+/-) double knockout (CBS+/-/MMP9-/-) mice and their various treatments (for example; 5'-azacytidine Mdivi-1 pyridoxal 5' phosphate) will come up with exciting results and innovative findings that have never been studied in bone pathology. Also the use of hydrogen sulfide throughout the study will not only validate the pathways but also confirm its therapeutic aspects in bone diseases.


application_id: 9766076
project_number: 5R01AR067188-05
project_title: Interplay of androgens microbiota and immunoregulation in lupus
administering_ic: NIAMS
award_notice_date: 2019-08-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 067188
program_official: MANCINI, MARIE
project_start_date: 2015-09-01
project_end_date: 2022-08-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
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:
DESCRIPTION (provided by applicant):  Resubmission Systemic lupus erythematosus (SLE) is much more prevalent in females than males in humans and in the (NZBxNZW)F1 (BWF1) mouse model of lupus. Although estrogens can exacerbate disease in females considerable evidence suggests that androgens play a critical role in protecting males from lupus in both humans and mice. The gut microbiota is now thought to play a major role in host health and disease and microbiota dysbiosis is associated with development of autoimmune diseases. Interestingly androgens can have a significant impact on the microbiota and vice versa. Recent studies in a mouse model of type 1 diabetes (T1D) suggest that the microbiota and androgens collaborate in what is now being referred to as the "microgenderome" to protect male mice from disease via currently unknown mechanisms. However little is known about the relationship between androgens and the microbiota in lupus. In preliminary studies we have found that both the microbiota composition and metabolomic profile differ significantly between mature female and male BWF1 mice and transfer of male microbiota to female BWF1 mice protects female recipients from disease and significantly enhances survival. These data suggest that the male environment confers protective properties on the microbiota by altering microbiota composition and/or metabolome. Metabolites from commensal bacteria have been found to induce Treg differentiation both directly and through DC. The gut CD103+ dendritic cells (CD103DC) are highly tolerogenic and generate regulatory T cells in the periphery that can control systemic immune responses. Our preliminary data showing sex-based differences in CD103DC function and the requirement for CD103+ cells for protection in male BWF1 mice strongly support the notion that CD103DC function as a critical link between the male gut microbiota and the immune response and may therefore play an important role in protecting BWF1 male mice from disease. Moreover preliminary analysis of the microbiota metabolome has identified a metabolite that is increased in male BWF1 mice that may have an impact CD103DC function. We therefore hypothesize that the androgen-modified male microbiota and its metabolites protect against lupus by acting through the gut CD103DC. This novel hypothesis will be addressed in lupus-prone BWF1 mice by 1) examining the impact of androgens on the gut microbiota and its metabolites; 2) exploring the role of male microbiota and its metabolites in protection from disease; and 3) determining the role that CD103DC play in male microbiota- mediated protection from disease. The proposed project will fill the gaps in our knowledge about the role of the androgen-gut microbiota relationship in immunoregulation and lupus and will lead to the development of novel therapeutic strategies using the microbiota and/or its metabolites for the treatment of lupus and other autoimmune diseases.

project_terms:
Address;Affect;Agonist;Androgen Receptor;Androgens;Autoimmune Diseases;Castration;Cell physiology;Complex;Cytoprotection;Data;Defect;Dendritic Cells;Development;Diabetes Mellitus;Disease;Environment;Estrogens;Exhibits;Feces;Female;Gonadal Steroid Hormones;Health;Human;Immune response;Immunologics;In Vitro;Inbred NOD Mice;Incidence;Inflammatory;Insulin-Dependent Diabetes Mellitus;Intestines;Knowledge;Lead;Link;Lupus;Mediating;Men's Role;Microbiological Techniques;Modeling;Mucosal Immune System;Mucous Membrane;Mus;Pathogenesis;Phytol;Play;Prevention strategy;Production;Property;Puberty;RXR;Receptor Signaling;Regulatory T-Lymphocyte;Role;Severity of illness;Systemic Lupus Erythematosus;Techniques;Therapeutic;Treatment Protocols;Tretinoin;Volatile Fatty Acids;Woman;autoreactivity;base;commensal bacteria;disorder prevention;dysbiosis;fecal transplantation;gender difference;gut microbiota;immunoregulation;imprint;in vivo;innovation;male;men;metabolome;metabolomics;microbiota;microbiota metabolites;microbiota profiles;mortality;mouse model;next generation sequencing;novel;novel therapeutics;public health relevance;sex

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Systemic lupus erythematosus (SLE or lupus) is an insidious disease without many treatment options. Women have a much higher incidence of SLE than men and male sex steroids (androgens) appear to protect genetically susceptible men from disease. Recently a role for the intestinal natural (non-pathogenic) bacterial flora in health anddisease (including inflammatory and autoimmune diseases) has been demonstrated and an important relationship between the natural bacterial flora in the gut and male androgens in disease has been identified. We have found that fecal transplants from healthy male mice into lupus-susceptible female mice protected them from disease. In this application we propose to study the relationship between gut flora and androgens in lupus in order to develop novel therapies for the treatment of lupus.


application_id: 9765860
project_number: 1R21NS111979-01
administering_ic: NINDS
award_notice_date: 2019-03-11
opportunity_number: PA-18-358
application_type: 1
activity_code: R21
ic: NS
serial_number: 111979
program_official: CORRIVEAU, RODERICK A
project_start_date: 2019-04-01
project_end_date: 2022-03-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 2186060
contact_pi: TEMEL, RYAN EUGENE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
project_title:
Targeting microRNA-33 to reduce intracranial atherosclerosis and other neurovascular hallmarks of vascular cognitive impairment and dementia

project_abstract:
Project SummaryIntracranial atherosclerosis (ICAS) is a public health concern for both its role in stroke and as a contributingfactor to vascular cognitive impairment and dementia (VCID). It is becoming widely accepted that poor vascularhealth facilitates poor brain health and that changes are needed to delay or prevent onset of VCID.Atherosclerotic vascular disease (AVD) is a chronic maladaptive inflammatory disease that can affect extra- andintracranial arteries. The combination of lipoprotein retention endothelial cell inflammationmonocyte/macrophage infiltration intracellular cholesterol accumulation impaired apoptotic cell clearance andextracellular matrix degradation leads to formation of advanced unstable atherosclerotic plaques that can limitor occlude blood flow to tissues causing acute or chronic tissue damage. ICAS often plays a causative role inischemic stroke and subsequent cognitive decline. ICAS has also been linked to both clinical signs of cognitivedecline and Alzheimer's disease pathology. Intracranial compared to extracranial atherosclerosis has a delayedonset of ~20 years but increases in prevalence and severity in individuals 60 years or older. With the steadyrise in the percentage of US citizens above the age of 60 ICAS will play an ever-growing role in the morbidityand mortality caused by VCID. Reducing low-density lipoprotein (LDL) concentration with statins is a primarytherapeutic approach to stabilize AVD and attenuate ischemic stroke risk. However statins only reduce strokerisk by ~20% and do not appear to reduce VCID suggesting that treating hypercholesterolemia alone is not anideal approach for reducing VCID. The obvious need for additional therapies that regress or stabilize ICAS hasbeen hampered by the paucity of suitable animal models. During an R01-funded study to determine the impactof microRNA-33 (miR-33) antagonism on cardiovascular AVD we fortuitously discovered that our NHP modelhad ICAS and other neurovascular hallmarks of VCID. We believe analysis of intracranial arteries and brainsfrom our NHPs could have a high impact on the field of VCID research because of the potential discovery of anew therapy and animal model for VCID.

project_terms:
Acute;Affect;Age;Alzheimer's Disease;Animal Model;Apoptotic;Arterial Fatty Streak;Atherosclerosis;Attenuated;Autophagocytosis;Blood Vessels;Blood flow;Brain;Cardiovascular system;Cells;Cerebrovascular Circulation;Cholesterol;Chronic;Clinical;Data;Disease;Elderly;Endothelial Cells;Event;Extracellular Matrix Degradation;Family;Family member;Funding;Genes;Gliosis;Health;Human;Impaired cognition;Impairment;Individual;Infiltration;Inflammation;Inflammatory;Intracranial Atheroscleroses;Ischemic Stroke;Life;Link;Lipoproteins;Low-Density Lipoproteins;MicroRNAs;Modeling;Morbidity - disease rate;Mus;Myelogenous;Pathology;Pharmacology;Play;Population;Prevalence;Public Health;Research;Risk;Role;Rupture;Severities;Stenosis;Stroke;Testing;Therapeutic;Tissues;Transient Ischemic Attack;brain health;cholesterol trafficking;fatty acid oxidation;hypercholesterolemia;intracranial artery;lipid metabolism;macrophage;member;monocyte;mortality;neurovascular;nonhuman primate;novel therapeutics;prevent;stroke risk;vascular cognitive impairment and dementia

public_health_relevance:
Project NarrativeIntracranial atherosclerosis (ICAS) can cause reduced cerebral blood flow transient ischemic attacks andischemic strokes leading to vascular cognitive impairment and dementia. ICAS is particularly detrimental to thehealth of the geriatric population since it develops later in life than cardiovascular atherosclerosis. This projectwill employ a unique nonhuman primate model to test the hypothesis that microRNA-33 antagonism reducesICAS and other neurovascular pathologies associated with VCID.


application_id: 9765804
project_number: 1R01DA048617-01
project_title: Influence of Orexin Antagonism on Motivation for Cocaine
administering_ic: NIDA
award_notice_date: 2019-04-22
opportunity_number: PA-18-345
application_type: 1
activity_code: R01
ic: DA
serial_number: 048617
program_official: GRANT, STEVEN J
project_start_date: 2019-05-01
project_end_date: 2021-04-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTCocaine use disorder continues to be a significant public health concern. Despite great strides in ourunderstanding of the neurobiological underpinnings of cocaine addiction in preclinical models a limited amountof research has translated those findings into clinical populations. Such translation is crucial to identifyneurobiological circuits that contribute to the problems posed by cocaine use disorder and guide treatmentbased on those clinical neuroscience findings. One area of intense interest in preclinical research is the role ofthe orexin (also known as hypocretin) system in addiction. Through extrahypothalamic transmission the orexinsystem plays a key part in motivation for maladaptive rewards like drugs of abuse. Antagonism of the orexinsystem attenuates motivation for cocaine escalation of cocaine intake and reinstatement of cocaine seekingbehavior. The first and only clinically available orexin antagonist suvorexant (Belsomra) attenuatesmotivation for cocaine and cocaine conditioned place preference as well as cocaine-associated impulsiveresponding in non-human animals. Orexin antagonism generally does not alter adaptive behaviors like food orwater intake nor does it change cocaine-induced locomotion. Taken together these preclinical findingssuggest that orexin system antagonism selectively reduces motivation for cocaine as well as othermaladaptive cocaine-associated behaviors. Although a robust preclinical literature supports the premise thatorexin antagonism attenuates motivation for cocaine along with cocaines other abuse-related effects thisarea remains unstudied in humans. The overarching goal of this project is to translate promising preclinicalfindings into clinical populations thereby demonstrating that the orexin system plays a key role in motivationfor cocaine in humans. To this end non-treatment seeking human subjects meeting diagnostic criteria forcocaine use disorder will sample doses of intravenous cocaine in experimental sessions following maintenanceon a range of oral suvorexant doses. A placebo-controlled double-blind within-subjects design will be usedsuch that all subjects experience all dose conditions in random order. After sampling a cocaine dose subjectswill make choices between that dose and an alternative reinforcer on a concurrent progressive-ratio choicetask that was developed and validated in our laboratory. The use of concurrent progressive-ratio schedules ofdrug and non-drug reinforcer availability will allow inferences to be made about the relative influence of orexinantagonism on motivation to obtain these two types of reinforcers. A battery of subjective drug-effect measuresand cognitive tasks will also be completed to evaluate how orexin antagonism influences other cocaine-associated outcomes in humans. This research will translate findings from preclinical research and provide theinitial evidence that orexin antagonism reduces motivation for cocaine as well as other cocaine-associatedmaladaptive behaviors in active cocaine users. The proposed work seeks to expand the scope of currentclinical neuroscience research on cocaine addiction by focusing on orexin.

project_terms:
Adaptive Behaviors;American;Animals;Area;Attenuated;Basic Science;Behavior;Clinical;Cocaine;Cocaine Dependence;Cocaine Users;Cues;Diagnostic;Disease;Dopamine;Dose;Double-Blind Method;Eating;Genetic;Goals;Human;Hypothalamic structure;Impulsivity;Intake;Intravenous;Knock-out;Laboratories;Lateral;Literature;Locomotion;Maintenance;Measures;Motivation;Neurobiology;Neuropeptides;Neurosciences;Neurosciences Research;Oral;Outcome;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Placebos;Play;Population;Pre-Clinical Model;Public Health;Reporting;Research;Rewards;Role;Sampling;Schedule;Self Administration;Short-Term Memory;Signal Transduction;System;Time;Translating;Translations;Visual;Water consumption;Work;addiction;analog;attentional bias;base;cocaine overdose;cocaine use;cognitive task;design;drug of abuse;experience;genetic manipulation;human subject;hypocretin;interest;knock-down;meetings;men;non-drug;opioid overdose;pre-clinical;pre-clinical research;preclinical study;preference;receptor;reinforcer;response;sleep regulation;transmission process

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


application_id: 9765384
project_number: 5K22HL141299-02
administering_ic: NHLBI
award_notice_date: 2019-07-24
opportunity_number: PAR-16-267
application_type: 5
activity_code: K22
ic: HL
serial_number: 141299
program_official: HUANG, LI-SHIN
project_start_date: 2018-08-20
project_end_date: 2021-07-31
study_section: NHLBI Mentored Transition to Independence Study Section[MTI(JA)]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
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
budget_start_date: 2019-08-01
project_title:
The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.

project_abstract:
Project Summary and AbstractHigh density lipoproteins (HDL) have a well-established inverse correlation with the occurrence ofcardiovascular disease. However the functional activities of HDL which mediate this protection arenot well understood. HDL are micellar complexes composed of lipids and an array of differentproteins which are likely to confer specific functions to the HDL particles that carry them. Of morethan 85 identified HDL associated proteins over 20% have known functions related to proteaseinhibition the majority of these are members of the Serine Protease Inhibitor (SERPIN) family ofproteins. This proposal will examine the structural interaction between the most abundant HDL-boundSERPIN alpha-1-antitrypsin (A1AT) and HDL particles and also the functional consequences of thisinteraction. Dr. Gordon will use individual particle electron tomography a novel molecular imagingtechnique to determine the structural details of the interaction between A1AT and HDL and to identifythe region of the A1AT protein involved in binding. Using reconstituted HDL enriched with A1AT Dr.Gordon will investigate the capacity of these particles to reduce vascular protease activity andsubsequent atherosclerosis development in a mouse model. Additionally a novel HDL targeting smallpeptide mimetic of A1AT will be developed and evaluated for its capacity to prevent atherosclerosisdevelopment and to stabilize existing plaque in an effort to prevent thrombus formation andsubsequent cardiovascular events such as heart attack stroke or pulmonary embolism. This work has been proposed by Dr. Scott Gordon a postdoctoral fellow of the National HeartLung and Blood Institute at the National Institutes of Health as part of an NHLBI K22 CareerTransition Award. Dr. Gordon performed his graduate studies on the composition and function of HDLand has extended his previous work in the current proposal. A team of experienced mentors with avariety of skills related to aspects of this proposal has been assembled by Dr. Gordon to assist in thesuccessful completion of the proposed research as well as the successful transition of Dr. Gordoninto an independent tenure track academic faculty position at a major research university in theUnited States.

project_terms:
ATP binding cassette transporter 1;Active Biological Transport;Acute;Acute-Phase Reaction;Anti-inflammatory;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherosclerosis;Binding;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Career Transition Award;Cause of Death;Cell Culture Techniques;Cholesterol;Complex;Coronary Angiography;Coronary Artery Bypass;Data;Developed Countries;Developing Countries;Development;Dimensions;Elastases;Endothelium;Event;Faculty;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Histologic;Human;Imaging Techniques;In Vitro;Individual;Inflammation;Inflammatory Response;Infusion procedures;LDL Cholesterol Lipoproteins;Label;Leukocyte Elastase;Lipids;Lipoprotein Binding;Maps;Mass Spectrum Analysis;Measures;Mediating;Mentors;Methionine;Methods;Morphology;Mus;Myocardial Infarction;National Heart Lung and Blood Institute;Oxides;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Plasma;Plasma Proteins;Population;Positioning Attribute;Postdoctoral Fellow;Production;Property;Protease Inhibitor;Protein Family;Proteins;Pulmonary Embolism;Reporting;Research;Residual state;Risk;Role;Rupture;Serine Proteinase Inhibitors;Site;Site-Directed Mutagenesis;Small Interfering RNA;Stroke;Structure;Testing;Therapeutic;Thrombus;Tissues;Transference;United States;United States National Institutes of Health;Universities;Untranslated RNA;Up-Regulation;Variant;Vascular Endothelium;Work;alpha 1-Antitrypsin;base;cardiovascular risk factor;crosslink;cytokine;elastase inhibitor;electron tomography;experience;experimental study;genetic variant;human subject;in vivo;knock-down;macrophage;member;men;molecular imaging;mouse model;neglect;neutrophil;novel;overexpression;oxidation;particle;peptidomimetics;preservation;prevent;protein degradation;protein function;public health relevance;reconstitution;research clinical testing;skills;study population;tenure track;tool;transcytosis;uptake

public_health_relevance:
Public Health Relevance StatementCardiovascular disease is the leading cause of death in developed countries and atherosclerosis orhardening of the arteries is responsible for the occurrence of the majority of cardiovascular eventssuch as heart attack and stroke. High density lipoproteins (HDL) also known as the goodcholesterol have an established correlation with reduced risk of cardiovascular events. This proposalfocuses on a specific sub-population of HDL and its protective potential against atherosclerosis.


application_id: 9764049
project_number: 3P30ES026529-02S1
project_title: Center for Appalachian Research in Environmental Sciences
administering_ic: NIEHS
award_notice_date: 2018-09-03
opportunity_number: PA-18-770
application_type: 3
activity_code: P30
ic: ES
serial_number: 026529
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2017-05-01
project_end_date: 2022-03-31
study_section: Environmental Health Sciences Review Committee[EHS(P3)-1]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Air;Analytical Chemistry;Appalachian Region;Area;Arsenic;Asthma;Atherosclerosis;Awareness;Bioinformatics;Chemicals;Child Health;Chromium;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Complex;Computational Biology;Core Facility;Development;Diabetes Mellitus;Disease;Ecology;Environment;Environmental Health;Environmental Risk Factor;Exposure to;Fostering;Foundations;Funding;Genetic Predisposition to Disease;Goals;Health;Health Professional;Health Sciences;Healthcare;Heart;Heart Diseases;Heavy Metals;Human;Incidence;Individual;Integrative Medicine;Interest Group;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical center;Mentorship;Metabolic Diseases;Mining;National Institute of Environmental Health Sciences;Nickel;Obesity;Outcome;Particulate;Pilot Projects;Population;Positioning Attribute;Public Health;Pulmonary Heart Disease;Radon;Research;Research Infrastructure;Research Personnel;Resources;Rivers;Rural;Science;Scientist;Stimulus;Structure;Talents;Toxic Environmental Substances;Toxicology;Training;Training Activity;Translations;Universities;Vision;Water;base;career;career development;early life exposure;health science research;innovation;interest;member;metabolomics;neonate;novel;population health;programs;recruit;socioeconomic disadvantage;water quality


application_id: 9763943
project_number: 1R01CA232574-01A1
project_title: Treatment-Induced Phenotypic Reprogramming in Prostate Cancer
administering_ic: NCI
award_notice_date: 2019-01-24
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: CA
serial_number: 232574
suffix: A1
program_official: VENKATACHALAM, SUNDARESAN
project_start_date: 2019-02-01
project_end_date: 2019-06-30
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: UROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The androgen receptor (AR) is a critical driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) and AR-targeting particularly incombination with microtubule-targeting taxane chemotherapy offers survival benefits in mCRPC patients.However therapeutic resistance invariably develops leading to mortality. Understanding the mechanismsunderlying resistance is critical to improving therapeutic outcomes. Our work and others' established that ARnuclear localization is inhibited by docetaxel (1st line taxane chemotherapy) in androgen-sensitive prostatetumors. In contrast CRPCs express AR splice variants that remain capable of nuclear trafficking contributing totaxane resistance. Signaling interactions between androgens/AR and transforming growth factor- (TGF-)determine prostate tumor growth and invasion by regulating apoptosis and epithelial-mesenchymal transition(EMT). We recently found that cabazitaxel (2nd line taxane chemotherapy) can reverse EMT resulting in amesenchymal-epithelial transition (MET) and kinesin-mediated multi-nucleation without affecting nuclear AR inin vitro and in vivo prostate cancer models. This work provided the first evidence that cabazitaxel inducesphenotypic changes leading to prostate tumor re-differentiation (in addition to apoptosis) dictated by androgensand TGF-. Here we hypothesize that treatment with cabazitaxel causes apoptosis in some prostate tumor cellsbut also diversifies surviving cells into a re-differentiated state (via MET) that confers therapeutic resistance whileretaining AR and kinesin activity. We will test this hypothesis by assessing if MET-mediated phenotypicreprogramming of prostate cancer epithelial cells drives therapeutic resistance to taxane chemotherapy/ADTcombinations and if this resistance can be overcome by TGF- blockade. Three Specific Aims will be addressed:Specific Aim 1 will delineate the role of AR cross-talk with TGF- in programming prostate tumor MET inresponse to cabazitaxel in models of CRPC. Specific Aim 2 will determine the mechanisms via which prostatetumor cells undergo taxane-mediated re-differentiation to overcome therapeutic resistance in pre-clinical modelsof advanced prostate cancer. Specific Aim 3 will test the effect of inhibition of kinesins and centrosomeclustering on microtubule-facilitated AR degradation to sensitize prostate tumors to cabazitaxel. The proposedproject will provide new insights into the contribution of TGF- AR and kinesins in taxane-mediated phenotypicchanges and define treatment sequencing to overcome resistance in recurrent disease.

project_terms:
Address;Affect;Androgen Antagonists;Androgen Receptor;Androgens;Apoptosis;Apoptotic;Automobile Driving;Cancer Patient;Cell Death;Cell model;Cells;Centrosome;Clinical Trials;Combined Modality Therapy;Cytoplasmic Receptors;Data;Disease;Disease model;Epithelial;Epithelial Cells;Epithelium;FDA approved;Gland;Goals;Growth;Heterogeneity;Human;Impairment;In Vitro;Individual;Kinesin;Link;Malignant neoplasm of prostate;Mediating;Mesenchymal;Mesenchymal Cell Neoplasm;Metastatic Prostate Cancer;Microtubule Polymerization;Microtubules;Mitotic;Modeling;Molecular;Motor;Neoplasm Metastasis;Nuclear;Nuclear Receptors;Patients;Pharmaceutical Preparations;Phenotype;Population;Pre-Clinical Model;Process;Property;Prostatic Neoplasms;RNA Splicing;Receptor Cross-Talk;Receptor Signaling;Recurrence;Recurrent disease;Resistance;Resistance development;Role;Signal Transduction;Testing;Therapeutic;Transforming Growth Factor beta;Transforming Growth Factors;Tumor Cell Invasion;Variant;Work;Xenograft procedure;addiction;advanced disease;androgen deprivation therapy;androgen sensitive;antitumor effect;beta Tubulin;castration resistant prostate cancer;chemotherapy;docetaxel;epithelial to mesenchymal transition;improved;in vivo;in vivo Model;inhibitor/antagonist;insight;mortality;overexpression;prostate cancer cell;prostate cancer model;prostate cancer progression;response;targeted treatment;taxane;therapeutic target;therapy outcome;therapy resistant;tool;trafficking;translational impact;treatment response;treatment strategy;tumor;tumor growth;tumor progression

public_health_relevance:
Our goal is to overcome the therapeutic cross-resistance to 2nd line taxane chemotherapy and androgen-deprivation therapy (ADT) or androgen-receptor (AR) targeting therapy in advanced metastatic prostatecancer. This project will examine the consequences of cabazitaxel treatment on reversion of epithelial-mesenchymal-transition (EMT) to mesenchymal-epithelial-transition (MET) on the tumor glandular re-differentiation in pre-clinical models of prostate cancer progression to advanced disease (models will includeandrogen sensitive tumors and castration-resistant prostate cancer CRPC). Profiling the EMT phenotypic andmechanistic programming by taxane chemotherapy antiandrogens and TGF will enable new insights intosequencing treatment strategies of ADT cabazitaxel and TGF- blockade to overcome therapeutic resistancein CRPC impair lethal prostate cancer and thus impact patient survival.


application_id: 9763317
project_number: 5R01AR060701-10
project_title: Novel Roles for Satellite Cells in Adult Skeletal Muscle Adaptation
administering_ic: NIAMS
award_notice_date: 2019-06-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2021-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
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
project_abstract:
DESCRIPTION (provided by applicant):  Under the current award we have acquired exciting new evidence that satellite cells are necessary for the proper remodeling of the extracellular matrix during hypertrophy. We reported that in muscle depleted of satellite cells there was a significant increase in fibrosis that was associated with a blunted long-term hypertrophic response. Our preliminary data show that activated satellite cells/myogenic progenitor cells (MPCs) are capable of repressing the synthesis of extracellular matrix components by fibroblasts through exosomal delivery of microRNAs. We hypothesize that the loss of satellite cells removes this "brake" leading to the over-production of collagen and fibrosis ultimately limiting long-term hypertrophic growth. We further hypothesize that fibrosis as a result of loss ofsatellite cells preferentially limits growth in fast muscle fibers whereas growth of slow fibers i limited by myonuclear domain size. Thus fast fibers display a relatively flexible myonuclear domain whereas slow fibers may have a more stringent requirement for satellite cells for growth. The objectives of this proposal are to use genetic mouse models and in vitro cell culture to investigate these novel roles for satellite cells in skeletal muscle adaptation by pursuing the following aims. Aim 1 will determine the mechanisms underlying satellite cell regulation of extracellular matrix remodeling during skeletal muscle hypertrophy. Aim 2 will determine if fibrosis attenuates long-term hypertrophy in satellite cell-depleted muscle and the influence of fiber type composition. Aim 3 will determine if there is a fiber type-specific requirement for satellite cell fusion during skeletal muscle hypertrophy. Our published work and new preliminary data clearly show that our understanding of satellite cell function in adult skeletal muscle adaptation remains incomplete. The studies described in this proposal address this fundamental gap in our knowledge and are expected to provide critical information necessary to more effectively evaluate the use of satellite cells as a therapeutic agent to prevent or restore the los of skeletal muscle mass associated with dystrophies cancer age and rehabilitation following disuse.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Affect;Age;Aging;Area;Atrophic;Attenuated;Award;Biological Assay;Cell Culture Techniques;Cell Therapy;Cell fusion;Cell physiology;Chronic;Clinical;Coculture Techniques;Collagen;Data;Deterioration;Environment;Expression Profiling;Extracellular Matrix;Fiber;Fibroblasts;Fibronectins;Fibrosis;Foundations;Gene Expression;Genes;Genetic;Grant;Growth;HIV;Heart failure;Hypertrophy;Immobilization;In Vitro;Individual;Knockout Mice;Knowledge;Limb structure;Maintenance;Malignant Neoplasms;Mediating;MicroRNAs;Molecular;Morbidity - disease rate;Mouse Strains;Mus;Muscle;Muscle Fibers;Muscle function;Operative Surgical Procedures;Phenotype;Plantaris muscle;Process;Production;Publishing;Quality of life;Regulation;Rehabilitation therapy;Reporter;Reporting;Rheumatoid Arthritis;Role;Sepsis;Series;Skeletal Muscle;Skeletal Muscle Satellite Cells;Soleus Muscle;Stem cells;Systemic disease;Tamoxifen;Testing;Therapeutic Agents;Therapeutic Uses;Time;Untranslated Regions;Wasps;Weight;Work;base;cell growth;exosome;experimental study;extracellular;flexibility;in vivo;loss of function;mortality;mouse model;muscle form;muscle hypertrophy;novel;patient population;physical inactivity;prevent;public health relevance;response;sarcopenia;satellite cell;skeletal muscle plasticity;skeletal muscle wasting;stem

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  A decrease in skeletal muscle mass is of clinical importance because it is associated with increased morbidity and mortality as well as a marked deterioration in the quality of life. A broad patient population is affected by significant losses n muscle mass including those afflicted by various systemic diseases (cancer sepsis HIV- AIDS heart failure) chronic physical inactivity rheumatoid arthritis limb immobilization and sarcopenia. The purpose of this grant is to better understand the role of skeletal muscle stems (satellite cells) in muscle growth thereby providing a foundation for their therapeutic use to prevent or restore losses in skeletal muscle mass.


application_id: 9762926
project_number: 5R01ES028268-02
project_title: Effects of Air Pollution on Stem Cell Health
administering_ic: NIEHS
award_notice_date: 2019-04-05
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028268
program_official: SCHUG, THADDEUS
project_start_date: 2018-08-15
project_end_date: 2023-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: HILL, BRADFORD GUY
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;Aging;Air;Air Pollution;Angiogenic Factor;Animal Model;Atherosclerosis;Attenuated;Biological Markers;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cardiovascular system;Cell Aging;Cell physiology;Cells;Cellular Metabolic Process;Cessation of life;Chronic;Clinical;Clinical Research;Competence;Data;Defect;Development;Endothelium;Exposure to;Flow Cytometry;Functional disorder;Future;Generations;Glycolysis;Goals;Health;Hypertension;Impairment;In Vitro;Individual;Inflammation;Inhalation;Injury;Insulin;Intervention;Ischemia;Isotopes;Lead;Limb structure;Link;Lung;Mediator of activation protein;Metabolic;Metabolic dysfunction;Metabolism;Morbidity - disease rate;Mus;Nose;Outcome;Oxidative Phosphorylation;Oxidative Stress;Particulate Matter;Pathologic Processes;Phenotype;Proliferating;Prospective Studies;Research;Resistance;Risk;Secondary to;Signal Pathway;Signal Transduction;Stem cells;Superoxide Dismutase;Superoxides;Techniques;Testing;Therapeutic Intervention;Tissues;Treatment Efficacy;Tube;Vascular Endothelial Growth Factors;Work;air filter;angiogenesis;base;burden of illness;cardiovascular disorder risk;cardiovascular injury;endothelial dysfunction;extracellular;fine particles;improved;in vivo;mortality;novel strategies;overexpression;premature;prevent;repaired;response;tissue repair


application_id: 9762924
project_number: 5R01ES028256-02
administering_ic: NIEHS
award_notice_date: 2019-05-16
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028256
program_official: TYSON, FREDERICK L
project_start_date: 2018-08-15
project_end_date: 2023-05-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 14750127
contact_pi: WANG, ZHISHAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-06-01
project_title:
Epigenetic mechanism of the synergistic tumorigenic effect of arsenic and benzo[a]pyrene co-exposure

project_abstract:
PROJECT SUMMARY/ABSTRACTArsenic and benzo[a]pyrene (BaP) are among the most common environmental pollutants and human exposure toarsenic and BaP mixture is very common. Our knowledge on the effect and mechanism of arsenic and BaP co-exposure is limited. The goal of this study is to determine the mechanism of the effect of arsenic and BaP co-exposure. Epigenetics refers to heritable changes in the pattern of gene expression that are not caused by changesin DNA sequence but are mediated by DNA methylation histone posttranslational modifications and noncodingRNAs. Cancer stem cells (CSCs) are cancer cells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiating cells. While the mechanism of arsenic toxic effect is not clearly definedit is thought that the toxic effect of BaP mainly depends on its metabolic activation and DNA adduct formation. Thereported effects of arsenic on DNA adduct level are controversial suggesting that other mechanisms may play akey role in the combined effect of arsenic and BaP co-exposure. Our preliminary studies found: (i) Arsenic and BaPco-exposure has a synergistic effect in inducing cell transformation CSC-like property and lung tumors; (ii) Arsenicand BaP co-exposure has no synergistic effect on BPDE-DNA adduct level. In contrast the co-exposure shows asynergistic effect in epigenetic deregulations as evidenced by increasing the levels of histone H3K9methyltransferase SUV39H1 and H3 repressive methylation mark H3K9me2. Moreover the co-exposure alsoshows a synergistic effect in reducing the level of suppressor of cytokine signaling 3 (SOCS3) and increasing Aktand Erk1/2 activation; (iii) ShRNA knockdown SUV39H1 reduces H3K9me2 level increases SOCS3 level reducesAkt and Erk1/2 activation and soft agar colony formation and CSC-like property; (iv) Stably re-expressing SOCS3reduces Akt Erk1/2 activation soft agar colony formation and CSC-like property; (v) Inhibiting Akt and Erk/1/2reduces soft agar colony formation and CSC-like property; and (vi) Arsenic and BaP co-exposure significantlyincreases aryl hydrocarbon receptor (AhR) nuclear localization and siRNA knockdown AhR greatly reduces thelevel of SUV39H1 in arsenic and BaP co-exposure-transformed cells. Based on our preliminary data our centralhypothesis is: (i) Arsenic and BaP co-exposure up-regulates HMTase SUV39H1 via synergistically activating AhR;(ii) Up-regulation of SUV39H1 leads to SOCS3 down-regulation; and (iii) Down-regulation of SOCS3 causes astronger Akt and Erk1/2 activation which enhances cell transformation and CSC-like property thus increasing lungtumorigenesis. Three aims are proposed: Aim 1: Arsenic and BaP co-exposure significantly enhances celltransformation and tumorigenesis by up-regulating HMTase SUV39H1 via synergistically activating AhR. Aim2: SUV39H1 up-regulation by arsenic and BaP co-exposure enhances cell transformation and tumorigenesisby down-regulating SOCS3 leading to stronger activation of Akt and Erk1/2. Aim 3: Simultaneously inactivatingboth Akt and Erk1/2 by a natural compound Withaferin A impairs the synergistic effect of arsenic and BaP co-exposure in inducing cell transformation and lung tumorigenesis in mice.

project_terms:
A/J Mouse;Agar;Arsenic;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;CISH gene;CRISPR/Cas technology;Carcinogens;Cells;Characteristics;DNA;DNA Adduction;DNA Adducts;DNA Methylation;DNA Sequence;Data;Down-Regulation;Environmental Health;Environmental Pollutants;Epigenetic Process;Epithelial Cells;Exposure to;Gene Expression Profile;General Population;Goals;Heritability;Histone H3;Histones;Human;Impairment;Knock-out;Knowledge;Literature;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Meat;Mediating;Metabolic Activation;Methylation;Methyltransferase;Molecular Target;Mus;Nuclear Receptors;Nucleotide Excision Repair;Oral Administration;Pharmacology;Play;Post-Translational Protein Processing;Prevention strategy;Property;Reporting;Risk;Role;Small Interfering RNA;Source;Stem cells;Suspensions;Toxic effect;Untranslated RNA;Up-Regulation;arsenic carcinogenesis;base;cancer cell;cancer risk;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;cigarette smoke;contaminated drinking water;cooking;cytotoxic;disorder prevention;exposed human population;inhibitor/antagonist;insight;knock-down;lung tumorigenesis;novel;overexpression;protective effect;small hairpin RNA;stem-like cell;tumorigenesis;tumorigenic

public_health_relevance:
PROJECT NARRATIVEArsenic and benzo[a]pyrene (BaP) are among the most common environmental pollutants and human exposureto arsenic and BaP mixture is very common representing a major environmental health concern. The long termgoal of this study is to determine the mechanism of toxic effect of arsenic and BaP co-exposure and identifymolecular targets for better treatment and prevention of diseases resulting from arsenic and BaP co-exposure.


application_id: 9762908
project_number: 5R01EY026158-04
project_title: Cone Rescue in Retinitis Pigmentosa
administering_ic: NEI
award_notice_date: 2019-08-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 026158
program_official: NEUHOLD, LISA
project_start_date: 2016-09-01
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(04)S]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: MCCALL, MAUREEN A
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractA major cause of blindness in North America is hereditary retinal degeneration and RetinitisPigmentosa (RP) is the leading cause. RP is a group of inherited diseases characterized bythe onset of night blindness the early loss of the peripheral visual field and ultimately theloss of central vision. The most common form of autosomal dominant form of RP is causedby a Pro23His mutation in rhodopsin that results in retinal degeneration  i.e. P23Hretinopathy. We have created and characterized a miniature pig model of P23H retinopathyto investigate therapeutic options to prevent or delay the onset of visual loss.Multiple therapeutic approaches have been or are being considered to prevent/delay theprogression of RP including cell-based gene and drug therapies. Gene transfer in Leber'sCongenital Amaurosis (LCA) a small subset of RP patients shows very strong therapeuticpromise. That said gene therapy for other forms of RP faces several challenges includingthe wide variety of mutations associated with the disease. Cellbased transplantation of rodphotoreceptors derived from a number of sources seeks to reverse the progression of RP.Although the early stage of RP is marked by the onset of rod degeneration in mid-peripheral retina only in the late stages of the disease when retinal degenerationapproaches the macula and cone degeneration ensues do most patients find themselveswith a severe visual handicap. It also is well established that in RP cone survival dependson normal rods. We have preliminarily observed that transplanted rod photoreceptorsderived from pig induced Pluripotent Stem Cells (iPSCs) injected beneath the retina in ourpig model of P23H retinopathy will rescue cones morphologically and functionally in the areacentralis (analogous to the macula in man). We will confirm this observation explore thesynergistic effect of neuroprotection with rod derived cone viability factor (RdCVF) andfurther investigate the mechanism of cone loss in our model. Our studies have the potentialto prevent the onset of functional blindness in the majority of patients with RP not onlythose with the P23H mutation.

project_terms:
ARHGEF5 gene;Adult;Animal Model;Area;Binding;Birth;Blindness;Cell Differentiation process;Cell Transplantation;Cell Transplants;Cells;Color Visions;Cone;Disabled Persons;Disease;Electrophysiology (science);Endoplasmic Reticulum;Evaluation;Face;Family member;Family suidae;Gene Transfer;Genes;Glucose;Hereditary Disease;Inherited;Label;Leber's amaurosis;Light;Mitochondria;Modeling;Molecular Conformation;Morphology;Mus;Mutation;Neuroprotective Agents;Night Blindness;North America;Opsin;Patients;Peripheral;Pharmacotherapy;Population;Prevention;Process;Reading;Resolution;Retina;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinal Pigments;Retinitis Pigmentosa;Rhodopsin;Rod Outer Segments;Series;Source;Starvation;Stem cell transplant;Structure;Symptoms;TXN gene;Therapeutic;Time;Transplantation;Vertebrate Photoreceptors;Vision;Visual;Visual Fields;base;fetal;gene therapy;glucose transport;glucose uptake;hereditary blindness;in vivo;induced pluripotent stem cell;macula;man;mutant;neuroprotection;overexpression;preservation;prevent;restoration;retinal rods;sensor;synergism

public_health_relevance:
Project NarrativeFunctional blindness in Retinitis Pigmentosa (RP) the most common form of hereditaryblindness is ultimately caused by the loss of central vision late in the course of disease from theloss of cone photoreceptors. We propose to transplant rod precursors derived from iPSC(induced Pluripotent Stem Cells) as well as a neuroprotective factor (rod-derived cone viabilityfactor  RdCVF) in our pig model of the most common form of RP to preserve/rescue conesfrom dying. Our ultimate aim is to prevent functional blindness accompanying the late stages ofRP in man.0925-0001/0002 (Rev. 08/12) Page Continuation Format Page


application_id: 9762631
project_number: 5R13OD021318-05
project_title: Comparative Medicine Resource Directors Meetings
administering_ic: OD
award_notice_date: 2019-08-15
opportunity_number: PA-13-347
application_type: 5
activity_code: R13
ic: OD
serial_number: 021318
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-09-01
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-C(90)S]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
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:
DESCRIPTION (provided by applicant): This application requests funds to support the 11th Comparative Medicine Resource Center Directors' Meeting in 2016 and then meetings in 2018 and 2020. The purpose of these meetings is to provide a forum for Directors of Resource Centers that are funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (ORIP) Division of Program Coordination Planning and Strategic Initiatives. The discussion and action items deriving from these meetings identify opportunities and challenges that Resource Directors face in administering and innovating resources in support of biomedical research. A Scientific Steering Committee will set the agenda for each meeting. Tentatively meetings will include a keynote address by a prominent Resource Director presentations by ORIP-funded scientists and NIH staff moderator led discussions and a poster session. The initial meeting will be held in Bethesda MD at the Doubletree Hotel for 2 days in August 2016. Bethesda offers the advantage of proximity to NIH and thus greater participation of NIH staff and scientists in the meeting. The location of subsequent biennial meetings will be determined after the first meeting.

project_terms:
Address;Biocompatible Materials;Biomedical Research;Collaborations;Development;Face;Fostering;Funding;Grant;Location;Medicine;Mission;Request for Applications;Request for Proposals;Research Infrastructure;Resources;Scientist;United States National Institutes of Health;comparative;design;innovation;meetings;posters;programs;public health relevance;symposium;working group

public_health_relevance:
PUBLIC HEALTH RELEVANCE   This grant will support three conferences over a five-year period to convene the Directors of Resource Centers funded by the National Institutes of Health Office of Research Infrastructure (ORIP) Division of Program Coordination Planning and Strategic Initiatives. The objectives of the conference are to provide a forum for Directors to discuss common issues and problems relevant to fulfilling the mission of ORIP to receive input and guidance from NIH staff and scientists and to share ideas for common solutions.


application_id: 9762248
project_number: 3U01AA026980-01S1
project_title: Alcoholic Hepatitis Network 3/9 University of Louisville
administering_ic: NIAAA
award_notice_date: 2018-09-25
opportunity_number: PA-18-591
application_type: 3
activity_code: U01
ic: AA
serial_number: 026980
suffix: S1
program_official: GAO, PETER
project_start_date: 2018-09-01
project_end_date: 2022-06-30
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adrenal Cortex Hormones;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collection;Conduct Clinical Trials;Data;Data Coordinating Center;Data Set;Databases;Development;Disease;Economic Burden;Educational workshop;Eligibility Determination;FDA approved;Foundations;Funding;Future;Goals;Granulocyte Colony-Stimulating Factor;Hepatitis B;Infection;Inflammasome;Inflammation;Informatics;Institution;Interleukin-1 Receptors;Interleukin-1 beta;Label;Laboratories;Life;Light;Literature;Liver;Liver diseases;Medical;Mission;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Observational Study;Oral cavity;Outcome;Pathogenesis;Patient Care;Patient Recruitments;Patients;Pentoxifylline;Pharmaceutical Preparations;Phase;Pilot Projects;Positioning Attribute;Predisposition;Prednisone;Public Health;Randomized;Recording of previous events;Research Design;Research Personnel;Resources;Role;Sampling;Severities;Systems Biology;Testing;Therapeutic;Therapeutic Studies;Translational Research;Treatment Efficacy;Universities;Validation;Work;Zinc;active method;anakinra;base;catalyst;drug testing;effective therapy;efficacy trial;evidence base;improved;insight;interest;liver injury;longitudinal database;meetings;mortality;new therapeutic target;novel;primary endpoint;prospective;receptor;repository;research study;secondary endpoint;standard of care;targeted treatment;therapeutic development;translational study;treatment arm


application_id: 9762188
project_number: 5R01HL131782-03
project_title: Monomeric G-proteins and Cardioprotection from Heart Failure
administering_ic: NHLBI
award_notice_date: 2019-08-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131782
program_official: SCHWARTZ, LISA
project_start_date: 2017-09-01
project_end_date: 2021-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: ANDRES, DOUGLAS ALLEN
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:
Monomeric G-proteins and Cardioprotection from Heart FailureHeart failure incidence in the United States is steadily increasing with annual costs in excess of $30 billion andthe cost is expected to increase 127% between now and 2030. Heart failure with reduced ejection fraction(HFrEF) occurs in ~45% of HF patients and is associated with longer survival compared to HF with preservedejection fraction; however treatment options are poor and are limited to increasing survival without improvingsystolic function. Success of agents such as -blockers to prolong lifespan (not necessarily quality of life) ofHFrEF draws attention away from the fundamental principle that in HFrEF the heart defect is failure to contractwith sufficient force to meet demand. This new proposal is motivated by our findings of a novel cardiacphenotype caused by deletion of the Rad-GTPase. Rad-null mice (Rad-/-) show increased cardiac contractilitythat persists well into senescence and out-performs age- and gender-matched animals. Rad-/- mice also showcardioprotection against chronic catecholamine stimulation and against chronic pressure overload. In thisproposal we will test two classes of potentially related but mutually exclusive mechanistic hypothesis. First wewill evaluate the contribution of altered Ca2+ homeostasis in response to Rad ablation; and second we willassess Rad contributions to the -adrenergic receptor (-AR) signaling axis. Three complementary Aims guideour studies. First we will test the hypothesis that Rad-ablation confers enhanced function via sarcolemmalCa2+ influx. These experiments will traverse scales of function from molecular to whole organ. Cardiacmagnetic resonance imaging (CMR) and echocardiography will also be used to measure in vivo heart function.Second we will evaluate the hypothesis that Rad deletion contributes to cardioprotection via enhancement ofintracellular Ca2+ synchrony and preservation of -AR signaling. Again assessments of heart structure andfunction will traverse scales from molecular to cellular to organ level and in vivo function. Our third aimfocuses on Rad-deletion as a potentially beneficial therapeutic approach. Overall this proposal tests a novelmechanism of augmentation of cardiac function that confers cardioprotection against sustained pressureoverload and chronic stress signaling.

project_terms:
ADRBK1 gene;Ablation;Acute;Adrenergic Receptor;Age;Agonist;Animal Model;Animals;Arrhythmia;Attention;Cardiac;Cardiac Myocytes;Catecholamines;Chronic;Chronic stress;Contracts;Data;Development;Disease;EFRAC;Echocardiography;Failure;Gender;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Heart;Heart Abnormalities;Heart Hypertrophy;Heart failure;Homeostasis;Hypertrophy;Incidence;Knockout Mice;Laboratories;Longevity;Magnetic Resonance Imaging;Measures;Molecular;Monomeric GTP-Binding Proteins;Mus;Myocardial;Myocardium;Organ;Pathologic;Pathway interactions;Patients;Phenotype;Quality of life;RNA Interference;Receptor Signaling;Reducing Agents;Regulation;Risk Factors;Signal Transduction;Stress;Structure;Symptoms;System;Testing;Therapeutic;Time;Tissues;United States;Ventricular Remodeling;Viral;base;beta-adrenergic receptor;cardioprotection;cost;experimental study;genetic manipulation;heart function;improved;in vivo;innovation;molecular scale;novel;preservation;pressure;receptor function;response;senescence;success

public_health_relevance:
Heart failure is a major health problem in the United States and a major risk factor is old age.By definition heart failure involves the inability of the heart to generate sufficiently forcefulcontractions - defined as an insufficient inotropic response. This proposal tests a novel putativetherapeutic direction that provides positive inotropic support to the failing myocardium along withprotection against stress-induced remodeling.


application_id: 9762082
project_number: 5R01DK080770-09
project_title: Renal Osteodystrophy: A Fresh Approach
administering_ic: NIDDK
award_notice_date: 2019-06-25
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 080770
program_official: CHAN, KEVIN E
project_start_date: 2008-04-01
project_end_date: 2021-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Renal osteodystrophy (ROD) represents the bone histologic abnormalities resulting from loss of renal function. It starts early during the loss of kidney function and is seen in virtually all chronic end stage kidney disease patients on dialysis (CKD-5D). A major component of ROD is bone loss leading to CKD-associated osteoporosis. Debilitating hip fractures occur in patients with CKD at a rate 4.4 times higher than in the general population with associated high costs morbidity and an annual mortality of 64%. CKD osteoporosis is distinctly different from post-menopausal osteoporosis. Presently no uniformly accepted CKD osteoporosis treatment protocol exists because of challenges related to racially specific bone turnover states. Therefore most physicians are reluctant to treat this disorder despite the profound impact on health and quality of life and its association with vascular calcifications. These vascular calcifications confer an increased risk for cardiovascular events which are the major cause of the over 20% annual mortality rate in CKD-5D patients. The goal of the proposed controlled randomized study is to test the concept that CKD osteoporosis can be successfully treated when treatment is individualized by patients' turnover status. The study will demonstrate that reversal of bone loss can be achieved by increasing bone formation in low turnover patients and by reducing bone resorption in normal or high turnover patients. A second aim of this study is to provide new information whether these treatments will also retard progression of vascular calcifications. Blood tests measuring FGF23 indicators of Wnt pathway activity bone resorption and formation will be followed to understand potential mechanisms and to evaluate their usefulness for prediction of changes in bone mass and vascular calcifications. CKD-5D patients with established osteoporosis will be enrolled into one of two treatment arms based on bone turnover status. Each arm will be adaptively randomized by race age and gender into treatment or control groups. In the low turnover arm teriparatide combined with cinacalcet will be given and in the normal or high turnover arm alendronate will be administered. Bone mineral density will be measured at baseline and after one year of treatment by quantitative computed tomography. Calcifications of the coronaries aorta and heart valves will also be measured at the same times by multi-detector computed tomography. If this proof-of-concept study is successful it will offer a heretofore unavailable treatment for osteoporosis i CKD-5D patients thus changing the prevailing clinical practice paradigm. This will provide immediate benefit to CKD patients by reducing fracture risk bone pain and cardiovascular risk while greatly improving their quality of life. These improvements will also convey major socioeconomic benefits by decreasing the high associated treatment costs. The proposed study is highly relevant to the NIDDK's mission of disseminating science-based information to improve the health and quality of life for patients with endocrine metabolic and kidney diseases.

project_terms:
Address;Affect;Age;Alendronate;Alkaline Phosphatase;Aorta;Biochemical;Blood;Blood Tests;Bone Density;Bone Diseases;Bone Pain;Bone Resorption;Categories;Chronic;Chronic Kidney Failure;Clinical;Control Groups;Coronary;Data;Dialysis procedure;Disease;End stage renal failure;Endocrine System Diseases;Enrollment;Event;FDA approved;Forteo;Funding;Gender;General Population;Goals;Health;Heart Arrest;Heart Valves;Hip Fractures;Histologic;Individual;Kidney Diseases;Link;Malignant Neoplasms;Measures;Metabolic Diseases;Minerals;Mission;Monitor;Morbidity - disease rate;Myocardial Infarction;N-terminal;National Institute of Diabetes and Digestive and Kidney Diseases;Operative Surgical Procedures;Osteogenesis;Osteoporosis;PTH gene;Pathway interactions;Patients;Physicians;Postmenopausal Osteoporosis;Procollagen;Quality of life;Race;Randomized;Randomized Controlled Trials;Renal Osteodystrophy;Renal function;Research;Safety;Science;Serum;Severities;Stroke;Telephone;Testing;Therapeutic;Time;Treatment Cost;Treatment Protocols;United States;United States National Institutes of Health;Vascular calcification;Visit;X-Ray Computed Tomography;arm;base;bone;bone loss;bone mass;bone turnover;calcification;cardiovascular risk factor;cinacalcet;clinical practice;coronary artery calcification;cost;detector;fibroblast growth factor 23;fracture risk;improved;individualized medicine;mortality;novel;patient response;primary endpoint;public health relevance;response;secondary endpoint;socioeconomics;tartrate-resistant acid phosphatase;treatment arm;treatment group;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: More than 30 million people in the United States have chronic kidney disease and this research will provide proof of concept for a novel osteoporosis treatment regimen for patients with late-stage chronic kidney disease. There is currently no established treatment regimen for chronic kidney disease associated osteoporosis even though it is associated with early and frequent debilitating hip fractures which require costly surgery result in reduced quality of life high mortality and impose an enormous socioeconomic burden. The study will also provide information whether this novel treatment will reduce the relentless progression of vascular calcifications in these patients which have been linked to heart attack cardiac arrest and stroke resulting in an annual mortality that exceeds many cancers.


application_id: 9761931
project_number: 5U01CE002711-05
administering_ic: NCIPC
award_notice_date: 2019-08-27
opportunity_number: RFA-CE-15-002
application_type: 5
activity_code: U01
ic: CE
serial_number: 002711
program_official: PANERO, MARIA SUSANA
project_start_date: 2015-09-30
project_end_date: 2020-09-29
study_section: ZCE1-EEO(02)
contact_pi_person_id: 9182607
contact_pi: WENDEL, MONICA L.
other_pis: NATION, MAURY A
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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-09-30
project_title:
Changing the Narrative:  Using Media to Shift Social Norms of Violence Among Youth in West Louisville

project_abstract:
DESCRIPTION (provided by applicant): Youth violence is a serious public health issue particularly in the disproportionate burden upon economically disadvantaged inner city and minority populations. Intentional injury is the leading cause of death among persons 10 to 24 years of age in Kentucky and the second leading cause of death for this age group nationally. Alarmingly Kentucky's homicide rate for this same age group is 10 times higher for Black males (38.7/100000) than for White males (3.9/100000). In Louisville KY substantial social and health disparities-including violence and related risk factors-are concentrated in West Louisville (WL) an economically disadvantaged urban primarily Black community. Led by the School of Public Health & Information Sciences (SPHIS) researchers at the University of Louisville (UofL) propose to establish the UofL Youth Violence Prevention Center partnering with researchers from Vanderbilt University. The specific aims of the proposed center include: 1. Strengthen the infrastructure to support youth violence prevention research and practice at the University of Louisville. 2. Develop implement and evaluate a community-level social norming campaign to change the norms of violence among youth in West Louisville using mass and social media. 3. Document the development and implementation of the social norming campaign to improve replication and scalability in other settings or communities. 4. Evaluate the relationship between community readiness community capacity and the implementation of the community-level social norming campaign. 5. Disseminate study findings in meaningful and actionable format to a variety of relevant audiences (i.e. community local organizations and leaders youth violence prevention researchers and practitioners academic peers and policy-makers). The interdisciplinary research team proposes a quasi-experimental design to examine the effectiveness of using a community-level 3-year social norming campaign utilizing new media to change norms of violence among youth 10-24 and introduce prosocial norms driven by cultural identity with WL as the intervention community and East Nashville TN as the control community. The researchers and a team of community collaborators will with a professional advertising agency to plan and design the campaign which will be deployed in Year 2. Surveys and interviews will capture data measuring our dependent variables of social norms and violent behavior (independent variables: campaign exposure by media type demographics) and population-level youth violence data from schools emergency departments and local police departments will offer measures of change in serious youth violence at the population level.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Intentional injury is the leading cause of death among youth ages 10 to 24 in Kentucky and the homicide rate in the state for the same age group is 10 times higher for Black males (38.7/100000) than for White males (3.9/100000). Youth in West Louisville a predominantly Black economically disadvantaged urban community are subjected to social norms of violence. A targeted community-level social norming campaign holds potential to shift existing norms and reduce serious violence among young people in this community.


application_id: 9761586
project_number: 5R01NS107548-02
administering_ic: NINDS
award_notice_date: 2019-08-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 107548
program_official: FOUNTAIN, JANE W
project_start_date: 2018-08-15
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
project_terms:
ABCG2 gene;AKT inhibition;Antineoplastic Agents;Blood - brain barrier anatomy;Blood capillaries;Brain;Brain Neoplasms;Cells;Cerebral hemisphere;Clinic;Clinical;Contralateral;Data;Development;Distant;Drug Efflux;Excision;FRAP1 gene;Failure;Glioblastoma;Goals;Human;Individual;Ipsilateral;Knowledge;Lateral;Lead;Mediating;Mission;Modeling;Molecular;Mus;National Institute of Neurological Disorders and Stroke;Natural regeneration;Outcome;P-Glycoprotein;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Primary Neoplasm;Public Health;Regulation;Research;Research Personnel;Signal Transduction;Solid;System;TNF gene;TNFRSF1A gene;Testing;Therapeutic;Translating;Treatment Efficacy;Treatment outcome;United States National Institutes of Health;Work;base;cerebral capillary;effective therapy;evidence base;expectation;improved;in vivo;inhibitor/antagonist;innovation;lapatinib;neoplastic cell;nervous system disorder;novel;novel strategies;overexpression;prevent;treatment strategy;tumor;uptake


application_id: 9760038
project_number: 3R01AT009268-02S1
project_title: Mechanisms underlying anabolic effects of cyclic compressive loading in muscle
administering_ic: NCCIH
award_notice_date: 2018-09-11
opportunity_number: PA-18-658
application_type: 3
activity_code: R01
ic: AT
serial_number: 009268
suffix: S1
program_official: MUDD, LANAY MARIE
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-R(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
project_abstract:
The loss of skeletal muscle mass is a main contributor to disability in numerous disease states and is also apredictor of mortality and a major factor in the loss of independence in the elderly. We propose that massage isa novel intervention to attenuate acute muscle atrophy or aid with regrowth after muscle loss in patients whoare unable to perform exercise. Massage is a manual therapy modality extensively used clinically for pain reliefand as a modulator of immune responses; however very few investigations have addressed the actualunderlying mechanisms of the beneficial effects of massage mainly because of the lack of consistency in theapplied load. Using an innovative cyclic compressive loading (CCL) device for small rodents mimickingmassage with a well-defined load we showed that CCL elevated protein synthesis when administered duringdisuse or recovery after atrophy and enhanced the regrowth response in adult rats in the massaged limbwhile no effect was seen in unperturbed or aged rats. Surprisingly we also found a positive regrowth responsein the contralateral non-massaged limb. We suggest that protein synthesis is elevated throughmechanosensitive anabolic pathways such as the focal adhesion complexes including focal adhesion kinase(FAK) and integrin-linked kinase (ILK) in the massaged limb and that the growth effect in the non-massagedlimb is mediated by a neuronal cross-over effect or by systemically-mediated mechanisms. These preliminarydata led to following hypothesis: Massage in the form of CCL exerts an anabolic effect on muscledirectly through mechanosensitive pathways as well as indirectly by neurally or systemically mediatedmechanisms to enhance muscle size in perturbed growth states. We will use CCL in rats to study themuscle growth response using growth perturbations i.e. disuse atrophy and regrowth after atrophy. In Aim 1we will establish mechanisms for the attenuated growth response to CCL in muscles from aged compared toadult rats and test the hypothesis that muscles from aged rats show an attenuated response to CCL becauseof a stiffer extracellular matrix and a change in the pool of proteins synthesized. In Aim 2 the mechanosensitivepathways responsible for the growth response in skeletal muscle from adult rats after CCL will be investigatedwith particular attention to FAK and the role of satellite cells. In Aim 3 we will test the hypothesis that theincrease in protein synthesis and muscle size in the contralateral non-massaged limb after CCL is due to asensory feedback-regulated cross-over effect but will also investigate systemic-mediated actions such ascytokines and exosome-mediated transfer of miRNAs. Results from these studies will indicate whethermassage is a viable intervention for preventing the loss of muscle mass during disuse or promoting regrowth ofmuscle after atrophy while determining the underlying mechanisms for the beneficial anabolic effects.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Adult;Aging;Animals;Atrophic;Attention;Attenuated;Biochemical Pathway;Biology;Clinical;Complementary Health;Complex;Congestive Heart Failure;Contralateral;Data;Development;Devices;Disease;Disuse Atrophy;Elderly;Endocrine;Exercise;Extracellular Matrix;Focal Adhesion Kinase 1;Focal Adhesions;Growth;Immune response;Integrative Medicine;Intervention;Investigation;Knowledge;Lead;Limb structure;Maintenance;Malignant Neoplasms;Manipulative Therapies;Massage;Mechanical Stimulation;Mechanics;Mediating;MicroRNAs;Modality;Morbidity - disease rate;Muscle;Muscle Weakness;Muscular Atrophy;NIH Program Announcements;Neurons;Pathway interactions;Patients;Periodicity;Play;Protein Biosynthesis;Proteins;Quality of life;Rattus;Recovery;Reproducibility;Research;Rodent;Role;Skeletal Muscle;Standardization;Symptoms;Testing;Therapeutic Intervention;aged;clinical pain;cytokine;direct application;disability;exosome;functional decline;innovation;integrin-linked kinase;mechanotransduction;mortality;muscle form;novel;pain relief;patient population;prevent;relating to nervous system;response;restoration;satellite cell;sensory feedback;skeletal muscle wasting


application_id: 9759348
project_number: 1F30CA232550-01A1
project_title: The role of MIF in mitochondrial metabolism and M2-TAM polarization
administering_ic: NCI
award_notice_date: 2019-02-22
opportunity_number: PA-18-673
application_type: 1
activity_code: F30
ic: CA
serial_number: 232550
suffix: A1
program_official: BIAN, YANSONG
project_start_date: 2019-03-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1 F09C-Q (20)]
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
project_terms:
Adopted;Anaerobic Bacteria;Binding;Biogenesis;Biological Assay;COPS5 gene;Cancer Patient;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;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Incidence;Interleukin-4;Laboratories;Lead;Link;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;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;tumorigenic;uptake


application_id: 9759334
project_number: 1R13HL147519-01
project_title: Vascular Discovery: From Genes to Medicine Scientific Sessions 2019
administering_ic: NHLBI
award_notice_date: 2019-03-04
opportunity_number: PA-18-648
application_type: 1
activity_code: R13
ic: HL
serial_number: 147519
program_official: CHARETTE, MARC F
project_start_date: 2019-05-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZHL1 CSR-X (F1)]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Councils on Arteriosclerosis Thrombosis and Vascular Biology (ATVB) and PeripheralVascular Disease (PVD) of the American Heart Association (AHA) hold an annual SpringMeeting the most recent of which Vascular Discovery: From Genes to Medicine was held inSan Francisco CA May 10-12 2018. The meeting was a resounding success with >830registrants representing 23 different countries. Five hundred and sixty-five abstracts weresubmitted an 8% increase over the previous year. These encouraging statistics providetangible evidence of the broad interest and commitment of the scientific community in the topicareas of ATVB PVD and vascular medicine and the overwhelming enthusiasm for the formatand atmosphere of this meeting. Basic scientists translational researchers and cliniciansseasoned investigators and early career scientists enjoy coming to this AHA Spring meeting.The next Vascular Discovery conference will be held May 14-16 2019 at the Marriott CopleySquare Hotel Boston. As with previous applications this proposal specifically requestssupport for our Young Investigator Travel Awards. Knowing that early stage investigators arethe future of our scientific progress a major emphasis of our annual conference is toencourage the active involvement of the younger cohort of investigators in the ATVB and PVDCouncils of the AHA and recognize their achievements. Young Investigator Travel Awardshave been supported by the NIH/NHLBI for 17 years. These awards are an integral part of ourstrategy to recruit retain and actively engage young investigators in the fields ofarteriosclerosis thrombosis vascular biology and vascular medicine research that are ofmajor importance to the NIH-NHLBI and the health of the U.S. population.!

project_terms:
Achievement;American Heart Association;Area;Arteriosclerosis;Atmosphere;Award;Basic Science;Biology;Blood Vessels;Boston;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Clinical;Collaborations;Communities;Country;Data;Development;Discipline;Education;Eye;Faculty;Fostering;Functional disorder;Funding;Future;Genomic medicine;Goals;Grant;Health;Heart Diseases;Individual;Interactive Communication;International;Medicine;Minority Groups;Mission;Morbidity - disease rate;National Heart Lung and Blood Institute;Oral;Peripheral Vascular Diseases;Physiology;Population;Request for Proposals;Research;Research Personnel;San Francisco;Science;Scientist;Seasons;Stream;Students;System;Talents;Technology;Thrombosis;Travel;Twitter;Underrepresented Groups;United States National Institutes of Health;Work;base;career;clinical application;cohort;crowdsourcing;flipped classroom;functional genomics;gene discovery;hands-on learning;innovation;interest;meetings;member;new technology;next generation;peer;posters;precision medicine;preclinical study;programs;recruit;statistics;success;symposium;translational physician;translational scientist

public_health_relevance:
This renewal application seeks support for Travel Awards for Young Investigators to attend the2019 Vascular Discovery: From Genes to Medicine Scientific Sessions. This conference isorganized by the Arteriosclerosis Thrombosis and Vascular Biology (ATVB) and PeripheralVascular Disease (PVD) Councils of the American Heart Association. The Vascular Discoveryconference provides unique opportunities for early stage investigators to meet peers presenttheir work and interact with senior colleagues across distinct disciplines that have an interest incardiovascular disease as a unifying theme.


application_id: 9758771
project_number: 3P30CA177558-06S4
project_title: Clinical Protocol and Data Management
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5639
contact_pi_person_id: 6772940
contact_pi: ARNOLD, SUSANNE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adherence;African American;Appalachian Region;Biometry;Cancer Center;Cancer Center Support Grant;Catchment Area;Child;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Medicine;Clinical Protocols;Clinical Research;Clinical Research Associate;Clinical Trials;Conduct Clinical Trials;Data;Data Collection;Devices;Disease;Doctor of Pharmacy;Ensure;Ethnic Origin;Female;Funding Agency;Gender;Genomics;Goals;Guidelines;Hispanics;Histologic;Incidence;Institution;Institutional Review Boards;Intervention;Investigation;Investigational Drugs;Kentucky;Latino;Leadership;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of prostate;Minority;Mission;Monitor;NCI Center for Cancer Research;National Cancer Institute;National Clinical Trials Network;Nephroblastoma;Neuroblastoma;Nurses;Participant;Pediatric Hematology;Pediatric Oncology;Pediatric Oncology Group;Peer Review;Performance;Physician Executives;Primary carcinoma of the liver cells;Procedures;Protocol Compliance;Protocols documentation;Race;Reporting;Research;Research Activity;Research Personnel;Research Priority;Resource Allocation;Resource Sharing;Risk;Safety;Services;Supervision;System;Toxic effect;Training;Translational Research;United States Food and Drug Administration;United States National Institutes of Health;Universities;Vision;Woman;anticancer research;base;cancer clinical trial;clinical care;clinical translation;data management;design;experience;improved;industry partner;informatics shared resource;investigator-initiated trial;leukemia/lymphoma;malignant breast neoplasm;minority children;named group;operation;osteosarcoma;patient safety;precision medicine;protocol development;quality assurance;response;support tools;working group


application_id: 9758770
project_number: 3P30CA177558-06S4
project_title: Leadership Planning and Evaluation
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5638
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Advisory Committees;Area;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Consultations;Decision Making;Department chair;Development;Doctor of Philosophy;Education;Ensure;Evaluation;Faculty Recruitment;Feedback;Fostering;Foundations;Funding;Funding Mechanisms;Future;Goals;Grant;Growth;Kentucky;Lead;Leadership;Maps;Medicine;Mentors;Mission;NCI Center for Cancer Research;National Cancer Institute;Outcome;Phase;Policies;Population Research;Precision Medicine Initiative;Prevention education;Process;Reporting;Research;Research Infrastructure;Resource Sharing;Resources;Retreatment;Review Committee;Science;Strategic Planning;Training and Education;Translational Research;Translations;Universities;Update;Vision;Work;anticancer research;base;cancer education;cancer prevention;cancer research center director;career development;clinical care;clinical translation;college;experience;inter-institutional;meetings;member;mentoring community;operation;outreach;precision medicine;programs;recruit;training opportunity;translational scientist


application_id: 9758768
project_number: 3P30CA177558-06S4
project_title: Community Outreach and Engagement
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5636
contact_pi_person_id: 9121886
contact_pi: VANDERPOOL, ROBIN C
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 The National Cancer Institute (NCI)-designated University of Kentucky (UK) Markey Cancer Center (MCC)defines its catchment area as the Commonwealth of Kentucky with a special focus on the underservedcommunities of Appalachian Kentucky. There is no greater need for a Comprehensive NCI Cancer Center thanin Kentucky which is recognized for the highest overall cancer incidence and mortality rates in the UnitedStates significantly elevated rates of cancer risk factors such as tobacco use and obesity and severesocioeconomic disparities. The MCC has been at the forefront of combatting cancer and its related disparitiesin Kentucky for over 40 years through innovative cancer research clinical care and community outreach. Ledby Dr. Robin Vanderpool (CP) Director of MCC Community Outreach and Engagement MCCs communityoutreach and engagement infrastructure includes: the MCC Network consisting of the MCC Research Network(MCCRN 6 community sites) and MCC Affiliate Network (MCCAN 18 community hospitals); the developingBehavioral and Community-Based Research Shared Resource Facility (BCBR SRF); the Kentucky CancerRegistry; multiple cancer center and state outreach programs; well-aligned MCC cancer research projects;UKs rurally placed health care professional education and community resources; and other vested localstate national and international stakeholders. Utilizing this unique infrastructure and diverse network ofpartners as well as data- and context-driven approaches to working with communities MCC has an extensiveportfolio of innovative and impactful projects focused on effective cancer control practices and health policyrecommendations that have reached thousands of Kentucky residents and health care professionals. Withcontinued CCSG funding the MCC is well positioned to use this remarkable and expanding infrastructure toimpact cancer within and beyond Kentucky and respond to emerging public health issues. The MCCsoverarching goal for community outreach and engagement is to accelerate science-to-practice translationacross the cancer care continuum by leveraging and expanding its outreach and engagement infrastructureand network of partners within and beyond the Commonwealth of Kentucky. Specific Aims are: (1) to enhancethe MCCs ability to define and characterize its catchment area using cancer surveillance data cancer registryand health insurance data linkages and locally derived population health assessment data; (2) to increasedissemination and implementation of evidence-based clinical practices and cancer control programming withinand beyond MCCs catchment area; and (3) to enrich bidirectional relationships and structures for conductingcommunity outreach and engagement within and beyond MCCs catchment area. In achieving these aimsMCC is solidly positioned to enhance and expand its existing community outreach and engagement initiativesover the next 5-year CCSG funding period to further reduce Kentuckys significant cancer burden and improvequality of life among all Kentuckians.

project_terms:
Appalachian Region;Basic Science;Behavior;Behavioral Research;Belief;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Centers for Population Health;Clinical Research;Communities;Community Health Education;Community Healthcare;Community Hospitals;Community Outreach;Comprehensive Cancer Center;Continuity of Patient Care;Data;Data Linkages;Education;Environmental Exposure;Faculty;Family;Fostering;Funding;Funding Mechanisms;General Population;Goals;Grant;Health;Health Communication;Health Insurance;Health Personnel;Health Policy;Health Professional;High Prevalence;Improve Access;Incidence;International;Kentucky;Knowledge;Localized Malignant Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Obesity;Patients;Pattern;Positioning Attribute;Professional Education;Public Health;Quality of life;Recommendation;Recording of previous events;Registries;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Risk Factors;Robin bird;Rural;SEER Program;Science;Screening for cancer;Services;Site;Solid;Structure;Survival Analysis;Survivors;Tobacco use;Training;Translations;Underserved Population;United States;Universities;anticancer research;base;cancer care;cancer education;cancer health disparity;cancer risk;clinical care;clinical practice;combat;community based participatory research;community center;evidence base;genetic linkage analysis;health assessment;improved;innovation;low socioeconomic status;member;mortality;neoplasm registry;neoplasm resource;opioid abuse;outreach;outreach program;population health;precision medicine;socioeconomic disparity;surveillance data;tumor


application_id: 9758766
project_number: 3P30CA177558-06S4
project_title: Drug Discovery Delivery and Translational Therapeutics Research Program
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5634
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 The Drug Discovery Delivery and Translational Therapeutics (DT) Program at the Markey Cancer Center(MCC) is scientifically focused on identifying novel targets and biomarkers and discovering and developingnew drugs targeting these biomarkers. The MCC catchment area population has both a high cancer riskrelated to excessive carcinogen exposure and lack of access to cutting-edge clinical trials due to geographicalisolation and poor socioeconomic status. The DT program vision is to understand the unique molecular andphenotypic markers of cancer in Kentucky as well as barriers to accessing care and integrate that knowledgeto inform drug discovery development and delivery of early phase clinical trial efforts for a hard-to-reachAppalachian Kentucky population. MCC investigators are international leaders in biomarker discovery (Theme1) with ongoing translational studies including more than 600 participants evaluating the role of environmentalcarcinogens and identifying biomarkers of lung cancer. DT pharmaceutical scientists work to discover anddevelop new anticancer agents targeting identified mutations and phenotypes (Theme 2) partnering withCancer Cell Biology and Signaling (CS) and Genomic Instability Epigenetics and Metabolism (GEM) programmembers. For example a novel modulator of 4E-BP1 phosphorylation a validated colon cancer target wasidentified from the Appalachian natural products repository. DT investigators lead clinical trials focusing oncancers relevant to the catchment area (Theme 3) and have enrolled more than 500 patients to lung colon andovarian interventional treatment and diagnostic trials. They regularly partner with Cancer Prevention andControl (CP) CS and GEM program members to inform and advance MCC basic science for exampletranslating early identification of the anticancer activity of PAR-4 in CS to clinical trials focused on a PAR-4secratagogue. DT is a cross-disciplinary program of 47 investigators from 6 colleges and 18 departments whowork together to develop novel anticancer therapies and translate these therapies into the clinic. Thisproductive program has total annual external cancer-related funding of $8.5M ($5.9M annual direct costs ofwhich 28% is from the NCI). Members published 366 publications over the current funding period 99 (27%) ofwhich are inter-programmatic 84 (23%) are intra-programmatic and 189 (52%) are inter-institutional. The DTprogram Co-leaders Drs. Jill Kolesar and Jon Thorson have a long-standing collaboration and bringcomplementary expertise in biomarker discovery drug development and early clinical trials. Both direct keyresources supporting the DT program the MCC Precision Medicine Center and the UK Center forPharmaceutical Innovation respectively. Each leader brings critical strengths including local national andinternational collaborations entrepreneurial relationships and active participation in NCI initiatives. Takentogether the DT program has a cohesive and collaborative team that translates novel biomarkers into targetsfor effective anticancer treatments.

project_terms:
Adjuvant;Appalachian Region;Automobile Driving;Basic Science;Binding Proteins;Bioinformatics;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Cancer Patient;Carcinogen exposure;Catchment Area;Cellular biology;Characteristics;Clinic;Clinical Cancer Center;Clinical Data;Clinical Pathology;Clinical Protocols;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Community Outreach;Complex;DNA;Development;Devices;Diagnosis;Diagnostic Trial;Direct Costs;EIF4EBP1 gene;Early Therapeutic-Clinical Trials Network;Early identification;Engineering;Enrollment;Environmental Carcinogens;Epigenetic Process;Eukaryotic Initiation Factors;Evaluation;Ewings sarcoma;Fatty Acids;Fli-1 protein;Frequencies;Funding;Genomic Instability;Geography;Goals;Grant;Health Services Accessibility;High-Risk Cancer;Hydroxychloroquine;Informatics;International;Intervention;Investigation;Investigational New Drug Application;Investments;Kentucky;Knowledge;Laboratory Research;Lead;Libraries;Ligands;Ligase;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Mission;Molecular;Molecular Abnormality;Molecular Target;Mutation;Natural Product Drug;Natural Products;Ovarian;PAWR gene;Participant;Pathology;Patients;Pharmacologic Substance;Pharmacy facility;Phase;Phenotype;Phosphorylation;Physicians;Population;Precision Medicine Initiative;Preclinical Testing;Protocols documentation;Publications;Publishing;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Role;Science;Scientist;Signal Transduction;Socioeconomic Status;Squamous Cell Lung Carcinoma;Therapeutic;Therapeutic Agents;Therapeutic Human Experimentation;Therapeutic Trials;Translating;Translations;Universities;Vision;Work;Writing;anticancer activity;anticancer research;anticancer treatment;biomarker discovery;cancer biomarkers;cancer cell;cancer clinical trial;cancer genomics;cancer prevention;cancer subtypes;cancer therapy;clinical development;clinical implementation;cohesion;college;cross disciplinary program;data management;design;drug candidate;drug development;drug discovery;druggable target;evidence base;exome sequencing;individual patient;inhibitor/antagonist;innovation;inter-institutional;malignant breast neoplasm;member;metabolomics;molecular marker;mutational status;neoplasm registry;new therapeutic target;novel;novel anticancer drug;novel marker;novel therapeutics;phenotypic biomarker;pre-clinical;precision medicine;programs;recruit;repository;research facility;screening;senior faculty;synergism;targeted agent;targeted biomarker;targeted treatment;translational study;treatment response;treatment trial;tumor


application_id: 9758765
project_number: 3P30CA177558-06S4
project_title: Cancer Prevention and Control Research Program
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5633
contact_pi_person_id: 9152491
contact_pi: HE, CHUNYAN
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 Markey Cancer Center's (MCC) Cancer Prevention and Control (CP) Research Program unites highlycomplementary strengths in the areas of population-based research and community-based cancer controlresearch with the overarching goal of reducing cancer disparities in Kentucky with an emphasis on the state'sAppalachian and rural populations. Kentucky has the highest overall cancer incidence and mortality ratesamong all 50 United States. Alarmingly the cancer incidence and mortality rates in Appalachian Kentucky arefar higher than the rates for the non-Appalachian area of the state. These elevated rates are driven by a varietyof underlying factors including low socioeconomic status low educational attainment high risk behaviorscultural barriers and environmental exposures. Strengths of the CP program include studies focused onuncovering the role environmental exposures play in Kentucky's high cancer incidence rates testingintervention programs that address unique cultural barriers and smoking cessation policy developmentinitiatives. CP program members are also national leaders in developing population-based methods andmeasures that facilitate inter-programmatic cancer research. The CP program combines these strengths toaddress 3 thematic areas: identification of social cultural behavioral genetic and environmental factors thatcontribute to the elevated cancer incidence and mortality rates (Theme 1); design testing implementation andevaluation of intervention strategies that address identified risk factors (barriers) and reduce the cancer burden(Theme 2); and development of population-based methods and measures that facilitate inter-programmaticcancer research directed at more precisely identifying the distribution of treatment patterns and biomarkers inthe population (Theme 3). Most recently the CP program recruited 2 National Cancer Institute-funded cancermolecular epidemiologists to build on its unique research resources. The current 28-member CP team drawsfrom 5 colleges and 12 departments at the University of Kentucky thus promoting active interdisciplinarytranslational research. CP productivity is reflected by total annual external cancer-related funding of over$9.7M ($6.7M annual direct costs) and 245 total publications in the current funding period 30 (12%) of whichare inter-programmatic 83 (34%) intra-programmatic and 162 (66%) inter-institutional. CP researchencompasses all segments of the cancer control continuum: prevention early detection treatment andsurvivorship. CP studies address a number of cancer sites including those that disproportionately contribute toKentucky's high cancer burden (i.e. lung colon breast and cervical cancers). Thus the CP program is integralto achieving the overall MCC mission to reduce cancer morbidity and mortality in the Commonwealth.

project_terms:
Address;Age;Appalachian Region;Area;Behavioral;Behavioral Genetics;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Control Research Program;Cancer Patient;Catchment Area;Collaborations;Colon Carcinoma;Colorectal Cancer;Communities;Country;County;Data Linkages;Data Set;Development;Diagnosis;Direct Costs;Early Diagnosis;Education;Effectiveness of Interventions;Environmental Carcinogens;Environmental Exposure;Environmental Risk Factor;Epidemiologist;Evaluation;Evidence based intervention;Exposure to;Funding;Genetic;Goals;Incidence;Informatics;Intervention;Intervention Studies;Kentucky;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Measures;Metals;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;Natural Language Processing;Obesity;Outcomes Research;Pathology;Pathology Report;Patients;Pattern;Play;Policy Developments;Population;Population Research;Poverty;Prevalence;Prevention;Process;Productivity;Program Research Project Grants;Provider;Publications;Registries;Reporting;Research;Research Personnel;Resources;Risk Factors;Role;Rural;Rural Population;Sampling;Site;Smoking;Social Identification;Testing;Time;Tissues;Translational Research;United States;Universities;Vulnerable Populations;Work;anticancer research;base;cancer health disparity;cancer prevention;cancer recurrence;cancer risk;cancer site;carcinogenesis;college;design;disadvantaged population;experience;federal poverty level;high risk;high risk behavior;high school;innovation;insight;inter-institutional;intervention program;low socioeconomic status;malignant breast neoplasm;member;mortality;neoplasm registry;novel;population based;programs;protein expression;recruit;repository;smoking cessation;social;social media;socioeconomics;survivorship;tool;trait;virtual


application_id: 9758764
project_number: 3P30CA177558-06S4
project_title: Cancer Cell Biology and Signaling Research Program
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5632
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Achievement;Adhesions;Adipocytes;Animal Model;Anoikis;Apoptosis;Appalachian Region;Area;Bacteria;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Survival;Cellular biology;Chloroquine;Climate;Clinic;Clinical Trials;Collaborations;Cytoskeleton;Development;Diabetes Mellitus;Direct Costs;Drosophila genus;Drug Combinations;Engineering;Ensure;Environment;Epithelial;Extracellular Matrix;FDA approved;Faculty;Funding;Future;Gene Proteins;Genes;Goals;Grant;Group Meetings;Growth Factor;Immune checkpoint inhibitor;Immunologist;Incidence;Individual;Institutes;Interdisciplinary Study;Intestinal Hormones;Joints;Kentucky;Legal patent;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medicine;Mentors;Mesenchymal;Mission;Morbidity - disease rate;NCI Center for Cancer Research;National Cancer Institute;Nature;Neoplasm Metastasis;Neurotensin;Obesity;Oral;PAWR gene;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Postdoctoral Fellow;Process;Program Description;Public Health;Publications;Publishing;Regulation;Research;Research Personnel;Research Project Grants;Retreatment;Role;Science;Signal Pathway;Signal Transduction;Stem Cell Leukemia;Stem cells;Stilbenes;System;Testing;Therapeutic;Transitional Cell;Translational Research;Translations;Tumor Cell Invasion;Tumor Suppressor Genes;Tumor Suppressor Proteins;Underserved Population;Universities;Zebrafish;base;breast cancer progression;cancer cell;cancer education;cancer initiation;cancer stem cell;cell motility;clinical translation;cohesion;collaborative environment;college;colon cancer treatment;cytokine;drug discovery;inhibitor/antagonist;insight;inter-institutional;melanoma;member;mortality;neoplastic cell;new therapeutic target;novel;novel drug combination;novel therapeutics;programs;recruit;resistance mechanism;response;smoothened signaling pathway;stem cell division;success;targeted treatment;therapy resistant;tool;tumor;tumor microenvironment;tumor progression


application_id: 9758763
project_number: 3P30CA177558-06S4
project_title: Redox Metabolism Shared Resource Facility
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
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_terms:
Adverse effects;Affect;Appalachian Region;Area;Australia;Basic Science;Bioenergetics;Biological;Biological Assay;Biology;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control Research;Catchment Area;Cell Respiration;Cells;Centers of Research Excellence;Chemotherapy-Oncologic Procedure;Clinical;Comprehensive Cancer Center;Consultations;Development;Education;Educational workshop;Equipment;Europe;Experimental Designs;Faculty;Free Radicals;Funding;Future;Genomics;Genus Hippocampus;Goals;Immunotherapy;Incidence;Injury;Institution;International;Investments;Kentucky;Knowledge;Leadership;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Mentors;Metabolic;Metabolic Pathway;Metabolism;Methodology;Methods;Mission;Mitochondria;Molecular;Morphologic artifacts;NCI Center for Cancer Research;National Cancer Institute;Neoplasm Metastasis;Normal tissue morphology;Nuclear Magnetic Resonance;Obesity;Oxidation-Reduction;Oxidative Stress;Oxides;Patients;Peer Review;Phase;Population;Post-Translational Protein Processing;Preparation;Principal Investigator;Protein Array;Proteins;Proteomics;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Science;Services;Signal Transduction;Strategic Planning;System;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States;United States National Institutes of Health;Universities;bench to bedside;biological systems;biomarker discovery;biomarker validation;cancer prevention;cancer therapy;data integration;differential expression;high risk population;improved;innovation;insight;interest;lens;member;metabolomics;metabolomics resource;mortality;nitrosative stress;oxidative damage;precision medicine;programs;recruit;response;service utilization;stable isotope;tumor metabolism


application_id: 9758762
project_number: 3P30CA177558-06S4
project_title: Flow Cytometry and Cell Sorting Shared Resource Facility
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5630
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
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_terms:
Address;Animals;Antibodies;Apoptosis;Applications Grants;Basic Science;Bioinformatics;Biological Assay;Biological Markers;Biometry;Blood;Cancer Center;Cancer Center Support Grant;Cancer Immunology Science;Cancer Science;Catchment Area;Cell Cycle;Cell Separation;Cell physiology;Cells;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Cloning;Collaborations;Complex;Computers and Advanced Instrumentation;Consult;Consultations;Core Facility;Cryopreservation;Data;Data Analyses;Dendritic Cells;Development;Doctor of Philosophy;Enzyme-Linked Immunosorbent Assay;Experimental Designs;Faculty;Flow Cytometry;Flow Cytometry Shared Resource;Fresh Tissue;Funding;Generations;Goals;Grant;Growth Factor;Health;Human;Immune;Immune system;Immunologic Monitoring;Immunologics;Immunology procedure;Individual;Informatics;Kentucky;Laboratories;Leadership;Malignant Neoplasms;Mentors;Mentorship;Mission;Monitor;National Cancer Institute;Necrosis;Pathology;Peer Review;Phenotype;Ploidies;Population;Production;Publications;Research;Research Design;Research Personnel;Research Support;Resource Sharing;Sampling;Services;Signal Transduction;Speed;Surface;System;T-Cell Proliferation;T-Lymphocyte;Techniques;Tissue Expansion;Training;Tumor Tissue;United States National Institutes of Health;Universities;anticancer research;antigen-specific T cells;base;cancer biomarkers;cancer immunotherapy;career;cell bank;cost effective;cytokine;cytotoxicity;design;enzyme linked immunospot assay;high dimensionality;improved;innovation;instrument;instrumentation;macrophage;meetings;member;novel;operation;phenotypic biomarker;pre-clinical;pre-clinical research;programs


application_id: 9758761
project_number: 3P30CA177558-06S4
project_title: Cancer Research Informatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5629
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adopted;Appalachian Region;Basic Science;Big Data;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cellular biology;Clinical;Clinical Cancer Center;Clinical Sciences;Clinical Treatment;Clinical Trials;Collaborations;Communities;Computational Science;Computer software;Data;Data Quality;Data Reporting;Data Set;Data Sources;Data Storage and Retrieval;Databases;Development;Ecosystem;Educational workshop;Ensure;Epigenetic Process;Evaluation Research;Faculty;Foundations;Funding;Genomic Instability;Goals;Grant;Healthcare;High Performance Computing;Human;Informatics;Information Technology;Institutes;Kentucky;Knowledge;Knowledge Discovery;Leadership;Machine Learning;Maintenance;Malignant Neoplasms;Medicine;Mentors;Mentorship;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Natural Language Processing;Outcome Measure;Pathology;Patient-Focused Outcomes;Patients;Peer Review;Phenotype;Population Research;Preparation;Research;Research Infrastructure;Research Personnel;Resource Informatics;Resources;Role;SEER Program;Science;Scientist;Services;Signal Transduction;Source;Supporting Cell;Technology;Therapeutic;Therapeutic Studies;Tissue Microarray;Training and Education;Translational Research;Treatment outcome;United States;Universities;analytical method;anticancer research;biomedical informatics;cancer cell;cancer genomics;cancer prevention;clinical decision support;clinical decision-making;cohort;data exchange;data management;data warehouse;design;drug discovery;evidence base;genomic biomarker;handheld mobile device;improved;informatics shared resource;innovation;interoperability;learning strategy;member;mortality;national surveillance;neoplasm registry;next generation sequencing;novel;population based;precision medicine;programs;recruit;research and development;research data dissemination;response;screening;sharing data;surveillance data;tool;tumor


application_id: 9758760
project_number: 3P30CA177558-06S4
project_title: Biostatistics and Bioinformatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5628
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI L
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_terms:
Address;Adoption;Appalachian Region;Applications Grants;Area;Basic Science;Bioinformatics;Bioinformatics Shared Resource;Biological;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Immunology Science;Cancer Surveillance Research;Cell Separation;Cellular biology;Classification;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Computer software;Consultations;Data;Data Analyses;Data Quality;Data Science;Databases;Development;Disease;Dose;Early Therapeutic-Clinical Trials Network;Education;Education and Outreach;Ensure;Epigenetic Process;Evaluation;Experimental Designs;Faculty;Flow Cytometry;Funding;Genomic Instability;Genomics;Grant;Growth;Hand;Human Resources;Immunologic Monitoring;Informatics;Journals;Kentucky;Lead;Leadership;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mentors;Mentorship;Metabolism;Methodology;Methods;Mission;Modeling;Molecular;Monitor;Multicenter Trials;NCI Center for Cancer Research;National Cancer Institute;Oxidation-Reduction;Pathology;Peer Review;Phase;Play;Population;Population Research;Population Study;Positioning Attribute;Precision medicine trial;Process;Quality Control;Reproducibility;Research;Research Design;Research Personnel;Research Priority;Research Support;Resource Sharing;Resources;Risk Factors;Role;Sample Size;Science;Series;Service provision;Services;Signal Transduction;Site;Statistical Data Interpretation;Statistical Methods;Survival Analysis;Technical Expertise;Testing;Therapeutic;Toxic effect;Training;Training Activity;Training Programs;Training and Education;Translational Research;Universities;Work;Writing;anticancer research;base;biomarker-driven;cancer cell;cancer health disparity;cancer immunotherapy;cancer prevention;computerized data processing;cost effective;data management;design;drug discovery;early phase trial;exosome;experience;genomic platform;health disparity;high throughput analysis;improved;innovation;investigator-initiated trial;lectures;malignant breast neoplasm;meetings;member;metabolomics;multidisciplinary;neoplasm registry;next generation sequencing;novel;population based;precision medicine;precision medicine clinical trials;programs;research study;skills;statistics;success;targeted treatment;translational clinical trial;translational study;working group


application_id: 9758759
project_number: 3P30CA177558-06S4
project_title: Biospecimen Procurement and Translational Pathology Shared Resource Facility
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5627
contact_pi_person_id: 8368087
contact_pi: JENNINGS, DARRELL
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 The Biospecimen Procurement and Translational Pathology Shared Resource Facility (BPTP SRF) is aMarkey Cancer Center (MCC)-managed resource. It facilitates the use of well-annotated human and animalspecimens and provides a wide range of translational pathology technical services in support of MCC clinicaltranslational population-based and basic science research. Over the award period the BPTP SRF hasincreased annual biospecimen dispensation from 1738 in FY12 to 4446 in FY17 (156% increase) increasedthe total number of MCC users by 23% (48 in FY17 up from 39 in FY12) including 38 peer-reviewed fundedMCC users in FY17 (49% of all BPTP users) and expanded its range of services. New services include:targeted and time sensitive collections such as intra-operative rapid fresh tissue collections supporting work incancer metabolism; the development of novel model systems (e.g. Warburg tissue slices for metabolicanalysis patient-derived xenograft organoids); review of all clinical trials including investigator-initiated trialsto identify specimen collection needs and develop collection protocols; fresh tissue collections and rapid bloodprocessing for clinical trials resulting in support for 40 clinical trials over the funding period. The addition of aresearch histology laboratory operated per clinical guidelines allows for an increased capacity for technicalservices such as histology immunohistochemistry molecular pathology laser capture microscopy andDNA/RNA extraction. BPTP SRF has increased its consent capacity through the cross training of all BPTPSRF staff as well as by using a universal opt-in consent for repository collections. BPTP SRF's name changereflects its increased focus on translational pathology facilitated by the support of faculty in the University ofKentucky (UK) Department of Pathology who assist BPTP SRF staff in the development and interpretation ofnovel assays on-site evaluation of specimen content and quality for fresh tissue dispense and identification ofretrospective study and tissue microarray cohorts from surgical archive specimens dating back to 1995. Thispartnership strengthened by BPTP's leadershipC. Darrell Jennings MD chair of the Department ofPathology and Laboratory Medicine with Associate Director Qiuying Shi MD Assistant Professor inPathologyensures MCC investigators have a clear path to the specimen resources and pathologic servicesessential to their work. The BPTP SRF has streamlined operations by transitioning to the OnCore databaseand adding a manager to oversee daily operations leveraging existing resources within the MCC including theClinical Research Office the Surveillance Epidemiology and End Results Kentucky Cancer Registry andCancer Research Informatics and Biostatistics and Bioinformatics SRFs as well as non-MCC entities such asthe Department of Pathology and Laboratory Medicine UK Office of Research Integrity and the Center forClinical and Translational Science.

project_terms:
Ambulatory Care Facilities;Animals;Appalachian Region;Archives;Area;Award;Back;Basic Science;Bioinformatics;Biological Assay;Biological Markers;Biological Models;Biometry;Blood;Cancer Center;Cancer Center Support Grant;Cancer Immunology Science;Clinical;Clinical Cancer Center;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Collection;Communities;Comprehensive Cancer Center;Computer software;Consent;Consultations;Custom;DNA;Data;Databases;Department chair;Development;Education;Ensure;Evaluation;Faculty;Familiarity;Formalin;Fostering;Freezing;Fresh Tissue;Funding;Future;Genetic;Genetic Markers;Genomics;Goals;Growth;Guidelines;Histologic;Histology;Histopathology;Hospitals;Human;Immunohistochemistry;In Situ;In Situ Hybridization;Informatics;Institutional Review Boards;Kentucky;Laboratories;Laboratory Research;Lasers;Leadership;Liquid substance;Malignant Neoplasms;Medicine;Metabolic;Microscopy;Mission;Modeling;NCI Center for Cancer Research;Names;Obesity associated cancer;Operative Surgical Procedures;Organoids;Outcome;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patient Care;Patients;Peer Review;Play;Population;Procedures;Protocols documentation;RNA;Research;Research Design;Research Personnel;Research Training;Resistance;Resource Sharing;Resources;Retrospective Studies;Role;SEER Program;Sampling;Science;Scientist;Services;Site;Slice;Specimen;Standardization;Students;Therapeutic Clinical Trial;Therapeutic Human Experimentation;Time;Tissue Banks;Tissue Embedding;Tissue Microarray;Tissues;Training;Training and Education;Translating;Translational Research;Tumor Tissue;United States Office of Research Integrity;Universities;Work;Xenograft procedure;anticancer research;biomarker evaluation;cancer health disparity;cancer immunotherapy;clinical investigation;cohort;consent capacity;digital imaging;direct patient care;faculty support;histological stains;human tissue;imaging system;innovation;interest;investigator-initiated trial;member;metabolomics;molecular pathology;neoplasm registry;next generation;novel;operation;patient population;patient privacy;population based;precision medicine clinical trials;professor;programs;prospective;repository;response;sample collection;tissue biomarkers;tumor;tumor metabolism


application_id: 9758758
project_number: 3P30CA177558-06S4
project_title: Career Enhancement
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5626
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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_terms:
Address;Appalachian Region;Award;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Trials;Communities;Complement;County;Data;Dedications;Development;Direct Costs;Education;Educational Curriculum;Ensure;Evolution;Extramural Activities;Faculty;Fostering;Funding;Geography;Goals;Grant;Growth;High School Student;Immersion Investigative Technique;Incidence;Individual;Investments;K-12 student;Kentucky;Lead;Link;Malignant Neoplasms;Mentors;Mentorship;Mission;Modernization;NCI Center for Cancer Research;National Cancer Institute;National Cancer Program;Outcome;Physicians;Population;Research;Research Personnel;Research Training;Resources;Rural;Scientist;Series;Surgeon;Time;Training;Training Programs;Training and Education;Translational Research;Underrepresented Minority;Universities;Writing;anticancer research;base;cancer education;career;career development;clinical practice;cohesion;early-career faculty;education research;educational atmosphere;elementary school;experience;faculty research;health disparity;health management;high school;higher education;improved;innovation;interest;meetings;member;mortality;next generation;oncology;outreach;pre-doctoral;programs;symposium;undergraduate student


application_id: 9758757
project_number: 3P30CA177558-06S4
project_title: Administration
administering_ic: NCI
award_notice_date: 2018-09-14
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5625
contact_pi_person_id: 9098327
contact_pi: GOSKY, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Markey Cancer Center (MCC) Administration provides efficient and effective administrative support toMCC's Director Senior Leadership Research Program Leaders Shared Resource Facility (SRF) Directorsand MCC members. The role of MCC Administration is to operationalize MCC's most critical research functionsby fulfilling the following Specific Aims: 1) to accelerate the remarkable evolution of the MCC by leveragingresources and expanding MCC's infrastructure; 2) to promote the strategic planning and evaluation efforts ofthe MCC; and 3) to support the comprehensive basic science clinical and cancer prevention activities of theMCC by fostering transdisciplinary and translational science. The MCC is a matrix cancer center withadministrative staff providing support to 119 MCC members from 28 departments in 8 University of Kentuckycolleges with 28 faculty recruited in the last 4 years. MCC Administration leverages the expertise of its teammembers while operating in an innovative and efficient manner. New initiatives supported since the last grantcycle include: 1) implementing iLab Solutions (Agilent Technologies) across SRFs; 2) deploying $4.2M for newseed grant opportunities; 3) developing the Markey Women Strong program in collaboration with the MarkeyCancer Foundation to provide two $50000 awards annually to female researchers in the MCC; 4) supporting a38% increase of direct cancer-related research funding from $19.9M to $27.4M (corresponding 36% increaseof total cancer-related research funding from $28.4M to $38.7M) between 2012-2017; 5) facilitating 7successful CCSG supplement applications; 6) initiating development of 2 SRFs (Oncogenomics and Behaviorand Community-Based Research); 7) providing full support for a Center of Biological Research Excellenceapplication and funded award; 8) establishing the Department of Toxicology and Cancer Biology and theCenter for Environmental and Systems Biochemistry to support research and educational efforts; 9) increasingthe number of MCC Network sites from 8 in 2013 to 24 in 2017; 10) creating the MCC Research Network; 11)promoting communication throughout the MCC and catchment area with a new website and additional socialmedia platforms; 12) fostering growth of the Clinical Research Office and creating the Clinical ResearchEnrollment and Development of Investigational Trials program to recognize faculty for clinical research efforts;13) overseeing the expansion of space including a dedicated Precision Medicine Center (PMC) a newinpatient floor with 63 additional beds and dedicated administrative space for the MCC Affiliate and Researchnetworks; 14) planning utilization of 2 MCC research floors (50329 sq. ft.) in the new Research Building 2scheduled to open in 2018; 15) creating the MCC Community Outreach Program and establishing the annualExpressions of Courage event for cancer survivors; and 16) facilitating development and implementation of the2017-2022 Strategic Plan.

project_terms:
Administrator;Award;Basic Science;Beds;Behavior;Behavioral Research;Biochemistry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Survivor;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Development;Enrollment;Ensure;Evaluation;Event;Evolution;Faculty;Faculty Recruitment;Female;Floor;Fostering;Foundations;Funding;Funding Agency;Future;Goals;Grant;Growth;Inpatients;Investigation;Kentucky;Leadership;Malignant Neoplasms;NCI Center for Cancer Research;Nursing Faculty;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Research Support;Resource Sharing;Resources;Retreatment;Role;Schedule;Secure;Seeds;Services;Site;Strategic Planning;Students;System;Technology;Toxicology;Training;Translational Research;Universities;Update;Vision;Woman;Work;anticancer research;base;biological research;cancer genomics;cancer prevention;cancer research center director;college;community based participatory research;experience;innovation;meetings;member;outreach;outreach program;precision medicine;programs;recruit;social media;square foot;success;symposium;web site


application_id: 9758751
project_number: 3P30CA177558-06S4
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2018-09-12
opportunity_number: PAR-17-095
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S4
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Achievement;Address;Appalachian Region;Area;Award;Basic Science;Behavioral Research;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Centers of Research Excellence;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Community Healthcare;Community Networks;Community Outreach;Community Physician;Comprehensive Cancer Center;County;Coupled;Data Sources;Development;Disease;Distress;Early Diagnosis;Ecology;Education;Education and Outreach;Environmental Risk Factor;Epigenetic Process;Faculty Recruitment;Fellowship;Flow Cytometry;Foundations;Funding;Genetic;Genomic Instability;Genomics;Health Professional;Healthcare;Immunotherapy;Incidence;Individual;Informatics;Institution;Intervention;Intervention Studies;Intervention Trial;Investments;Kentucky;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolism;Methods;Minority;Minority Graduate Student;Mission;Molecular;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Obesity;Obesity associated cancer;Outcome;Oxidation-Reduction;Pathology;Patients;Phase;Phenotype;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention therapy;Preventive;Program Development;Publications;Publishing;Quality of life;Radon;Registries;Research;Research Infrastructure;Research Personnel;Resistance;Resource Sharing;Resources;Risk Factors;Role;SEER Program;Science;Scientist;Screening for cancer;Services;Signal Transduction;Site;Strategic Planning;Target Populations;Therapeutic;Training;Transcend;Translating;Translational Research;Translations;Underserved Population;Universities;anticancer research;authority;base;bench to bedside;biomedical informatics;cancer care;cancer genomics;cancer health disparity;cancer prevention;cancer research center director;cancer site;cancer survival;cancer therapy;career development;clinical development;clinical translation;cohort;college;community based participatory research;cost;drug discovery;genetic epidemiology;health assessment;health disparity;high school;higher education;improved;innovation;instrumentation;inter-institutional;medically underserved;meetings;member;metabolomics;mortality;multidisciplinary;next generation;novel anticancer drug;oncology;outreach;personalized diagnostics;personalized intervention;population health;precision medicine;precision medicine clinical trials;programs;prospective;recruit;repository;response;screening;standard of care;synergism;targeted treatment;treatment response;tumor;tumor metabolism;undergraduate student


application_id: 9756587
project_number: 3R01CA133429-11S1
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2018-09-18
opportunity_number: PA-18-852
application_type: 3
activity_code: R01
ic: CA
serial_number: 133429
suffix: S1
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2019-11-30
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
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:
Abstract Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately136000 new cases and 50000 deaths are predicted for the year 2017; this mortality is predominantly due tothe development of disseminated advanced disease. A better understanding of the metastatic tumor and itsmicroenvironment is urgently needed in order to improve the overall survival of colorectal cancer patients. Mylab has been intensively focused on elucidating the role of a novel family of protein phosphatases PHLPP (PHdomain Leucine-rich-repeats Protein Phosphatase) in inhibiting colon cancer initiation and progression. Wehave made substantial progress in understanding the functional importance of PHLPP as a tumor suppressoras well as the molecular mechanism underlying PHLPP regulation. The main goal of the parent R01 grant is todetermine the effect of PHLPP-loss on modulating colon cancer metabolism. We have been highly productivein the past 4 years with 15 total publications. Recently our efforts on examining PHLPP-mediated regulation ofcellular metabolism in colon cancer have led to exciting new findings and opened up new collaborationopportunities. Locally advanced tumor cells often invade into surrounding adipose tissue with a direct contactwith adipocytes. However how adipocytes support tumor growth and progression is poorly understood. Wediscovered a direct metabolic crosstalk between colon cancer cells and adipocytes in the tumormicroenvironment. The overall objective of studies proposed here is to develop a mechanistic understanding ofadipocytes-mediated tumor promoting effects in colon cancer. The central hypothesis driving this proposal isthat colon cancer cells grown in the presence of adipocytes in the tumor microenvironment will adapt a distinctmetabolic program that enhance cancer stem cell-like properties by upregulating mitochondrial fatty acidoxidation (FAO). Specifically we will further delineate the role of mitochondrial FAO in mediating the tumorpromoting effect of adipocytes and determine how adipocyte-induced activation of FAO regulates cancer stemcell properties both in vitro and in vivo. To ensure the success of this study I have established newcollaboration with Dr. Daret St Clair an expert in mitochondrial biology. This collaboration represents a naturalextension of research interests of both laboratories. Through close interactions we have built a stronginvestigative team that has the requisite expertise innovative model systems and state-of-the-art technology tomake rapid progress. Results from this study will provide novel insights into the molecular mechanismunderlying the tumor-promoting effect of adipocytes in colon cancer. Furthermore developing a mechanisticunderstanding of how mitochondrial FAO promotes cancer stem cell properties will help to identify newtherapeutic interventions to target and eliminate cancer stem cells in order to prevent cancer relapse andimprove treatment outcomes.

project_terms:
Address;Adipocytes;Adipose tissue;Apoptosis;Area;Automobile Driving;Biological Models;Biology;Cancer Etiology;Cancer Relapse;Cell Survival;Cells;Cessation of life;Collaborations;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Development;Disease;Ensure;Epithelial Cell Proliferation;Fatty Acids;Funding;Glucose;Glycolysis;Goals;Grant;Growth;Healthcare;Hexokinase 2;Human;In Vitro;Incidence;Intestines;Invaded;Laboratories;Malignant Neoplasms;Manuscripts;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modification;Molecular;Molecular Target;Neoplasm Metastasis;Nonesterified Fatty Acids;Obesity;PH Domain;Parents;Peer Review;Phosphorylation;Productivity;Property;Protein Family;Protein phosphatase;Publications;Publishing;Reagent;Regulation;Research;Role;Source;Starvation;Stem cells;Technology;Treatment outcome;Tumor Suppressor Proteins;United States;Work;advanced disease;cancer cell;cancer initiation;cancer stem cell;cell growth regulation;colon cancer patients;colon cancer progression;design;experimental study;fatty acid metabolism;fatty acid oxidation;improved;in vivo;innovation;insight;interest;knock-down;leucine-rich repeat protein;lipid biosynthesis;macromolecule;metabolomics;mortality;neoplastic cell;novel;novel therapeutic intervention;nutrient deprivation;prevent;programs;stable isotope;stem-like cell;success;tumor;tumor growth;tumor initiation;tumor metabolism;tumor microenvironment;tumor progression;tumor xenograft

public_health_relevance:
PROJECT NARRATIVEObesity is associated with increased incidence and mortality of a wide variety of human cancers includingcolorectal cancer. By providing novel insights into the molecular mechanism underlying adipocyte-mediatedtumor promoting function our study will address a significant health care challenge by revealing potentialmolecular targets for treating obesity-associated colon cancer.


application_id: 9756291
project_number: 5R01AG060056-02
project_title: APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2019-06-05
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 060056
program_official: WISE, BRADLEY C
project_start_date: 2018-08-15
project_end_date: 2023-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease risk;Antioxidants;Apolipoprotein E;Astrocytes;Autopsy;Biological Assay;Brain;Brain Diseases;Cell Death;Cell Survival;Cells;Cerebrum;Coculture Techniques;Cognitive;Consensus;Data;Development;Disease;Down-Regulation;Enzymes;Genes;Genetic;Genotype;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glutathione;Glutathione Disulfide;Glycolysis;Human;Impaired cognition;In Vitro;Individual;Knowledge;Late Onset Alzheimer Disease;Link;Longevity;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mus;NADP;Neurons;Oxidation-Reduction;Oxidative Stress;Pathology;Patients;Pattern;Pentosephosphate Pathway;Pharmacology;Population;Protein Isoforms;Proteins;Proteomics;Radiolabeled;Reduced Glutathione;SLC2A1 gene;Sampling;Small Interfering RNA;Testing;Time;Tissues;Translating;age related;aged;base;brain tissue;cell type;cognitive function;enzyme pathway;genetic risk factor;glucose metabolism;glucose uptake;high risk;human tissue;in vivo;inhibitor/antagonist;innovation;knock-down;metabolomics;mouse model;neuronal survival;new therapeutic target;novel;overexpression;oxidative damage;prevent;response;stable isotope;therapeutic target;uptake


application_id: 9756267
project_number: 5P30AG028383-14
project_title: Core E: Outreach and Recruitment Core
administering_ic: NIA
award_notice_date: 2019-07-11
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6812
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_abstract:
Project Summary/Abstract: Outreach and Recruitment CoreThe Outreach and Recruitment (OR) Core functions as a key link between the UK-ADC and the local and statecommunities. OR Core programs and activities have created and will maintain an educated local communityeager to receive updated information on AD and to participate in our Centers research. Through OR Coreefforts the UK-ADC will continue to work with both the Commonwealth of Kentucky and UK partners indirecting state and institutional responses to meeting dementia health care needs and increasing healthliteracy in the elderly. Over the past five years the OR Core has taken the lead in developing innovativepartnerships and products to support research participation by African Americans the largest minority group inKentucky. We will continue to emphasize recruitment and retention of research participants at the earlieststages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging theseparticipants in the ADC longitudinal cohort as well as agreement to brain donation in support of theNeuropathology Core willingness to engage in clinical studies and therapeutic trials that support the ClinicalCore and donation of antemortem biospecimens (plasma DNA CSF and neuroimaging) that support allCores. In the next cycle we will maintain and further build on these efforts and partnerships through thefollowing specific aims:Aim 1. Recruit and retain individuals into our longitudinal cohort ADC-affiliated research studies and nationalinitiatives with a special focus on recruitment and retention of African Americans.Aim 2. Increase community awareness of AD and related disorders through the promotion of health literacythat further enhances recruitment and retention of minority participants in research.Aim 3. Evaluate the effectiveness of our outreach recruitment and educational activities with both qualitativeand quantitative metrics of success.Aim 4. Support and collaborate with the other Cores to reach UK-ADC goals.The OR Core plays a critical role in the UK-ADC and works closely with the other Cores to support recruitmentand retention activities for research protocols clinical trials and national initiatives; increase communityawareness of AD and maintain a strong presence in the African-American community; support educationalinitiatives for the lay community in collaboration with key partners. These functions are vital to the UK-ADCmission to catalyze outstanding and innovative research outreach education and clinical programs.

project_terms:
Address;African American;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Biological Markers;Brain;Catchment Area;Clergy;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communication;Communities;Community Actions;Consent;DNA;Data Collection;Database Management Systems;Databases;Dementia;Development;Disease;Education;Educational Activities;Effectiveness;Elderly;Enrollment;Event;Extramural Activities;Failure;Fostering;Future;Goals;Health Promotion;Healthcare;Individual;Intervention Trial;Kentucky;Lead;Link;Longitudinal cohort;Minority;Minority Groups;Minority Participation;Mission;Outcome Measure;Participant;Plasma;Play;Poa plant;Program Development;Protocols documentation;Recording of previous events;Recruitment Activity;Reporting;Research;Research Activity;Research Support;Resources;Role;System;Therapeutic Trials;Time;Translational Research;Translations;Universities;Update;Work;cohort;dementia care;dementia risk;demographics;design;education research;health literacy;healthcare community;innovation;meetings;member;minority communities;neuroimaging;neuropathology;outreach;parity;participant retention;programs;recruit;research study;response;success;volunteer;willingness


application_id: 9756266
project_number: 5P30AG028383-14
project_title: Core D: Neuropathology Core
administering_ic: NIA
award_notice_date: 2019-07-11
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6811
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_abstract:
Project Summary/Abstract: Neuropathology CoreThe overall objective of the Neuropathology Core of the University of Kentucky Alzheimers Disease Center(UK-ADC) is to support research on normal brain aging presymptomatic Alzheimers disease (pAD) mildcognitive impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders.Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from our ClinicalCore. We will perform short post-mortem interval autopsies in relation to our clinical cohort and we willmaintain a high autopsy rate. This Core is optimally tailored to help address important research questions.The Core will provide brain tissue specimens CSF and synaptosomes for investigators at UK other ADCsand outside investigators. The Core will also provide consensus conference determined diagnosesquantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain regions A 1-40and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all autopsied cases toinvestigators. This brain bank has been operating continuously for over three decades with a strong trackrecord so special care will be taken to ensure diagnostic excellence consistency and continuity. The Corewill maintain a tissue bank of the above specimens and frozen serum plasma buffy coats and CSF from livingpatients. Special emphasis will be placed on defining the neuropathological findings in the brains of the oldestold (>85 years) and providing investigators with specimens from cognitively intact control subjects with no Adeposition and sparse tau pathology (successful cerebral aging) and also cognitively intact subjects withabundant plaques and neurofibrillary tangles. Providing these samples will contribute to clinical-pathologicalcorrelation studies and cutting-edge research that include sponsored studies related to AD genomics oxidativestress hippocampal sclerosis dementia with Lewy bodies amyloid precursor protein processing Downsyndrome and neuroinflammation. Frequent consensus conferences will be held with the Clinical Core andBiostatistics Core to help define clinical-pathological diagnoses on all autopsied subjects. This Core is stronglyintegrated with other Cores of the UK-ADC and exploits unique opportunities to conduct clinical-pathologicalcorrelative studies on longitudinally followed subjects. Through these methods we will better understandnormal brain aging and the transition to dementia with the focused goal of contributing to therapeutic orpreventive measures. The Neuropathology Core complements the other Cores of the UK-ADC to provide extremely essentialdiagnoses and tissue samples that are required for many cutting-edge researchers at the University ofKentucky and elsewhere. We will build on our track record of excellence using innovative tools related to brainautopsies neuropathological diagnoses tissue banking and state-of-the-art clinical-pathological correlation.

project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Biological;Biological Markers;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Trials;Cognition Disorders;Cognitive;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Diagnosis;Diagnostic;Disease;Down Syndrome;Ensure;Freezing;Frontotemporal Lobar Degenerations;Genetic study;Genomics;Goals;Impaired cognition;Individual;Infrastructure;Institutes;Investigation;Kentucky;Laboratory Research;Lesion;Lewy Body Dementia;Medical Genetics;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preparation;Preventive measure;Protocols documentation;Publishing;Religion and Spirituality;Research;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Serum;Services;Specimen;Staging;Standardization;Synaptosomes;Syndrome;Tauopathies;Therapeutic;Thinness;Time;Tissue Banks;Tissue Sample;Tissues;Universities;Work;abeta deposition;age related;age related neurodegeneration;aging brain;amyloid precursor protein processing;blood product;brain tissue;cerebrovascular pathology;cohort;data management;digital;experience;genome wide association study;hippocampal sclerosis;innovation;meetings;mild cognitive impairment;mixed dementia;neuroinflammation;neuropathology;normal aging;novel;pre-clinical;protein TDP-43;repository;symposium;synucleinopathy;tau Proteins;tool


application_id: 9756264
project_number: 5P30AG028383-14
project_title: Core C: Data Management and Statistical Core
administering_ic: NIA
award_notice_date: 2019-07-11
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6810
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD 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
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_abstract:
Program Summary/Abstract: Data Management and Statistical CoreThe Data Management and Statistical (DMS) Core can be conceptualized as the lynchpin for integration of theADC Cores and is vital to the success of the UK-ADC. Its critical roles include managing a large centralizeddatabase consulting with ADC-affiliated researchers and working to develop and apply innovative statisticalmethodology for data analysis. Data management efforts focus on collecting and storing high quality data.This focus begins with the leadership and vision and attention to detail provided by the DMS Core. This corehas an enviable track record of timely and accurate reporting of a high volume of data to NACC. Furtherweekly Core meetings are popular with UK-ADC investigators who find that the expert advice provided by ourseasoned investigators improves their success in pilot studies grant applications and publications. The Corealso participates as a full partner to the research mission of the UK-ADC emphasizing transitions andtranslations. One such partnership with the Clinical and Neuropathology Cores relates to clinico-pathologicalmodels of mixed dementias. A key element of this DMS Core is the well-established track record of developingnovel methodology to analyze data collected at the UK-ADC and from other cohorts with a focus on elderlysubjects transitions to MCI and eventually dementia. The Core also provides training for students enrolled inthe graduate programs in Gerontology Public Health Epidemiology and Biostatistics Psychology andStatistics. It is committed to developing younger faculty to become productive ADC investigators. In keepingwith the mission of the UK-ADC faculty in this Core also contribute to the dementia research community atlarge through service on external advisory committees study sections manuscript reviews and data safetymonitoring boards. The DMS Core will continue these critical responsibilities through the following specificaims.1: Create and maintain a web-based integrated data warehouse for ADC Cores and projects.2: Provide expertise on experimental design and statistical analysis.3: Support the clinical neuropathological and educational/outreach missions of the ADC.4: Contribute to the activities of the dementia community at large through service and research.

project_terms:
Adopted;Advisory Committees;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Area;Attention;Biological Markers;Biometry;Cerebrospinal Fluid;Clinical;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Consult;Data;Data Analyses;Data Collection;Data Element;Data Quality;Databases;Dementia;Elderly;Enrollment;Epidemiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Future;Generations;Genetic;Gerontology;Growth;Health Services Research;Image;Kentucky;Leadership;Literature;Manuscripts;Mentors;Methodology;Methods;Mission;Modeling;Neuroepidemiology;Online Systems;Paper;Participant;Pathologic;Pathology;Phase;Pilot Projects;Psychology;Public Health;Publications;Records;Reporting;Research;Research Design;Research Personnel;Research Support;Risk Factors;Role;Scanning;Seasons;Secure;Services;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Translational trial;Translations;Universities;Ursidae Family;Vision;central database;cohort;data management;data warehouse;direct application;doctoral student;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;student training;success


application_id: 9756262
project_number: 5P30AG028383-14
project_title: Core B: Clinical Core
administering_ic: NIA
award_notice_date: 2019-07-11
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6809
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_abstract:
Project Summary/Abstract: Clinical CoreThe Clinical Core of the UK-ADC maintains a well-characterized community-based cohort focused onnormal aging and early transitional disease states and follows individuals longitudinally until brain autopsy.We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority GatewayClinic where autopsy is promoted but not required) allowing major contributions in the area of clinical-pathological correlative studies definition of early preclinical and pre-dementia disease state pathologyand basic translational research. The UK-ADC Clinical Core emphasizes: 1) collection of demographicclinical genetic and autopsy data from large numbers of subjects readily available as potential researchsubjects for current and future research needs 2) provision of non-autopsy biospecimens includingantemortem imaging and CSF biomarkers in a sub-cohort of subjects and 3) efforts to further advance thediscovery and development of novel therapeutics for AD. We are major contributors to nationalcollaborative initiatives such as NACC ADCS ADNI NCRAD and ADGC. Our research cohort is stronglymotivated to participate in research as evidenced by 304 unique active (living) subjects who haveparticipated in clinical studies over the report period. The Clinical Core has supported 40 grants and affiliatedprojects focused on specific research questions beyond standard UK-ADC data collections culminating in 64direct and 18 indirect publications supported by Core activities. Antemortem biomarker collections over thecurrent funding cycle include 361 clinical and 267 standardized research MRI scans 229 CSF collections and90 A-PET scans in order to more fully characterize our normal control and early transitional (MCI) cohort.Another major strength of our center lies in our robust minority outreach and engagement. Our efforts inconjunction with the OR Core have led to above-par for local and regional area minority engagement in ADCand affiliated studies. We have effectively engaged minority subjects in perceived invasive and therapeuticresearch efforts at a level of participation that has previously been considered untenable by most ADCs andnon-NIA funded centers nationally (37.6% unique minority subjects engaged in interventional trials). Theseefforts and successes will continue in the next five years under the harmonized and integrated Clinical Coreefforts that have proven successful at the UK-ADC. We will continue to play a leading role in clinicaltranslational research and development of potential novel therapeutic strategies to prevent or modifypathogenesis of AD and related disorders. Overall the Clinical Core will continue to provide an infrastructureand environment that will continue to contribute to our success in advancing multidisciplinary innovative ADresearch supporting our center theme of Transitions & Translation.

project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Basic Science;Biological Markers;Blood;Brain;Cessation of life;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Collection;Communities;Correlative Study;Data;Data Collection;Data Set;Dementia;Development;Disease;Education and Outreach;Environment;Extramural Activities;Foundations;Funding;Genetic Markers;Grant;Heart;Image;Impairment;Individual;Industry;Infrastructure;Intervention Trial;Kentucky;Leadership;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Medical Genetics;Minority;Minority Participation;Mission;Pathogenesis;Pathologic;Pathology;Pharmaceutical Preparations;Phase;Play;Population;Positron-Emission Tomography;Publications;Reporting;Research;Research Personnel;Research Project Grants;Research Subjects;Research Support;Role;Schedule;Specimen;Standardization;Therapeutic Human Experimentation;Tissues;Translational Research;Translations;United States National Institutes of Health;Universities;Work;active lifestyle;base;cohort;data management;innovation;meetings;minority communities;minority subjects;multidisciplinary;normal aging;novel therapeutics;operation;outreach;pre-clinical;prevent;programs;research and development;success;therapeutic development


