# projects

application_id: 9723178
project_number: 5R01HL137910-02
project_title: HDAC6 regulation of ICAM-1 expression and endothelial inflammatory signaling in sepsis
administering_ic: NHLBI
award_notice_date: 2019-04-30
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 137910
program_official: AGRAWAL, NITIN
project_start_date: 2018-06-15
project_end_date: 2022-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummarySepsis is a life-threatening disease with high morbidity and mortality. New therapeutic strategiesare urgently needed to treat this devastating disease. Uncontrolled endothelial inflammatoryresponses which often leads to inflammatory vascular injury contribute to the pathogenesis ofmultiple organ failure in sepsis. HDAC6 a histone deacetylase has been reported to modulatenuclear and non-nuclear protein function through deacetylation. In this project we willinvestigate HDAC6 regulation of endothelial inflammatory injury during sepsis. In our preliminarystudies we demonstrated that HDAC6 knockdown or selective HDAC6 inhibition preventedTNF- induced endothelial ICAM-1 expression which was associated with increased -tubulinacetylation and reduced STAT1 activation. Furthermore in mouse models of sepsis HDAC6inhibition blocked sepsis-induced lung ICAM-1 expression induced -tubulin acetylation andsuppressed STAT1 activation in lung tissues which was associated with reduced lunginflammatory injury and increased survival rate. In the proposed studies we will conduct a serialof experiments to assess the role of HDAC6 in sepsis-induced endothelial inflammatoryresponses and to investigate therapeutic mechanisms of HDAC6 inhibition against endothelialinflammatory signaling in sepsis.

project_terms:
Acetylation;Binding;Blood Vessels;Cell Adhesion Molecules;Cell Communication;Cell physiology;Cessation of life;Clinical Trials;Cytoplasm;Cytoskeleton;Data;Deacetylase;Deacetylation;Development;Disease;Endothelial Cells;Endothelium;Future;Gene Expression;HDAC4 gene;HDAC6 gene;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intercellular adhesion molecule 1;JAK2 gene;Knockout Mice;Leukocytes;Life;Lung;Mediating;Mediator of activation protein;Microtubule Stabilization;Microtubules;Morbidity - disease rate;Multiple Organ Failure;Nuclear;Pathogenesis;Play;Regulation;Reporting;Role;STAT1 gene;STAT1 protein;Sepsis;Signal Pathway;Signal Transduction;Structure of parenchyma of lung;Survival Rate;TNF gene;Testing;Therapeutic;Therapeutic Effect;Tubulin Interaction;alpha Tubulin;experimental study;inhibitor/antagonist;knock-down;mortality;mouse model;novel;novel therapeutic intervention;novel therapeutics;prevent;protective effect;protein function;transcription factor;tumor

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of HDAC6 in sepsis-inducedendothelial inflammatory signaling. The studies will validate the therapeutic potential of HDAC6 inhibitionagainst inflammatory vascular injury in sepsis. The proposed studies will provide important information forfuture clinical trials.


application_id: 9722542
project_number: 1R21AI144648-01
project_title: Conditional Null Mutants in the Study Essential Gene Products of Chlamydia
administering_ic: NIAID
award_notice_date: 2019-02-11
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AI
serial_number: 144648
program_official: VINCENT, LEAH REBECCA
project_start_date: 2019-02-11
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (81)]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Chlamydia trachomatis represents a significant health concern world-wide. A substantialburden exists due to the prevalence and the combined health and socioeconomic impact ofacute and chronic disease. All Chlamydia species express a type III secretion system (T3SS)and this mechanism likely contributes significantly to overall pathogenesis. Chlamydiae areobligate intracellular parasites that undergo a complex developmental cycle and this biologyhas historically impeded rapid progress in understanding pathogenesis. The newly acquiredability to inactivate chlamydial genes via insertion or deletion mutagenesis has greatly facilitatedcharacterization of virulence factors. Unfortunately significant barriers remain in the applicationof genetics in elucidating molecular mechanisms of virulence. For example there is currentlyno mechanism to generate null strains for gene products that are absolutely essential forchlamydial propagation in cell culture. To this end we have adapted the fluorescence-reportedallelic exchange mutagenesis technique to facilitate creation of conditional null strains inessential genes. Preliminary data describing such a situation for a type III effector gene arepresented herein. We propose to validate and further develop our approach while revealing thefunction of a highly important effector protein. At the end of these studies we will haveestablished new approaches that will benefit the entire Chlamydia research community andadvance the understanding of how T3S manifests during chlamydial infection.

project_terms:
Acute Disease;Alleles;Biology;Carrier Proteins;Cell Culture Techniques;Cell Nucleus;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Code;Communities;Complement;Complex;Coupled;Data;Deletion Mutagenesis;Development;Engineering;Epithelial Cells;Essential Genes;Fluorescence;Gene Expression;Genes;Genetic;Goals;Growth;Health;Human;Infection;Insertional Mutagenesis;Label;Literature;Mass Spectrum Analysis;Modeling;Molecular;Mutagenesis;Nature;Pathogenesis;Phase;Phenotype;Precipitation;Prevalence;Protein Export Pathway;Proteins;Reporting;Research;Role;Sexually Transmitted Agents;Sexually Transmitted Diseases;Sorting - Cell Movement;Techniques;Type III Secretion System Pathway;Virulence;Virulence Factors;Work;design;gene product;genetic manipulation;hepatocyte growth factor-regulated tyrosine kinase substrate;interest;member;mutant;new technology;novel;novel strategies;obligate intracellular parasite;particle;protein expression;protein transport;socioeconomics;success;tissue culture;tool

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease relies on a specializedsecretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis.This proposal contains work designed to use mutagenesis of specific genes that are essentialfor chlamydial survival to determine their specific contributions to chlamydial disease.


application_id: 9722327
project_number: 5UL1TR001998-04
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2019-06-08
opportunity_number: PAR-15-304
application_type: 5
activity_code: UL1
ic: TR
serial_number: 001998
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Contact PD/PI: Kern Philip APROJECTSUMMARYTheUniversityofKentucky(UK)CenterforClinicalandTranslationalScience(CCTS)hascreatedanintegratedhomeforclinicalandtranslationalresearchtopromotescientificprogressanddiscoveriesateveryphaseofthetranslationalcontinuum.TheCCTShasfundamentallytransformedtheresearchenvironmentnotonlyatUKbutthroughoutCentralAppalachiathroughthedevelopmentofastrongresearchnetworktheAppalachianTranslationalResearchNetwork(ATRN)withintegratedresearchpartnershipsincludingotherCTSAhubs.Whencombinedwithanin-depthunderstandingoftheuniqueandserioushealthchallengesfacedbyCentralAppalachianresidentstheUKCCTSispositionedtoleadlocalregionalandnationalresearcheffortsthatfocusonthesignificanthealthdisparitiesinthispopulation.OuroverarchinggoalasaCTSAhubistocontinuetochampioninnovationinthefullspectrumofclinicalandtranslationalresearchwhileeducatingtheworkforceofthefutureengagingourcommunitiesinbiomedicalscienceandworkingwiththenationalnetworktoadvancecohesivemulti-centerclinicaltrialswhichwillultimatelyelevatethehealthandqualityoflifeofthepopulaceofCentralAppalachia.SpecificallytheUKCCTSwill:1)Leadinstitutionalinnovationinthedeliveryofefficienteffectiveclinicalandtranslationalresearch.2)Developadiverseworkforceacrossmultipledisciplinesthatadvancestranslationalresearchandexcelsinteam-basedscience.3)MeettheuniqueneedsofCentralAppalachianresidentsbyextensivelyengagingandcollaboratingwithourregionalruralandcommunity-basedpartners.4)Catalyzeinnovativeresearchincludingnoveldrugdevelopmentandinformaticsmethodologieswithparticularfocusonbringinginnovationtospecialpopulationsandacrossthelifespan.5)CreateanefficientclinicaltrialsnetworkcenteredatUKandextendingintoourpartnerhealthcaresystemsthatwillbeanessentialandleadingcomponentoftheCTSAconsortiuminvolvingparticipantsthroughoutafourstateregionofruralCentralAppalachia.TheUKCCTSbenefitsfromacollaborativeenvironmentfoundononlyafewuniversitycampuses.UKhas16collegeswith11involvedintheUKCCTS(includingsixbiomedicalcolleges)ononecentralcampus.ThisphysicalproximityofouracademicandhealthcarecommunitiesalongwithacultureofcollaborationcreatesacloselyknitunifiedacademiccommunityandpositionstheUKCCTStodemonstratetheimpactofcollaborativetranslationalresearchandleadershipinteamscience.OureffortshavealreadybeensuccessfulattransformingthecultureoftheUKacademicmedicalcentertoonethatmorekeenlyappreciatesscholarshipinnovationandtranslationalscience.Wenowplantobuildonthesestrengthstoadvancetranslationalsciencetothenextlevelwithfurtherdevelopmentofourclinicaltrialnetworksdevelopmentofnovelinformaticsprogramsandcontinueddevelopmentoftheworkforcethroughouttheregion.TheseeffortswillbenefitthemedicallyunderservedresidentsofCentralAppalachiaandwillsignificantlycontributetothenationalCTSAprogram.  1 Project Summary/Abstract Page 287Contact PD/PI: Kern Philip A

project_terms:
Abbreviations;Academic Medical Centers;Affect;Agriculture;Appalachian Region;Arts;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Community Healthcare;Data;Development;Discipline;Diverse Workforce;Education;Engineering;Environment;Fostering;Future;Goals;Health;Healthcare;Healthcare Systems;Home environment;Informatics;Institutes;Institution;Interdisciplinary Study;Kentucky;Lead;Leadership;Longevity;Medical center;Methodology;Mission;Multi-Institutional Clinical Trial;Participant;Patient Recruitments;Personal Satisfaction;Phase;Population;Positioning Attribute;Quality of Care;Quality of life;Research;Research Training;Role;Rural;Rural Community;Rural Population;Scholarship;Science;Solid;Target Populations;Translational Research;Trust;Universities;West Virginia;Workforce Development;base;biomedical informatics;catalyst;cohesion;collaborative environment;college;data management;data warehouse;drug development;food environment;health care service organization;health disparity;healthcare community;improved;innovation;medical schools;medically underserved;named group;novel;novel therapeutics;programs;rural area;success

public_health_relevance:
PROJECT NARRATIVEThe University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) is strategicallypositioned in Central Appalachia to catalyze efforts to connect the populace of this medically underservedregion with significant health disparities to the national CTSA network. The UK CCTS is recognized locallyand regionally for affecting change and building robust partnerships across the CTSA network in CentralAppalachia and at UK creating an efficient platform for clinical and translational research and training all toimprove quality of care health and well-being for the rural populations of this region.1Project Narrative Page 288


application_id: 9720915
project_number: 5R01CA230758-02
project_title: Characterize the role of EBF1 in breast cancer progression
administering_ic: NCI
award_notice_date: 2019-08-23
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 230758
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 11716117
contact_pi: WU, YADI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Attenuated;Autophagocytosis;B-Lymphocytes;Biogenesis;Bioinformatics;Biological;Brain;Breast Cancer Cell;Breast Cancer cell line;Cell Death;Cells;Cessation of life;Clinical;Data;Disease;EP300 gene;Early identification;Ensure;Environment;Event;Feedback;Genes;Genetic Transcription;Goals;Growth;HIF1A gene;Homeostasis;Human;Hypoxia;Hypoxia Inducible Factor;Immunocompetent;Interruption;Intrinsic factor;Knockout Mice;Knowledge;Luciferases;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;NCI-Designated Cancer Center;Neoplasm Metastasis;Nutrient;Oxygen;Pathogenesis;Pathologist;Pathway interactions;Patients;Play;Process;Reaction;Reagent;Regulation;Research;Response Elements;Role;Sampling;Signal Transduction;Specimen;Stress;System;Talents;Testing;Therapeutic;Tumorigenicity;Work;alternative treatment;base;breast cancer progression;cancer initiation;druggable target;in vivo;inhibitor/antagonist;innovation;insight;interest;knock-down;malignant breast neoplasm;mouse model;multidisciplinary;neoplastic cell;novel;outcome forecast;overexpression;prevent;programs;response;targeted treatment;transcription factor;treatment strategy;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;uptake


application_id: 9719772
project_number: 5R21AI139956-02
project_title: Post-transcriptional regulation in Borrelia burgdorferi by the BpuR RNA-binding protein
administering_ic: NIAID
award_notice_date: 2019-05-20
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 139956
program_official: ILIAS, MALIHA R
project_start_date: 2018-06-11
project_end_date: 2021-11-30
study_section: Special Emphasis Panel[ZRG1-IDM-B(81)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT All organisms from bacteria to humans need to recognize where they are and respond accordingly.A pathogen must sense its location in the infectious cycle then produce factors necessary for that site whilerepressing synthesis of inappropriate factors. It has become increasingly obvious that many bacteria utilizepost-transcriptional mechanisms to control levels of important proteins. In our studies of the Lyme diseasebacterium Borrelia burgdorferi we discovered that a previously-undescribed type of bacterial RNA-binding protein named BpuR is critical for mammalian infection. B. burgdorferi that were geneticallyengineered to dysregulate BpuR were found to be significantly impaired in ability to colonize mice.Transcriptomic and proteomic analyses indicate that BpuR exerts significant impacts upon expression levels ofa substantial number of B. burgdorferi proteins. A series of complementary yet independent studies isproposed to define mechanisms by which BpuR controls levels of infection-associated proteins in the bacteria.Results will greatly enhance understanding of pathogenic mechanisms of the Lyme disease spirochete inaddition to serving as models for post-transcriptional regulation in bacteria.

project_terms:
Awareness;Bacteria;Bacterial RNA;Binding;Borrelia;Borrelia burgdorferi;Code;Complex;Data;Engineering;Eukaryota;Genetic Engineering;Genetic Transcription;Human;Immunoprecipitation;Impairment;Infection;Knowledge;Lead;Location;Lyme Disease;Mass Spectrum Analysis;Messenger RNA;Modeling;Mus;Mutation;Names;Organism;Pathogenesis;Pathogenicity;Physiological;Physiology;Post-Transcriptional Regulation;Production;Property;Proteins;Proteomics;RNA;RNA Binding;RNA immunoprecipitation sequencing;RNA-Binding Proteins;Regulatory Pathway;Series;Site;Structure;Superoxide Dismutase;Technology;Transcript;Translations;Untranslated RNA;Virulence Factors;insight;mutant;pathogen;protein expression;soft drink;transcriptome sequencing;transcriptomics;vector tick

public_health_relevance:
PROJECT NARRATIVEThe Lyme disease bacterium's BpuR protein regulates expression of multiple virulence factors and bacteriathat do not correctly control BpuR levels are severely impaired in ability to cause mammalian infection. Studiesin this proposal will determine the mechanisms by which BpuR exerts post-transcriptional controls on proteinexpression levels providing valuable insights on physiological and pathogenic properties of the Lymespirochete.


application_id: 9719764
project_number: 5R01AI140758-02
project_title: Mechanisms of actin cytoskeleton modulation by Pneumoviruses
administering_ic: NIAID
award_notice_date: 2019-05-23
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AI
serial_number: 140758
program_official: KIM, SONNIE
project_start_date: 2018-06-11
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(02)M]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: LEUNG, DAISY W
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;Address;Affect;Affinity Chromatography;Bacteria;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biological Models;Biophysics;Bronchiolitis;Calorimetry;Cell physiology;Cells;Cellular Morphology;Cellular biology;Childhood;Co-Immunoprecipitations;Complex;Coupled;Cytoskeletal Proteins;Cytoskeleton;Data;Deuterium;Disease;Dyes;Elderly;Elements;Epithelial;Family;Fluorescent in Situ Hybridization;Human;Human Metapneumovirus;Hybrids;Hydrogen;Immunocompromised Host;In Vitro;Individual;Infection;Life Cycle Stages;Ligation;Lower Respiratory Tract Infection;Mass Spectrum Analysis;Mediating;Microscopy;Modification;Molecular;Molecular Sieve Chromatography;Mutation Analysis;NMR Spectroscopy;Nature;Nucleocapsid;Pathogenesis;Phosphoproteins;Physiological;Play;Pneumovirus;Pneumovirus Infections;Population;Process;Proteins;RNA;RNA Viruses;Respiratory Syncytial Virus Infections;Respiratory Tract Infections;Respiratory syncytial virus;Role;Structure;System;Testing;Time;Titrations;Viral;Viral Proteins;Virus;Virus Diseases;Virus Replication;X-Ray Crystallography;cell motility;cellular targeting;effective therapy;human pathogen;insight;intercellular communication;light scattering;member;mutant;new therapeutic target;novel;pathogen;pathogenic virus;polymerization;respiratory;structural biology;therapeutic development;therapeutic target;viral RNA;virology


application_id: 9718088
project_number: 5R01AG053999-04
project_title: Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2019-04-22
opportunity_number: PAR-15-358
application_type: 5
activity_code: R01
ic: AG
serial_number: 053999
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-09-15
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)R]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractWe propose that an early and possibly treatable contributor to the multifactorial etiology of Alzheimer's disease(AD) involves dyshomeostasis of amylin a pancreatic hormone that crosses the blood brain barrier and hasamyloidogenic properties similar to those of the -amyloid (A) peptide. This hypothesis is supported byrecent work from our lab and others showing large amylin deposits in brains of AD patients. Moreover wefound >4-fold higher brain amylin level in ApoE4 carriers particularly in patients with type-2 diabetessuggesting a link of the accumulation of amylin in the brain with ApoE and metabolic risk factors. Using ratsexpressing human amylin in the pancreas and amylin knockout we found that the brain amylin accumulation islikely promoted by elevated blood levels of oligomerized amylin via the interaction with plasma low densitylipoproteins and causes neuroinflammation and neurologic deficits. Here we propose to test these ideas.Planned studies will determine physiological and functional changes in the brain using a rat modelexpressing human amylin in the pancreas and appropriate controls (Aim 1). We will specificallyidentify therapeutic targets to reduce amylin-induced cytotoxicity in the brain. Pharmaceuticalinterventions will reinforce mechanistic insights while also informing on mechanisms that underlie thebrain amylin accumulation and potential functional effects in humans. Human studies will elucidateamylin-APOE and amylin-A interactions contributing to AD pathology (Aim 2). Here we collaboratewith the University of Kentucky AD Center which has a large repository of brain plasma andcerebrospinal fluid specimens from clinically well-characterized subjects. We also collaborate with theQueen Square Brain Bank for Neurological Disorders of the University College of London andMedical Research Council of King's College London which provided for this project brain specimensfrom early onset familial AD patients (PSEN1 and APP mutation carriers). These brain specimens willbe used to elucidate a potential relationship between the brain amylin accumulation and AD-type ofplaque i.e. early onset familial AD (associated with increased A oligomerization) vs. late onset AD(attributed to the impaired A clearance). To further elucidate the pathobiology of amylin-Ainteraction we crossed the human amylin expressing rat with the TgF344-19 rat model of AD. Thesuccessful completion of this project offers the potential to refining diagnosis and tailoring specifictherapies to modify/ delay/ prevent brain injury and cognitive decline in aging and metabolic disorders.

project_terms:
4 hydroxynonenal;Abeta clearance;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease model;Alzheimers disease biomarker;Amyloid;Amyloid beta-Protein;Animal Model;Apolipoprotein E;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Brain Injuries;CREB1 gene;Carnosine;Cell Culture Techniques;Cell model;Cerebrospinal Fluid;Cerebrovascular Circulation;Clinical;Clinical Data;Cognitive;Data;Dementia;Deposition;Diagnosis;Disease Progression;Early Onset Familial Alzheimer's Disease;Eicosanoids;Etiology;Genotype;Goals;Hormones;Human;Hypertrophy;Impaired cognition;Impairment;Injections;Injury;Interleukin-1 beta;Intervention;Kentucky;Knock-out;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipid Peroxidation;London;Low-Density Lipoproteins;Malondialdehyde;Measures;Mediating;Medical Research;Membrane;Metabolic;Metabolic Diseases;Modeling;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pancreatic Hormones;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Peroxides;Pharmacologic Substance;Physiological;Plasma;Prevention strategy;Property;Protein Isoforms;Rattus;Research Project Grants;Rest;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Specimen;Testing;Toxic effect;Transgenic Animals;Universities;Vascular Diseases;Work;apolipoprotein E-4;brain tissue;cerebrovascular;clinically relevant;college;cytotoxicity;data modeling;diabetic;diabetic rat;experimental study;human data;human disease;human tissue;inflammatory milieu;inhibitor/antagonist;insight;islet amyloid polypeptide;lipid peroxidation inhibitor;mutation carrier;nervous system disorder;neuroinflammation;neurotoxicity;neurovascular unit;novel;presenilin-1;prevent;repository;therapeutic evaluation;therapeutic target

public_health_relevance:
NarrativeWe have recently discovered that in addition to plaques laden with -amyloid brains of Alzheimer's diseasepatients contain large deposits of amylin an amyloidogenic hormone secreted from the pancreas. In thisresearch project we propose to use human tissue clinical data transgenic animals and cell models to 1)decipher mechanisms of brain amylin pathology in humans 2) determine the impact of amylin deposition onthe neurovascular unit and 3) test clinically relevant therapies to modify/ reduce/ prevent amylin-mediateddeleterious effects in the brain. The successful completion of this project offers the potential to refiningdiagnosis and tailoring specific therapies to modify/ delay/ prevent cerebrovascular injury and cognitive declinein aging and metabolic disorders.


application_id: 9717802
project_number: 3R01NS070899-09S2
project_title: Alzheimer's disease supplement to NS070899 linking polyglucosans to AD
administering_ic: NINDS
award_notice_date: 2018-09-21
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: NS
serial_number: 070899
suffix: S2
program_official: LEENDERS, MIRIAM
project_start_date: 2018-08-01
project_end_date: 2019-06-30
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This is an Administrative Supplement request in response to NOT-AG-18-008 for Alzheimer's Disease and itsrelated Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused onAlzheimer's disease for R01NS07899 entitled Regulation signaling and dynamics of glucan phosphatases.The requested funds are to perform experiments proposed within the scope of R01NS07899 but were notoriginally focused on Alzheimers disease. The parent grant focuses on defining the molecular mechanism ofLafora disease (LD). LD is a fatal neurodegenerative glycogen storage disease. The pathogenic agent and ahallmark of LD are aberrant glycogen-like intracellular polyglucosan body (PGB) inclusions. In the parentgrant we propose to: 1) define these PGBs in terms of their physiochemical make-up 2) define the metabolicmachinery that generates them and 3) develop putative therapeutics to remove them. Recent work hasidentified PGBs in Alzheimers disease patient samples and we see that these PGBs are localized in similarregions as tau. A significant strength of this supplement is that it brings together three PIs that have non-overlapping and complementary expertise. The supplement will also utilize the wealth of expertise andresources provided by the UK Alzheimers Disease Center (ADC). In this supplement we will utilize ourextensive expertise with PGBs to:Aim 1: Establish the physiochemical properties of PGBs in Alzheimers disease models.Aim 2: Define central carbon metabolism using steady state metabolomics in Alzheimers models.Aim 3: Identify and develop an amylase to degrade Alzheimers disease PGBs as a putative therapeutic.

project_terms:
Acute;Administrative Supplement;Affect;Alzheimer's Disease;Alzheimer's disease model;Amygdaloid structure;Amylases;Antibodies;Astrocytes;Biochemical;Biochemical Pathway;Brain;Brain Diseases;Carbohydrates;Carbon;Cells;Cellular Metabolic Process;Cessation of life;Cytoplasmic Granules;Data;Dementia;Disease;Disease model;Energy Metabolism;Epilepsy;Event;Foundations;Funding;Genes;Glucans;Glycogen;Glycogen Storage Disease;Goals;Grant;Human;In Situ;In Vitro;Inclusion Bodies;Inherited;Lafora Disease;Length;Life;Link;Liver;Medial;Metabolic;Metabolic Pathway;Metabolism;Molecular;Mus;Muscle;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Parents;Pathogenesis;Pathogenicity;Patients;Phosphoric Monoester Hydrolases;Play;Positioning Attribute;Process;Progressive Myoclonic Epilepsies;Property;Proteins;Regulation;Reproducibility;Resources;Role;Sampling;Seizures;Signal Transduction;Somatotype;Surface;Teenagers;Therapeutic;Tissues;United States National Institutes of Health;Water;Work;brain cell;cell type;crystallinity;experimental study;glycogen metabolism;in vivo;inorganic phosphate;insight;loss of function mutation;metabolic profile;metabolomics;mouse model;neuron apoptosis;neurotoxicity;novel;parent grant;particle;polyglucosan;response;tau Proteins;tau aggregation;therapeutic target;ubiquitin-protein ligase

public_health_relevance:
Lafora disease is a catastrophic epilepsy that strikes healthy teenagers it leads to constant ever-worseningseizures until it results in death after 10 years and is caused by abnormal glycogen called polyglucosan bodies(PGBs) that builds up in the patients brain cells. We recently identified similar PGBs in Alzheimers disease(AD)patient samples and we see that these PGBs are localized in similar regions as tau. We will utilize fundsfrom this Administrative Supplement to establish the role of these PGBs in AD and define if they are atherapeutic target.!


application_id: 9717618
project_number: 3R01CA193220-04S1
project_title: Ubiquilins regulate EMT migration and invasion of human lung cancer
administering_ic: NCI
award_notice_date: 2018-09-18
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: CA
serial_number: 193220
suffix: S1
program_official: AULT, GRACE S
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:
SUMMARYThe overall hypothesis of this proposal is that Ubiquilin1 suppresses critical signaling pathways thatdrive the pathogenesis of both Alzheimer's disease and cancer. These two diseases represent two of the largestburdens on the healthcare systems in all developed countries. In the U.S. the annual national expenditure forthese two diseases combined is ~$300 billion dollars. Currently in the U.S. there are ~5.4 million people livingwith Alzheimer's disease and there will be ~1.7 million new cancer cases diagnosed this year. Only byunderstanding the basic molecular biochemical and genetic causes of these diseases will we be able to makesignificant progress in treating these patients. Interestingly it has been reported but largely ignored that thereare common signaling pathways that are altered to drive the onset of both Alzheimer's disease and cancer.This proposal seeks to understand how the of scaffold protein Ubiquilin1 regulates seemingly opposingcellular outcomes in epithelial cells and neuronal cells. Loss of Ubiquilin1 in epithelial cells increasesproliferation and migration whereas in neuronal cells it causes cell death. Amazingly there are a number ofadditional signaling pathways that behave in a similar cell-type and context-dependent manner includingamyloid precursor protein (APP) growth factor receptors (such as IGF1R) and focal adhesion complexes suchthat aberrant activation of processes contributes to both tumorigenic phenotypes as well as progression ofAlzheimer's disease. We are the first to show that loss of Ubiquilin1 as seen in cancer and Alzheimer'sdisease causes increased growth factor receptor signaling and increased focal adhesion formation andsignaling. In this proposal we will examine the detailed molecular and biochemical regulation of theseprocesses by Ubiquilin1 and we will examine the cell-type and context-dependent differences of Ubiquilin1function in epithelial and neuronal cells. This information will shed light on the basic mechanisms thatcontribute to multiple diseases afflicting millions of people every year.

project_terms:
Adaptor Signaling Protein;Address;Alzheimer's Disease;Amyloid beta-Protein Precursor;Binding;Biochemical;Biochemical Genetics;Biological;Biology;C-terminal;Cause of Death;Cell Culture Techniques;Cell Death;Cell Differentiation process;Cell Survival;Cell physiology;Cells;Complex;Data;Developed Countries;Developing Countries;Diagnosis;Disease;Epidermal Growth Factor Receptor;Epithelial;Epithelial Cells;Expenditure;FRAP1 gene;Family;Family member;Focal Adhesions;Goals;Growth Factor Receptors;Healthcare Systems;Heat-Shock Response;Human;IGF1R gene;Light;Link;Literature;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Mus;N-terminal;Neurodegenerative Disorders;Neurons;Outcome;Partner in relationship;Pathogenesis;Pathologic;Pathway interactions;Patients;Phenotype;Physiological;Play;Process;Proliferating;Protein Region;Proteins;Receptor Signaling;Regulation;Reporting;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Tetanus Helper Peptide;Tetracyclines;Tissues;Trans-Activators;UBA Domain;UBQLN1 gene;Ubiquitin;associated symptom;cancer survival;cell growth;cell type;chaperonin;embryonic stem cell;established cell line;human disease;in vivo;loss of function;member;migration;mouse model;multicatalytic endopeptidase complex;reduce symptoms;small hairpin RNA;tumorigenic;ubiquilin

public_health_relevance:
NARRATIVE Alzheimer's disease and cancer are seemingly caused by contrasting cellular processes; aberrant celldeath for Alzheimer's disease and aberrant cell survival for cancer. The family of adapter proteinsUbiquilins are lost in both cancer and in Alzheimer's disease. The goal of this proposal is to determinehow Ubiquilin proteins normally function to keep epithelial cells from aberrantly proliferating whilekeeping neuronal cells from dying.


application_id: 9717488
project_number: 3R01HL133723-03S2
project_title: Adventitial-medial interactions in thoracic aortic diseases
administering_ic: NHLBI
award_notice_date: 2018-09-20
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: HL
serial_number: 133723
suffix: S2
program_official: MCDONALD, CHERYL
project_start_date: 2016-06-01
project_end_date: 2020-05-31
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractAlzheimer's disease (AD) is closely linked to cardiovascular risk factors. The renin-angiotensinsystem contributes to cardiovascular diseases through its bioactive peptide angiotensin II(AngII) acting on AT1 receptor. There is compelling evidence that AngII and AT1 receptorcontribute to AD. The important role of AngII and AT1 receptor has also been enhanced byseveral ongoing clinical trials to determine effects of AT1 receptor antagonism on improvingcognitive dysfunction and neuropathology of AD. The parent grant is studying the role of AngIIinfusion on mechanisms of thoracic aortic aneurysms. AngII infusion in mice shows impairmentof memory and recognition accompanied by higher gene expression involved in -amyloidgeneration and AD although related neuropathology and potential mechanisms have not beendetermined. This Administrative Supplement will test a central hypothesis that AngIIpromotes cognitive decline correlated with region-specific changes in cerebral arteries that areaugmented by vascular smooth muscle cell-specific deletion of LRP1. We will use our well-established AngII-infusion mouse model as well as a unique mouse model (smooth muscle cell-specific LRP1 -/-) described in the parent grant. Mice will be infused with AngII in both maleand female mice to answer 4 questions that are within the scope of the parent grant: (1) IsAngII infusion induced cognitive decline dependent on blood pressure increase? (2) Is AngII-induced cognitive dysfunction influenced by hypercholesterolemia? (3) Does the AngII-inducedcognitive decline correlate with region-specific changes in cerebral artery pathology? (4) Doesdeletion of LRP1 in smooth muscle cells augment the cognitive decline and cerebral vascularpathology during AngII infusion? The proposed project will be benefitted from (1) Water maze(the standard method for AD) to determine cognitive function in our Rodent Behavior Core (2)sophisticated Light Microscopy Core on campus that permits detailed characterization ofcerebral vascular structure in mice and (3) our well-respected Alzheimer's Disease Center andcollaboration with neurological scientists (Dr. Johnson at our institution and Dr. Holtzman atWashington University). We are confident that the experiments proposed in this AdministrativeSupplement will assimilate preliminary data to enable development of an R01 that will focus onproviding new insights into understanding mechanisms of AD. The potential R01 application willalso be strengthened by a spectrum of mouse models and pharmacological tools that havealready been developed in the parent grant or other awards we received and well-recognizedAD mouse models in our Alzheimer's Disease Center and from Dr. Johnson.

project_terms:
Administrative Supplement;Alzheimer's Disease;Amyloid;Angiotensin II;Aortic Diseases;Award;Behavior;Blood Pressure;Cardiovascular Diseases;Chest;Clinical Trials;Collaborations;Data;Development;Female;Gene Expression;Generations;Impaired cognition;Infusion procedures;Institution;Link;Medial;Memory impairment;Methods;Mus;Neurologic;Pathology;Peptides;Pharmacology;Renin-Angiotensin System;Rodent;Role;Scientist;Smooth Muscle Myocytes;Structure;Testing;Thoracic Aortic Aneurysm;Universities;Vascular Smooth Muscle;Washington;Water;cardiovascular risk factor;cerebral artery;cerebrovascular;cognitive function;experimental study;hypercholesterolemia;improved;insight;light microscopy;male;memory recognition;mouse model;neuropathology;parent grant;receptor;tool


application_id: 9717412
project_number: 3R01DC017025-01S1
project_title: ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss
administering_ic: NIDCD
award_notice_date: 2018-08-16
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: DC
serial_number: 017025
suffix: S1
program_official: CYR, JANET
project_start_date: 2018-03-22
project_end_date: 2023-02-28
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY The long-term goal of this project is to investigate mechanisms underlying noise-induced cochlearsynaptopathy and hidden hearing loss. Noise is a common risk factor for hearing loss. Recent studieshave demonstrated that even a single episode of noise overexposure induces transient hearing lossi.e. temporal threshold shift (TTS) noise-exposed animals could have no hair cell loss but haveextensive spiral ganglion neuron (SG) and synapse degeneration. In particular low spontaneous rate(LSR) auditory nerves and their synaptic connections with inner hair cells are preferentially lost. Thenoise-exposed animals and humans demonstrate normal hearing threshold and sensitivity (i.e.hidden hearing loss) in the early stage but will eventually exhibit other hearing disorders and hearingloss. Currently the underlying mechanism for such cochlear synaptopathy remains unclear. Noise stimulates hair cell and neuron over-activation and increases K+ efflux that leads toincreasing extracellular K+ concentration. It is well-established that high extracellular K+ can inducetoxicity leading to second cell death in the brain following injury and stroke. We hypothesize thathigh excess extracellular K+ following noise exposure can also cause SG synapse and neurondegeneration in the cochlea. We previously found that ATP purinergic P2X receptors in the cochleaare required for sinking K+ to re-enter into cells. A recent study also demonstrated that P2X2receptors are necessary for the development of TTS. In addition we found that P2X2 mutation canincrease susceptibility to noise and induce hearing loss. These studies indicate that P2X receptorsmay have a critical role in noise-induced cochlear synaptopathy and hidden hearing loss. In thisproject we will first test whether high extracellular K+ can cause SG synapse and neurondegeneration (Specific Aim 1 SA1). Then we will identify and characterize P2X receptor expressionin SG neurons including LSR and HSR (high spontaneous rate) fiber synaptic endings and testwhether P2X receptors can mediate K+-sinking in the SG neurons. In SA3 we will test whetherdeficiency of P2X receptors can induce and exacerbate cochlear synaptopathy and hearing lossfollowing noise exposure and high-K+ challenge. Completion of these studies will directly reveal themolecular mechanism underlying noise-induced cochlear synaptic degeneration and hidden hearingloss. These novel studies will also open a new therapeutic avenue for targeting noise-induced hearingloss and cochlear synaptopathy.

project_terms:
Acoustic Nerve;Address;Animals;Apoptosis;Apoptotic;Area;Astrocytes;Auditory system;Brain;CASP3 gene;Cell Death;Cells;Cessation of life;Cochlea;Data;Development;Exhibits;Fiber;Gap Junctions;Gene Family;Generations;Genetic;Goals;Hair Cells;Hearing;Hearing problem;Homogeneously Staining Region;Human;Injury;Inner Hair Cells;Mediating;Microscopy;Molecular;Mutation;Nerve Degeneration;Nerve Fibers;Neurons;Noise;Noise-Induced Hearing Loss;Optics;P2X-receptor;Pathway interactions;Play;Postsynaptic Membrane;Predisposition;Protein Isoforms;Purinoceptor;Research;Resolution;Risk Factors;Role;Stroke;Synapses;Techniques;Technology;Testing;Therapeutic Intervention;Toxic effect;extracellular;hearing impairment;light microscopy;novel;novel therapeutics;public health relevance;receptor;receptor expression;receptor function;reconstruction;spiral ganglion

public_health_relevance:
Public Health Relevance Statement: In this proposal we will define novel purinergic mechanism underlying noise-inducedcochlear synaptopathy and hidden hearing loss using multiple state-of-the-art techniques. Thiswill enhance our understanding of genetic causes underlying noise-induced hearing loss. Thisstudy will provide invaluable clues for developing and applying protective and therapeuticinterventions for noise-induced hearing loss in particular hidden hearing loss.


application_id: 9717386
project_number: 1K18DC017116-01A1
project_title: Function of taste papillae mechanoreceptors
administering_ic: NIDCD
award_notice_date: 2019-02-19
opportunity_number: PAR-18-564
application_type: 1
activity_code: K18
ic: DC
serial_number: 017116
suffix: A1
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2019-02-19
project_end_date: 2020-03-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractAlong with taste we perceive the texture and location of food in the oral cavity and thesemodalities contribute to food choice. The first step leading to the perception of location andtexture is activation of oral cavity mechanosensory neurons most of which reside in thetrigeminal ganglion. Some of these neurons project to gustatory regions and modulate tasteresponses beginning at the first gustatory relay (NST). Yet little is known about the sensitivesreceptive field properties or response specificity of these neurons. The goal of this applicationis to redirect the research program of a taste scientist through the acquisition of new researchskills (genetic encoded calcium imaging of the trigeminal ganglion neurons) to answerquestions concerning how these neurons function. With these tools in-hand the long-term goalis to 1) elucidate the classes of mechanosensitive neurons based on functional characteristicsgenetic expression and structural characteristics. 2) to manipulate these neurons to determinetheir specific role in the central nervous system coding of oral cavity stimuli and contributions tobehavioral food choice.

project_terms:
Afferent Neurons;Anatomy;Animals;Area;Attention;Behavior;Behavioral;Burning Mouth Syndrome;Calcium;Caliber;Cells;Characteristics;Classification;Code;Data;Detection;Development;Eating Disorders;Epithelial;Fiber;Filiform Papilla;Food;Functional Imaging;Fungiform Papilla;Future;Genetic;Genetic Identity;Goals;Hand;Housing;Image;Imaging Techniques;Individual;Investigation;Laboratories;Learning;Light;Liquid substance;Location;Martes zibellina;Mechanoreceptors;Modality;Molecular;Morphology;Mucous Membrane;Neuraxis;Neurons;Oral;Oral cavity;Organ;Perception;Peripheral;Peripheral Nervous System Diseases;Positioning Attribute;Potato;Property;Research;Role;Scientist;Sensory;Sensory Receptors;Skin;Smell Perception;Specificity;Stimulus;Structure;Structure of trigeminal ganglion;Surface;Taste Buds;Taste Perception;Techniques;Temperature;Texture;Tongue;Touch sensation;Training;Trigeminal System;base;experimental study;food flavor;interest;nerve supply;olfactory stimulus;oral sensory;programs;receptive field;response;skills;somatosensory;tongue papilla;tool

public_health_relevance:
Project Narrative:Somatosensory neurons innervating the tongue function normally to contribute to numerousperceptual qualities including texture of food and location of gustatory stimuli which thencontribute to food choice. Understanding their role in normal function is the first step indetermining their role when food choice is disrupted (eating disorders) or when sensory neuronfunction is disrupted (peripheral neuropathies and/or burning mouth syndrome) .


application_id: 9717232
project_number: 5R01DK074816-10
project_title: RORalpha and Hepatic Zonal Regulation
administering_ic: NIDDK
award_notice_date: 2019-06-10
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2007-09-01
project_end_date: 2022-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The restricted expression of specific hepatic genes in pericentral or periportal regions ofthe adult liver a phenomenon known as zonal regulation is a fascinating aspect of liverbiology. Elegant studies in the past 10 years have uncovered the role of the b-cateninsignaling pathway in controlling zonal expression. Our recent studied using a novelmouse model system developed by us indicates that the retinoic acid-related orphanreceptor alpha (RORa) also plays a role in controlling zonal gene expression.Furthermore studies in other tissues have shown that RORa contributes to thedifferentiation and proliferation of stem cells but this property has not been evaluated inthe liver. We propose to use genetically modified mice and contemporary high-throughput genomic technologies to explore the role of RORa in the function and stemcell properties of pericentral hepatocytes. Since many hepatotoxins including ethanoland pharmaceuticals such as acetaminophen specifically damage pericentralhepatocytes a better understanding of the mechanisms controlling gene expression inand the self-renewing properties of this subpopulation of hepatocytes will help developstrategies to reduce hepatocyte injury in humans.

project_terms:
Acetaminophen;Adult;Binding;Binding Sites;Biological Models;Biology;Carbon Tetrachloride;Cell Lineage;Cell Separation;Cell Surface Proteins;Central Vein;ChIP-seq;Conflict (Psychology);Data;Enhancers;Ethanol;Exhibits;Flow Cytometry;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genomics;Goals;Grant;Hepatic;Hepatocyte;Human;Individual;Injury;Knockout Mice;Link;Liver;Liver Regeneration;Lobule;Methods;Modeling;Mus;Mutate;Mutation;Natural regeneration;Nucleic Acid Regulatory Sequences;Orphan;Partial Hepatectomy;Pattern;Pharmacologic Substance;Play;Property;RORA gene;Regulation;Response Elements;Role;Signal Pathway;Site;Staggerer Mouse;Stem cells;Technology;Testing;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Tretinoin;alpha-Fetoproteins;beta catenin;fascinate;hepatotoxin;improved;in vivo;insight;interest;liver function;liver injury;mouse model;novel;promoter;receptor;self-renewal;stem cell division;transcription factor;transcriptome sequencing

public_health_relevance:
Many hepatotoxins and pharmaceuticals specifically damage a subset of hepatocytesthat are found in the pericentral region of the adult liver. Studies proposed in the grantwill investigate the role of the transcription factor RORa as well as the factors Rev-erba/b in the function and stem cell properties of these unique pericentral hepatocytes.The long-term goal of these studies is to improve strategies that will reduce liver injury inhumans.


application_id: 9717100
project_number: 5R01CA187273-05
project_title: Suppression of Prostate Tumor Growth and Metastasis by Inhibition of Vimentin
administering_ic: NCI
award_notice_date: 2019-06-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 187273
program_official: CHEN, WEIWEI
project_start_date: 2015-07-01
project_end_date: 2021-06-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
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): Advanced prostate tumors that often metastasize to the lung bone and other vital tissues are resistant to conventional therapy. Prostate apoptosis response-4 (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells. Although baseline levels of Par-4 secreted by cells are inadequate to induce apoptosis normal cells can be induced to produce robust secretion of Par-4 protein that targets cancer cells in a paracrine manner. Accordingly secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 in cancer cells to trigger apoptosis in primary and metastatic tumors. Importantly secreted Par-4 induces cancer-specific apoptosis but it does not induce apoptosis in normal cells as GRP78 is expressed only on the surface of cancer cells not on normal cells. "Small-molecule" drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would therefore represent an important therapeutic advance. In preliminary studies we synthesized and screened newly developed 3-arylquinolines as well as related quinolones and quinothiolones for the secretion of Par-4 protein from normal mouse and human fibroblast and epithelial cells. This screening led to the identification of 2-amino-7-(NN-dimethylamino)-3-(2'-fluorophenyl)quinoline (called "Arylquin-1") as a member of a new class of agents that trigger robust secretion of Par-4 from normal cells at nanomolar non-toxic concentrations. As expected Par-4 secreted from these normal cells induced paracrine apoptosis in diverse prostate and lung cancer cell cultures but not in normal cell cultures. Usinga biotinylated biologically active version of Arylquin-1 we identified vimentin a protein linkedto motility invasion EMT and metastasis as the molecular target of Arylquin-1 that in turn produces Par-4 secretion. In this study we will determine the effect of Arylquin-1 on Par-4 secretion from normal cells and apoptosis in prostate cancer cell culture and in vivo on tumor growth in prostate cancer models. Computational dynamics revealed that Arylquin-1 forms a stable interaction with a hydrophobic pocket on vimentin. We will therefore determine the domains of Par-4 and vimentin that bind to each other to elucidate the mechanism underlying inhibition of Par-4 secretion by vimentin and its release by Arylquin-1. Consistent with the interaction of Arylquin-1 with vimentin our preliminary studies also indicated that Arylquin-1 inhibits motility and invasion in prostate cancer cells by an apoptosis-independent mechanism. We will therefore study whether Arylquin-1 inhibits motility invasion and EMT in cell culture and metastasis in mouse models of prostate cancer via vimentin-dependent mechanisms. Developing agents that selectively promote Par-4 secretion from normal cells induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.

project_terms:
Apoptosis;Apoptotic;Binding;Biological;Biology;Cancer Etiology;Cell Culture Techniques;Cell Surface Receptors;Cells;Cessation of life;Chemicals;Conditioned Culture Media;Development;Epithelial;Epithelial Cells;Family;Fibroblasts;GRP78 gene;Growth;Human;Hydrophobicity;Impaired wound healing;Knockout Mice;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mesenchymal;Metastatic Neoplasm to the Lung;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Normal Cell;Organ;PAWR protein;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Primary Neoplasm;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Quinolones;Resectable;Resistance;Role;Structure-Activity Relationship;Surface;Testing;Therapeutic;Tissues;Toxic effect;Tumor Suppressor Proteins;Vimentin;analog;androgen deprivation therapy;bone;cancer cell;cell motility;conventional therapy;extracellular;in vivo;insight;member;men;metastatic process;mouse model;nanomolar;novel;paracrine;prostate cancer cell;prostate cancer metastasis;prostate cancer model;public health relevance;quinoline;receptor;response;screening;small molecule;therapy resistant;tumor;tumor growth;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed studies will examine the role of vimentin in intracellular sequestration of the tumor suppressor Par-4 and the ability of a novel small molecule 3-arylquinoline called Arylquin-1 which targets vimentin in releasing Par-4 from vimentin for secretion and paracrine apoptosis of prostate cancer cells. Moreover owing to its vimentin-targeting ability Arylquin-1 will be also studied for inhibition of prostate cancer cell motility invasion EMT and tumor metastasis that are promoted by vimentin function. Both cell culture and mouse models of prostate cancer will be used to determine the effect of Arylquin-1 on Par-4 secretion apoptosis and inhibition of EMT and metastasis.


application_id: 9716402
project_number: 5R01HL133723-04
project_title: Adventitial-medial interactions in thoracic aortic diseases
administering_ic: NHLBI
award_notice_date: 2019-05-31
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 133723
program_official: MCDONALD, CHERYL
project_start_date: 2016-06-01
project_end_date: 2021-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Thoracic aortic diseases including aneurysm and dissection are an area of major unmet medicalneed due to a paucity of knowledge on the underlying mechanisms. Our long-term interest in thoracicaortic diseases using mouse models has provided compelling evidence that (1) AngII-induced thoracicaortic diseases are characterized by luminal dilation and intralamellar hematoma in the ascending aortawhich are most pronounced in the outer medial layers resembling observations in human ascendingaortic aneurysm and dissection (2) interaction between angiotensin II (AngII) and its receptor subtypeAT1a receptor plays a crucial role in the development of thoracic aortic aneurysm and dissection (3)deletion of AT1a receptors in fibroblasts not in smooth muscle cells (SMCs) is responsible for the AngII-induced thoracic aortic pathologies (4) SMC-specific deficiency of LRP1 (an important protein inmaintaining vascular integrity) augments AngII-induced thoracic aortic diseases. Consistent with ourfindings thoracic aortic pathologies in mice with genetic deletions (without other manipulations) in SMCsincluding LRP-1 TGF-R2 and fibulin-4 have striking similarities to AngII-induced thoracic aorticdiseases. The ascending aorta is a unique aortic region in which SMCs are derived from two distinctembryonic origins the cardiac neural crest (CNC) and second heart field (SHF). On the basis of our owndata and the literature evidence we hypothesize that thoracic aortic aneurysm and dissection resultfrom AngII stimulation of adventitial fibroblasts interacting with subpopulations of medial SMCsthat form an outer sleeve in disease-prone areas. Two aims are proposed to test this hypothesis.Aim 1 will determine whether fibroblast migration or plasticity is actuated by AT1a receptors andcontributes to the pathological processes of thoracic aortic aneurysm and dissection. Aim 2 willdetermine whether SMCs from different embryonic origins have intrinsically different functions thatcontribute to thoracic aortic aneurysm and dissection. Lineage tracking and in vivo manipulations will beused for the experiments proposed in these two aims. Completion of the proposed aims will provideinsights into understanding whether cellular communication between fibroblasts in the adventitia andSMCs in the media of the aorta plays a crucial role in the development of ascending aortic aneurysmsand dissection and whether region specific characterization of thoracic aortic diseases is attributed to thebiparental feature of the SMC origin in the ascending aorta.

project_terms:
Aneurysm;Angiotensin II;Angiotensin II Type 1 Receptor Blockers;Aorta;Aortic Aneurysm;Aortic Diseases;Area;Attenuated;Blood Vessels;Cardiac;Chest;Communication;Complex;Data;Development;Disease;Dissection;Distributional Activity;Drug Targeting;Embryo;Expert Opinion;FBN1;Fibroblasts;Genetic;Guidelines;Heart;Hematoma;Human;Individual;Infusion procedures;Knowledge;Lead;Level of Evidence;Literature;Losartan;LoxP-flanked allele;Medial;Mediating;Medical;Modeling;Mus;Neural Crest;Pathologic;Pathologic Processes;Pathology;Patients;Pericytes;Phenotype;Plant Roots;Play;Process;Proteins;Recommendation;Reporting;Role;Severities;Signal Transduction;Site;Smooth Muscle Myocytes;Testing;Thoracic Aortic Aneurysm;Thoracic aorta;Transforming Growth Factor beta;Tunica Adventitia;ascending aorta;base;bicuspid aortic valve;cell dedifferentiation;clinical investigation;constriction;experimental study;fibulin-4;in vivo;insight;interest;migration;mouse model;mutant;receptor;response;therapy development;transdifferentiation

public_health_relevance:
NarrativeThe thoracic aorta is a common site of aneurysms and dissection that lead todevastating effects for the afflicted individuals. Currently there is no medical therapythat has been validated to provide any benefit. To provide mechanistic insight to assistdevelopment of therapies this project will determine how angiotensin II mediates thecomplex interactions between the outer (adventitia) and middle (media) layer of theaorta to promote these diseases.


application_id: 9715793
project_number: 1R01CA237643-01
project_title: Targeting epigenetic heterogeneity to improve lung cancer immunotherapy response
administering_ic: NCI
award_notice_date: 2019-03-11
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: CA
serial_number: 237643
program_official: SOMMERS, CONNIE L
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Antibodies;CXCL9 gene;Cancer Etiology;Cancer Patient;Cell surface;Cells;Cessation of life;ChIP-seq;Clinical Trials;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Gene Expression;Genes;Genetic Transcription;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunosuppressive Agents;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Malignant neoplasm of lung;Methyltransferase;Molecular;Mus;NGFR Protein;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;PDCD1LG1 gene;Patients;Pharmaceutical Preparations;Phase;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;SLEB2 gene;Sorting - Cell Movement;Squamous Cell;Squamous cell carcinoma;T-Lymphocyte;Testing;Therapeutic;Time;Transplantation;Tumor stage;anti-PD-1;anti-PD-L1;arm;base;cancer immunotherapy;cell type;clinically relevant;combinatorial;effector T cell;improved;inhibitor/antagonist;migration;mouse model;neoplastic cell;neutrophil;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment


application_id: 9714299
project_number: 1R01DC017770-01
project_title: Communities Helping the Hearing of Infants by Reaching Parents: The CHHIRP Navigator Trial
administering_ic: NIDCD
award_notice_date: 2019-04-01
opportunity_number: PA-18-385
application_type: 1
activity_code: R01
ic: DC
serial_number: 017770
program_official: KING, KELLY ANNE
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adherence;Adoption;Advisory Committees;Age-Months;Behavior Disorders;Birth;Caring;Characteristics;Child;Clinic;Collaborations;Communication impairment;Communities;Community Health;Complex;Congenital Disorders;Cost Savings;Cost effectiveness research;Data;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Early Diagnosis;Early Intervention;Education;Effectiveness;Emotional;Employment;Environment;Failure;Family;Feedback;Funding;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Tests;Hybrids;Impairment;Improve Access;Incidence;Individual;Infant;Intervention;Joints;Kentucky;Language Development;Learning;Learning Disorders;Life;Measures;Medical;Methods;Modality;Neonatal;Neonatal Screening;Newborn Infant;Occupational;Outcome;Outpatients;Parents;Patient Care;Patients;Penetration;Preventive service;Process;Public Health;Randomized Controlled Trials;Recording of previous events;Reporting;Research;Research Methodology;Research Personnel;Self Efficacy;Sensory;Sensory Disorders;Social Development;Speech;System;Testing;Third-Party Payer;Time;Training;Translational Research;United States;cancer care;care systems;childhood hearing loss;cognitive development;community clinic;community intervention;community setting;cost;cost effective;cost effectiveness;deafness;design;disparity reduction;early childhood;economic cost;effectiveness research;effectiveness trial;falls;hearing impairment;hearing loss treatment;hearing screening;implementation research;implementation strategy;implementation trial;improved;innovation;intervention program;navigator intervention;peer support;prevent;programs;randomized trial;recruit;research to practice;scale up;screening;social;socioeconomics;standard care;standard of care;trial design


application_id: 9712984
project_number: 5KL2TR001996-04
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2019-07-02
opportunity_number: PAR-15-304
application_type: 5
activity_code: KL2
ic: TR
serial_number: 001996
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS 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:
PROJECT SUMMARYThe University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to establish aCareer Development Core to build upon the current KL2 program which is in its fifth year of NIH support. Thecurrent program provides two to three years of release time (75% effort) and research funding support formentored career development designed to accelerate academic growth of the next generation of clinical andtranslational scholars. This program has garnered strong institutional support with notable scholar productivity;in five years two NIH-supported training slots have been expanded to six slots. All eight program graduateshave each made important contributions to science through research and have successfully competed forextramural funding seven as PIs. The current KL2 cohort consists of six scholars. The scholar programsupports career development across the full spectrum of clinical and translational science includingtranslational clinical community/policy studies and novel methodology development (e.g. biomedicalinformatics) focusing on a broad array of health topics. Scholars and mentors represent a wide range ofcolleges and disciplines including Medicine Nursing Health Sciences Public Health Education Engineeringand Arts & Sciences (Health Psychology). To build on these achievements this new program requests NIHsupport for four KL2 scholars. The training of three additional institutionally sponsored early-career scholarswill be integrated with these NIH-supported scholars to establish a cohort of seven scholars. The foundation ofthe proposed program will continue to be practical research experiences within interdisciplinary teams guidedby experienced mentors. In addition to prepare future leaders of the evolving academic discipline of Clinicaland Translational Research (CTR) new efforts designed to promote program excellence are proposed. Theyinclude: 1) new Faculty Oversight and Workforce Integration Committee structures; 2) use of educationaltechnology to develop vigorous yet efficient new competency programs designed to strengthen thefoundational training for future leaders in CTR; and 3) developing a new institutionally sponsored ClinicalScientist Pipeline Program targeting residents fellows and early career clinical faculty to provide a strongerlinking of our successful undergraduate and early faculty career training programs. These initiatives aredesigned to accelerate the career development of future leaders of the biomedical research workforce who willbe prepared to address today's complex research challenges and spearhead advances in human health.

project_terms:
Academia;Achievement;Address;Aptitude;Arts;Behavioral;Biomedical Research;Centers of Research Excellence;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Competence;Complement;Complex;Dentistry;Development;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Education;Educational Curriculum;Educational Technology;Engineering;Enhancement Technology;Ensure;Environment;Evaluation;Extramural Activities;Faculty;Foundations;Funding;Future;Good Clinical Practice;Growth;Health;Health Occupations;Health Psychology;Health Sciences;Healthcare;Human;Incubated;Industry;Instruction;Kentucky;Leadership;Link;Location;Medicine;Mentors;Methodology;NCI Scholars Program;Nursing Faculty;Outcome;Pharmacy facility;Policies;Population;Process;Productivity;Program Development;Psychology;Public Health;Public Health Education;Research;Research Training;Resource Development;Resources;Role;Scholarship;Science;Scientist;Self Efficacy;Social Work;Structure;Students;Talents;Teacher Professional Development;Time;Training;Training Programs;Training Support;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;base;biomedical informatics;career;career development;clinical development;clinical practice;cohort;college;design;early-career faculty;evidence base;experience;improved;interest;member;next generation;novel;programs;recruit;skills;training opportunity;translational medicine;undergraduate student;workforce needs


application_id: 9712983
project_number: 5TL1TR001997-04
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2019-07-02
opportunity_number: PAR-15-304
application_type: 5
activity_code: TL1
ic: TR
serial_number: 001997
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
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:
PROJECTSUMMARYTheUniversityofKentucky(UK)CenterforClinicalandTranslationalScience(CCTS)TrainingPrograminClinicalandTranslationalScience(UKTL1program)willprepareprofessionalandpredoctoralstudentstoassumeleadershiprolestodirectteamscienceacrosstheclinicalandtranslationalresearch(CTR)spectrum.OverthelastfiveyearstheUKTL1programhasleveragedUKsCTRstrengthstoprovideamultidisciplinaryandtransdirectionaltrainingprogramthatintegratestraineesacrossdiversefieldstoprovidearigorousandsolidresearcheducationinCTR.Withthisapproachwehaveachievedourgoalofincreasingthenumberofinvestigatorswhobridgethegapbetweenbasicscienceadvancesandtheirapplicationtoclinicalmedicine.Thishasbeenaccomplishedbyprovidingahighlycollaborativetrainingenvironmentthatincubatesscholarsandmentorswithaninnovativeandnurturingstructuretodevelopresearchcompetenciesinateam-basedenvironment.ThesuccessoftraineesinthefirstfundingcycleandthedevelopmentofaninnovativetrainingprocesstoengageevengreaternumbersofstudentsinCTRarethefoundationforthefollowingSpecificAims:1)toincreasethepipelineofinvestigatorsengagedinCTR;2)totrainacrossthespectrumofCTR;and3)topreparescholarstoparticipateeffectivelyinteamscience.TomeetouraimsweproposetoincreasethenumberofpredoctoralTL1studentssupportedeachyearandtoincludeanew12-monthintensiveCTRexperiencetomeetanidentifiedneedamongprofessionalstudentsandmedicalprofessionalsinresidency.WewillcontinuetosolicitapplicationsbroadlyacrosscampusoffernewexperientialtrainingincommunityresearchinruralpopulationsinCentralAppalachiaanddevelopdoctoral-leveltraininginbiomedicalinformaticstakingadvantageoftherecentinfluxofleadershipandexpertiseinthisareaatUK.Finallywewillprovidetraineeswiththelatestskillsetstoparticipateeffectivelyininterdisciplinaryandcollaborativeteamscience.Theseinitiativeswillacceleratethecareerdevelopmentoffutureleadersofthebiomedicalresearchworkforcewhocanaddresstodayscomplexresearchchallengesandspearheadadvancesinhumanhealth.

project_terms:
Address;Appalachian Region;Area;Basic Science;Biomedical Research;Certification;Clinical Medicine;Clinical Research;Clinical Sciences;Collaborations;Communication;Communities;Competence;Complex;Dentistry;Development;Development Plans;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Educational Status;Engineering;Environment;Ethics;Feedback;Fellowship;Foundations;Funding;Future;Goals;Grant;Growth;Health;Health Sciences;Healthcare;Human;Incubated;Individual;Infrastructure;Interdisciplinary Study;Kentucky;Leadership;Learning;Manuscripts;Measures;Medical;Medicine;Mentors;Monitor;National Research Service Awards;Oral;Outcome;Pathway Analysis;Pharmacy facility;Population;Positioning Attribute;Preparation;Process;Productivity;Psychology;Public Health;Publications;Research;Research Personnel;Research Training;Residencies;Role;Rural Population;Science;Social Work;Solid;Structure;Students;TNFSF15 gene;Talents;Time Management;Training;Training Programs;Translational Research;Universities;Writing;antiretroviral therapy;base;biomedical informatics;career;career development;cohort;college;education research;experience;graduate student;innovation;instructor;multidisciplinary;patient oriented;posters;pre-doctoral;professor;programs;skills;success;training opportunity


application_id: 9712936
project_number: 5R01EY028188-03
project_title: Understanding signal processing in retinal bipolar cell pathways
administering_ic: NEI
award_notice_date: 2019-06-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 028188
program_official: GREENWELL, THOMAS
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 11294714
contact_pi: BORGHUIS, BART GERARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have developed a powerful mouse model to study information processing in parallel retinal bipolar cellpathways. Bipolar cells are essential for transmitting the photoreceptor output to the ganglion cells whichsignal visual information to a range of target areas in the brain. Bipolar cells divide into about a dozen typesand constitute the first level of information processing in the visual system. While several aspects of bipolarcell function have been addressed in retinal slice preparations of a variety of species information aboutthree fundamental aspects of bipolar cell signaling is still lacking. First is a concise quantitative descriptionof the spatio-temporal receptive field for any genetically identified bipolar cell type. Second is acomprehensive account of the neural mechanisms that govern the input-output transfer function of each BCtype based on light-evoked responses with intact circuitry (whole-mount retina preparation). Third is theimpact of light-adaptive mechanisms on bipolar cell visual function.We will leverage our recently developed live-cell imaging and whole-cell recording methods toaddress these issues. Specifically we will make targeted electrophysiological recordings in the whole-mount retina of transgenic mice with genetically identified bipolar cells; we will use two-photon fluorescenceimaging with genetically encoded fluorescent biosensors for calcium and glutamate in transgenic mice withloss-of function mutations in the OFF bipolar pathways; and we will use advanced visual stimulationmethods to elucidate mechanisms of light-adaptation at the bipolar cell level. These studies will providevaluable information about how bipolar cells encode visual information and how visual sensitivity ismaintained under varying stimulus conditions. Understanding information processing in identified retinalsignaling pathways is critical for the study and potential treatment of developmental and neurologicaldisorders and retinal disease.

project_terms:
Address;Aging;Amacrine Cells;Area;Axon;Biosensor;Brain;Calcium;Cell physiology;Cells;Electrophysiology (science);Equilibrium;Feedback;Glutamate Receptor;Glutamates;Glycine;Goals;Image;Individual;Kainic Acid Receptors;Kinetics;Knowledge;Light;Light Adaptations;Lighting;Maps;Measures;Methods;Molecular;Natural regeneration;Neurons;Optic Nerve;Output;Pathway interactions;Photic Stimulation;Photoreceptors;Preparation;Process;Property;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Route;Series;Shapes;Signal Pathway;Signal Transduction;Slice;Stimulus;Stratification;Structure;Synapses;Testing;Transgenic Mice;Vision;Visual;Visual system structure;Whole-Cell Recordings;base;cell type;developmental disease;experimental study;extrastriate visual cortex;fluorescence imaging;gamma-Aminobutyric Acid;ganglion cell;information processing;innovation;live cell imaging;loss of function mutation;luminance;mouse model;nervous system disorder;neural circuit;neuromechanism;parallel processing;postsynaptic;preservation;prevent;receptive field;receptor;response;retinal rods;signal processing;spatiotemporal;transmission process;two-photon;visual information;visual processing;voltage;voltage gated channel

public_health_relevance:
Vision critically depends on the transmission of visual information from the photoreceptors in the retina tocentral visual areas in the brain. Space limitations within the optic nerve in particular prevent individualphotoreceptor cells to contact central areas in the brain directly. Instead the photoreceptor output isintegrated and processed by neural circuits within the retina to generate a more compact representation ofthe visual image for transmission to the brain. The goal of this proposal is to further our understanding of acritical information-processing step within the retina that is performed by the retinal bipolar cells. In a seriesof innovative experiments we will measure and compare information processing properties across bipolar cells types identify the neural mechanisms that give rise to their unique visual encoding and study howstimulus conditions impact bipolar cell function. Understanding information processing in retinal bipolar cells is an essential prerequisite for understanding the neural circuit functions that need to be reestablishedthrough regenerating and restoring neuronal connections during retinal disease and aging an `audacious goal' established by the NEI.


application_id: 9710719
project_number: 5R01NS108529-02
project_title: The integrated stress response and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2019-03-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 108529
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2018-06-15
project_end_date: 2023-03-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
congressional_district: 03
department: NEUROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Address;Affinity Chromatography;Amino Acids;Anabolism;Attenuated;Biological Assay;Brain Injuries;Cell Death;Cessation of life;Chronic;Data;Disease;Double-Stranded RNA;Enzymes;Experimental Designs;Functional disorder;Gene Expression;Genes;Glucose;Grant;Homeostasis;Hypoxia;Hypoxia Inducible Factor;Impairment;In Vitro;Inflammation;Intracranial Hemorrhages;Iron;Mediating;Mediator of activation protein;Metabolism;Mitochondria;Mus;Nutrient;Oligodendroglia;Outcome;Oxidative Stress;PERK kinase;Pathogenesis;Pathway interactions;Peptide Initiation Factors;Pharmacological Treatment;Pharmacology;Phosphotransferases;Play;Procollagen-Proline Dioxygenase;Proteasome Inhibition;Protein Synthesis Inhibition;Recovery;Recovery of Function;Response to stimulus physiology;Ribosomes;Role;Signal Pathway;Signal Transduction;Spinal Cord Contusions;Spinal cord injury;Spinal cord injury patients;Starvation;Stress;Stroke;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissue Sample;Tissues;Transcriptional Activation;Translating;Translational Regulation;Translations;Traumatic CNS injury;Up-Regulation;Work;base;biological adaptation to stress;central nervous system injury;cytotoxic;deprivation;endoplasmic reticulum stress;functional decline;functional outcomes;genetic approach;improved;in vivo;inhibitor/antagonist;loss of function;new therapeutic target;novel;novel therapeutics;response;stressor;targeted treatment;transcription factor;transcription factor CHOP;transcriptome sequencing;white matter;white matter damage


application_id: 9710630
project_number: 5R01DC016957-02
project_title: Behavioral Parent Training for Families with Deaf and Hard of Hearing Preschoolers
administering_ic: NIDCD
award_notice_date: 2019-05-31
opportunity_number: PA-17-118
application_type: 5
activity_code: R01
ic: DC
serial_number: 016957
program_official: KING, KELLY ANNE
project_start_date: 2018-06-06
project_end_date: 2019-12-31
study_section: Psychosocial Development, Risk and Prevention Study Section[PDRP]
contact_pi_person_id: 8804342
contact_pi: STUDTS, CHRISTINA RUTH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe prevalence of disruptive behavior problems among deaf or hard of hearing (DHH) children is double that ofnormal hearing children but this underserved population rarely receives behavioral interventions. Behavioralproblems in DHH children often are attributed to delays in language development yet even when languageoutcomes improve in response to early intervention behavioral problems frequently persist. Although parentingbehaviors have been largely overlooked in the literature investigating the etiology and maintenance of disrup-tive behavior problems in young DHH children their effects on child behavior are well-established in the normalhearing population. Behavioral parent training (BPT) programs have consistently demonstrated efficacy andeffectiveness in reducing disruptive behavior problems comorbidities parental stress and depression andlong-term costly consequences in children with normal hearing especially when delivered in early childhood.The hearing healthcare setting is ideal as a delivery venue for behavioral services because of consistent con-tacts from infancy through adolescence; parents trust and familiarity with the setting and providers; and lack ofstigma. This type 1 hybrid effectiveness-implementation trial will be conducted in 10 state-funded hearinghealthcare clinics testing an evidence-based BPT adapted to meet the needs of parents of underserved DHHchildren. The specific aims are: (1) To systematically adapt an evidence-based BPT by incorporating the pref-erences and perspectives of the target population and key stakeholders; (2) using a cluster-randomized trialdesign to test the effects of the adapted BPT on parent behaviors child behaviors adherence to wearinghearing rehabilitation devices and language development outcomes; and (3) based on the ConsolidatedFramework of Implementation Research to identify factors within the domains of the inner setting outer set-ting intervention characteristics process and provider characteristics influencing implementation of the inter-vention in each clinic as well as implementation outcomes (i.e. acceptability adoption recruitment/retentionfidelity and costs). The ADAPT-ITT framework will guide the systematic adaptation process. Examples of pos-sible adaptations include modifications to content (e.g. incorporation of scenarios relevant to DHH children inmaterials and activities inclusion of facilitative language techniques in skills training) and context (e.g. deliveryin hearing healthcare settings incorporation of language and hearing data in behavioral assessments). If theadapted BPT is effective behavioral problems among DHH children could be successfully addressed in hear-ing healthcare. The use of a type I hybrid design will allow us to simultaneously test effectiveness and gatherinformation on multilevel factors influencing the quality of implementation. Results of this study will inform hear-ing healthcare systems regarding resources and strategies needed to deliver this intervention in new settingsto a new population. This project could inform a transformation of care in hearing healthcare settings to scaleup the integration of much-needed behavioral services into their already-interdisciplinary clinics.

project_terms:
Address;Adherence;Adolescence;Adoption;Adult;Behavior;Behavior Therapy;Behavior assessment;Behavioral;Caring;Characteristics;Child;Child Behavior;Child Rearing;Clinic;Cluster randomized trial;Communities;Comorbidity;Criminal Justice;Data;Device or Instrument Development;Early Intervention;Educational Intervention;Effectiveness;Environment;Etiology;Failure;Familiarity;Family;Funding;Healthcare;Healthcare Systems;Hearing;Hybrids;Intervention;Intervention Studies;Language;Language Development;Literature;Maintenance;Mental Depression;Methods;Modification;Outcome;Parents;Phase;Population;Prevalence;Problem behavior;Process;Provider;Rehabilitation device;Research Personnel;Resources;Schools;Services;Stress;Substance abuse problem;Target Populations;Techniques;Testing;Time;Training;Training Programs;Translating;Translational Research;Translations;Trust;Underserved Population;base;behavioral adherence;checkup examination;cost;cost outcomes;deaf;design;early childhood;effectiveness trial;evidence base;experience;hard of hearing;health care settings;health related quality of life;implementation research;implementation trial;improved;improved outcome;infancy;innovation;language outcome;normal hearing;pilot trial;preference;prevent;primary outcome;recruit;research to practice;response;scale up;skills training;social stigma;treatment as usual;trial design

public_health_relevance:
PROJECT NARRATIVEDespite being more likely than normal hearing children to experience disruptive behavior problems childrenwho are deaf and hard of hearing (DHH) rarely receive behavioral interventions to prevent the long-term costlyoutcomes of behavior problems. This project will systematically adapt an evidence-based parent trainingintervention to increase its acceptability and relevance for parents of young DHH children. Effectiveness of theadapted intervention and its implementation in real world hearing healthcare clinics will be assessed.


application_id: 9709969
project_number: 3UG3DA044798-02S1
project_title: Kentucky Communities & Researchers Engaging to Halt the Opioid Epidemic-CARE2HOPE
administering_ic: NIDA
award_notice_date: 2018-09-14
opportunity_number: PA-18-591
application_type: 3
activity_code: UG3
ic: DA
serial_number: 044798
suffix: S1
program_official: CRUMP, ARIA
project_start_date: 2017-08-15
project_end_date: 2019-07-31
study_section: ZDA1(18)-R
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: COOPER, HANNAH LF
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
project_abstract:
Epicenters of opioid misuse and related harms (e.g. HCV overdose HIV) are expanding from cities to ruralareas in the US. These seismic epidemiologic shifts are crises that rural public health systems have yet tomeet and a wide implementation chasm exists for drug-related health services in rural areas. Kentucky  apredominately rural state at the forefront of these drug-related epidemics  is starting to close this chasm bymounting an unprecedented expansion of syringe service programs (SSPs). Between 2015 and 2018 thenumber of legal SSPs operating in Kentucky surged from 0 to 40. This Kentucky expansion is part of a broadertrend in the Appalachian region and other rural areas. This expansion represents a scale out that takes SSPsto implementation contexts that differ qualitatively from their urban origins. Rural areas may present aconstellation of barriers and facilitators to SSP adoption fidelity and sustainment that differ from those incities. Cost for example may be a more significant barrier to adoption fidelity and sustainment in rural areaswhere budgets are far more constrained. SSP staff may generate novel ways to implement core componentsthat suit rural contexts and SSP impact on risk behaviors and service use among clients may also be differentin rural areas (e.g. transportation barriers and the paucity of local services may limit successful linkage toother services). Notably little research has explored these possibilities: a recent Medline search using variantsof the terms SSP rural and implementation science identified no articles. The proposed study is a firststep toward establishing the next generation of implementation science to enhance the effectiveness of thisnew wave of rural SSPs. Guided by the Consolidated Framework for Implementation Research we will use aqualitative multiple case study design to study SSPs that recently opened in 7 rural Kentucky counties to (1)Identify perceived barriers and facilitators in the rural implementation context to adopting and sustaining SSPsand explore strategies to overcome barriers to adoption and sustainment. (2) Analyze the extent to whichSSPs are faithful to established core components; identify emerging novel approaches to implementing corecomponents that these SSPs may have innovated; and examine the processes through which select salientfeatures of the implementation context may have influenced this fidelity and innovation. (3) Explore PWIDperceptions of whether and how SSP core components influence HIV HCV and overdose risk behaviors anddrug-related health service use among SSP clients and other local PWID. This is a supplement toCARE2HOPE (DA044798). Led by Drs. Young and Cooper CARE2HOPE is designed to build evidence-based interventions (EBIs) for epidemics of opioid misuse and related harms in 12 rural Kentucky counties atan epicenter of these intertwined national crises. Several CARE2HOPE counties are considering enhancingSSPs as part of their EBI. This supplement will help identify barriers to SSP fidelity or sustainment that theycould address. It will also generate hypotheses for a new line of high-impact rural SSP implementation science.

project_terms:
Address;Adopted;Adoption;Appalachian Region;Back;Budgets;Case Study;Centers for Disease Control and Prevention (U.S.);Cities;Client;Communities;County;Disease Outbreaks;Effectiveness;Epidemic;Epidemiology;Evidence based intervention;Face;Future;HIV;HIV/HCV;Harm Reduction;Health Promotion;Health Services;Health system;Hepatitis C virus;Heroin;Incidence;Indiana;Injecting drug user;Kentucky;Knowledge;Legal;Medical;Movement;Needle-Exchange Programs;Needles;New York;Newly Diagnosed;North Carolina;Overdose;Perception;Pharmaceutical Preparations;Population;Process;Program Sustainability;Public Health;Recording of previous events;Research;Research Design;Research Personnel;Risk;Risk Behaviors;Rural;Science;Services;Sterility;Syringes;System;Testing;Transportation;Travel;Variant;Water;West Virginia;base;cost;design;health service use;heroin use;implementation research;implementation science;innovation;meetings;mortality;next generation;novel;novel strategies;opioid epidemic;opioid misuse;opioid mortality;opioid use;overdose risk;prescription opioid misuse;programs;rural area;rural counties;trend;young adult

public_health_relevance:
Epicenters of opioid misuse and related harms (e.g. HCV overdose HIV) are expanding fromcities to rural areas in the US. These seismic epidemiologic shifts are crises that rural publichealth systems have yet to meet and a wide implementation chasm exists for drug-relatedhealth services in rural areas. Kentucky  a predominately rural state at the forefront of thesedrug-related epidemics  is starting to close this chasm by mounting an unprecedentedexpansion of syringe service programs (SSPs). The proposed study is a first step towardestablishing the next generation of implementation science to enhance the effectiveness of thisnew wave of rural SSPs.


application_id: 9709207
project_number: 5R01AI090048-08
project_title: Novel aminoglycoside adjuvants and stand-alone agents to combat tuberculosis
administering_ic: NIAID
award_notice_date: 2019-06-05
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AI
serial_number: 090048
program_official: XU, ZUOYU
project_start_date: 2011-08-01
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)M]
contact_pi_person_id: 8970083
contact_pi: GARNEAU-TSODIKOVA, SYLVIE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTTuberculosis (TB) is the deadliest global infection (1.4 million deaths in 2015) having recently surpassedHIV/AIDS. ~250000 of these deaths were from multidrug-resistant (MDR) TB with only ~50% success intreatment of MDR-TB. Unless new strategies to combat or prevent emergence of drug-resistant TB arefound the global spread of MDR-TB will be an epidemic of epic proportions. Kanamycin A (KAN) is anantibiotic of last resort used to treat MDR-TB. Resistance to KAN signifies extensively drug-resistant(XDR) TB which is nearly incurable. One-third of KAN-resistant TB is caused by upregulation of theacetyltransferase Eis in Mycobacterium tuberculosis (Mtb) caused by mutations in the eis promoter. Weinvestigated the mechanism of Eis and discovered and validated several Eis inhibitor scaffolds in theprevious funding period. In Aims 1 and 2 of this application we propose to develop a novel strategy tocombat and forestall KAN resistance in TB. These Aims are focused on the preclinical development ofthese Eis inhibitors for their ultimate use as a combination therapy with KAN against MDR-TB. In Aim 3we propose to determine the mechanism(s) of the anti-Mtb activity of novel compounds that werediscovered to inhibit Eis and potently inhibit Mtb bacteria without KAN ultimately to develop them astherapeutics against both drug-resistant and drug-resistant TB.

project_terms:
AIDS/HIV problem;Acetyltransferase;Adjuvant;Adjuvant Therapy;Aminoglycosides;Anti-Bacterial Agents;Antibiotics;Antitubercular Agents;Area;Bacteria;Biochemical;Biological;Biological Assay;Cells;Cessation of life;Chemicals;Combined Modality Therapy;Complex;Consultations;Coupled;Crystallization;Development;Drug resistance;Drug resistance in tuberculosis;Drug-sensitive;Epidemic;Evaluation;Exhibits;Extreme drug resistant tuberculosis;Funding;Future;Genotype;Genus Mycobacterium;Human;In Vitro;Infection;Kanamycin;Kanamycin A;Knock-out;Laboratories;Lead;Measurement;Mediating;Modeling;Multidrug-Resistant Tuberculosis;Mutation;Mycobacterium tuberculosis;Mycobacterium tuberculosis H37Rv;Pathogenicity;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Property;Reporting;Resistance;Resort;Safety;Solubility;Structure;Testing;Therapeutic;Toxic effect;Tuberculosis;Up-Regulation;analog;clinical development;combat;cytotoxicity;design;experience;extensive drug resistance;genome sequencing;inhibitor/antagonist;innovation;interest;macrophage;mouse model;mutant;novel;novel strategies;pre-clinical;preclinical development;preclinical study;prevent;promoter;research clinical testing;resistance mechanism;scaffold;structural biology;success;synergism

public_health_relevance:
NARRATIVETuberculosis (TB) kills 1.4 million annually worldwide and is currently the deadliest infection with~250000 of these deaths resulting from multidrug-resistant (MDR) TB for which the treatment successrate is only 50%. This project is focused on developing innovative kanamycin adjuvants (Eis inhibitors)for their use with kanamycin to forestall and combat MDR-TB. Additionally the project is focused onelucidating the mechanism and development of other novel anti-TB agents to kill the pathogenicmycobacteria without the need of using KAN ultimately to develop these agents as therapeutics againstboth drug-resistant and drug-resistant TB in the US and worldwide.


application_id: 9708339
project_number: 1S10OD025178-01A1
project_title: Imaging and Physiology Core: High Frequency High Resolution Ultrasound Imaging System
administering_ic: OD
award_notice_date: 2019-05-23
opportunity_number: PAR-18-600
application_type: 1
activity_code: S10
ic: OD
serial_number: 025178
suffix: A1
program_official: WANG, GUANGHU
project_start_date: 2019-06-01
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1 SBIB-Y (30)]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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:
Project Abstract: This Shared Instrumentation Grant details the critical need of this User base for theVisualSonics Vevo 3100 Imaging System. This instrument will be installed in the stable and existing Imagingand Physiology Core. The Users come from various departments and have significant funding from multiplecomponents of the NIH. This instrument effectively replaces two existing Vevo 770 units which have reachedthe end of their usable lives. The Vevo 3100 is the current platform for small animal (primarily mouse)sonographic imaging and is designed to precisely discriminate subtle differences in tissue structure andmotion. Given that many of the Users are interested in heart failure and diabetes the Vevo 3100 can offeraccess to early stage changes in diastolic function. Many of these same features (i.e. detailed 3/4D imaging)are also essential to expand the User base to include our NIH-funded cancer investigators. Furthermorebecause the Vevo 3100 is the platform of the future additional features will be activated soon (but not on the2100). It is important to note that this system is replacing two aging Vevo 770s. Unfortunately the Vevo 770has been discontinued and all repair support for it will end in December 2018 (i.e. before the planned startdate of this S10). This Core has extensive ultrasound experience leadership and financial support to maintainits instrumentation. Thus the Vevo 3100 will be incorporated into a stable efficient and productive core facilitysupported by a dedicated institutionally supported staff member. Furthermore the choice of this ultrasoundplatform over CT or MRI is justified because: the operating costs of CT/MRI are much higher; they are lessflexible (e.g. real-time percutaneous injection is not possible); they require a much larger footprint (and costlyremodeling of research space); they require additionally trained support staff; they are not amenable toteaching to trainees for use on their own; they are not portable; 4D ultrasound imaging is approaching MRI inquality; and finally CT/MRI are much slower. Thus replacement of the current Vevo 770 units with the Vevo3100 is the most logical and cost-effective option. Unfortunately there are no comparable ultrasound imagingplatforms available to the Users who have large NIH-funded portfolios of grants. Thus the integration of theVevo 3100 into the Imaging and Physiology Core will ensure that the multi-million-dollar research portfolio ofthe Users is served appropriately for the Users ongoing needs; current technological gaps are eliminated; andfuture needs will be met. As detailed in the proposal the Vevo 3100 will be operated by seasoned andexperienced institute-supported sonographer and will be covered by an institute-provided service contract forat least five years. The Core already has sufficient administrative support to handle electronic billing of Usersand has a documentable and growing flow of income (i.e. charges to Users). The Core is led by a highlyexperienced cardiac physiologist who is committed to helping other investigators meet their experimental goalsand grow their research programs to make meaningful impacts on human disease.

project_terms:
4D Imaging;Aging;Animals;Cardiac;Charge;Contract Services;Core Facility;Diabetes Mellitus;Educational process of instructing;Ensure;Financial Support;Frequencies;Funding;Future;Goals;Grant;Heart failure;Image;Income;Injections;Institutes;Leadership;Magnetic Resonance Imaging;Malignant Neoplasms;Motion;Mus;Physiology;Research;Research Personnel;Resolution;Seasons;Structure;System;Time;Tissues;Training Support;Ultrasonography;United States National Institutes of Health;base;cost;cost effective;design;experience;flexibility;human disease;imaging platform;imaging system;instrument;instrumentation;interest;member;programs;repaired

public_health_relevance:
Project Narrative: The investigators represented in this proposal are engaged in understanding the molecularregulation of cardiovascular disease diabetes and cancer. To maintain and grow their clinically translatablework these investigators need to replace and upgrade their current ultrasound imaging systems which havereached the end of their usable lives.


application_id: 9707999
project_number: 1RF1AG062480-01
administering_ic: NIA
award_notice_date: 2019-04-17
opportunity_number: PA-18-484
application_type: 1
activity_code: RF1
ic: AG
serial_number: 062480
program_official: ARUNKUMAR, NANDINI
project_start_date: 2019-05-01
project_end_date: 2021-08-01
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
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: 2019-05-01
project_title:
Prebiotics Intervention to Reduce Alzheimer's Disease Risk via Brain-Gut Axis in an APOE4 Mouse Model

project_abstract:
Project SummaryApolipoprotein 4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD). It has beenshown that cognitively normal APOE4 carriers develop vascular and metabolic deficits decades before theaggregation of beta-amyloid (A) and neurofibrillary tau tangles. Emerging evidence shows that the gutmicrobiota plays a critical role in determining brain metabolic and vascular integrity and changes in gutmicrobiome balance have the potential to contribute greatly to AD pathogenesis. The rationale of the study isto determine if dietary interventions can be used to modify gut microbial composition and activity which willconsequently protect brain vascular and metabolic functions and reduce neuroinflammation and AD-likepathology. We will use a dietary supplement containing prebiotic: Inulin a non-digestible carbohydrate fiberfermented in the gastrointestinal tract to increase beneficial microbiota and feed the mice that thatoverexpresses human A via 5 familial-AD mutations and expresses human APOE4 (E4FAD). The centralhypothesis is that Inulin is protective of brain functions via the modulation of gut microbiome. We to test thehypothesis by pursuing the following three Specific Aims: 1) Identify Inulin's effects on gut microbiome andassociated metabolism using multi-omics; 2) Assess inulin's effects on brain vascular and metabolic functionsthrough neuroimaging; 3) Determine Inulin's effects on neuroinflammation using molecular assays. The projectis innovative because it employs novel and multidisciplinary methods to focus on early interventions that maybecome an effective way to prevent AD-induced dementia for APOE4 carriers via brain-gut axis. The project isalso innovative because it challenges the current paradigm as it pertains to AD treatment. Instead of removingA or tau after they appear or after the onset of cognitive decline we shift the focus to early interventions thatmay become an effective way to reduce risk for AD-induced dementia especially through gut microbiomemodulation. The project will have tremendous positive impact as they will enhance our understanding of brain-gut interactions in the context of APOE genotypes. In addition microbiome analysis and neuroimaging areavailable for humans and Inulin-related diets are commercially available; therefore our approach has hightranslational value. Outcomes from the study will provide valuable information for future clinical trials withprebiotic diet to reduce AD risk for cognitively normal APOE4 carriers.

project_terms:
Abeta clearance;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Amyloid;Amyloid Proteins;Amyloid beta-Protein;Anxiety;Apolipoproteins;Biological Assay;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Butyrates;Carbohydrates;Cell Respiration;Cerebrovascular Circulation;Clinical Trials;Cognitive;Dementia;Deposition;Development;Diet;Dietary Intervention;Diffusion;Early Intervention;Equilibrium;Escherichia coli;Extravasation;Fiber;Functional disorder;Future;Gastrointestinal tract structure;Gene Expression;Gene Expression Profile;Genes;Genotype;Germ-Free;Glucose;Goals;Hippocampus (Brain);Human;Impaired cognition;Impairment;Inflammation;Intervention;Inulin;Lipopolysaccharides;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measurable;Measures;Metabolic;Metabolism;Methods;Microglia;Modification;Molecular;Mus;Mutation;Natural Immunity;Outcome Study;Pathogenesis;Pathology;Pathway interactions;Patients;Permeability;Pilot Projects;Play;Production;Public Health;Research;Role;Salmonella enterica;Shotguns;Spectrum Analysis;Structure;Taxonomy;Testing;Volatile Fatty Acids;abeta accumulation;adaptive immunity;dietary supplements;familial Alzheimer disease;feeding;gastrointestinal;genetic risk factor;gut microbiome;gut microbiota;gut-brain axis;host-microbe interactions;innovation;metabolomics;metagenomic sequencing;microbial;microbial community;microbiome analysis;microbiota;microorganism;mouse model;multidisciplinary;multiple omics;neuroimaging;neuroinflammation;neuropathology;neurovascular;novel;outcome prediction;overexpression;prebiotics;preservation;prevent;scyllo-inositol;tau Proteins;tau aggregation;transcriptomics

public_health_relevance:
NarrativeThe proposed research is relevant to public health because we will use multi-omics approaches neuroimagingand molecular assays to assess efficacy of prebiotic inulin diet for protecting brain vascular and metabolicfunctions via gut microbiome modification in mice that carry APOE4 genes the strongest genetic risk factor forAlzheimer's disease (AD). Because multi-omics and neuroimaging methods are readily to be used in humansand inulin diet is commercially available the findings from the study will provide valuable information and maypave a way for future dietary clinical trials to reduce AD risk for pre-symptomatic APOE4 carriers.


application_id: 9707682
project_number: 5R00AA023560-04
project_title: Analysis of an ethanol-sensitive pathway regulating anterior craniofacial development
administering_ic: NIAAA
award_notice_date: 2019-05-31
opportunity_number: PA-14-042
application_type: 5
activity_code: R00
ic: AA
serial_number: 023560
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-06-01
project_end_date: 2021-05-31
study_section: NSS
contact_pi_person_id: 10890031
contact_pi: LOVELY, CHARLES BENJAMIN
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of ethanol-induced developmental defects including craniofacial dysmorphology such as lower jaw hypoplasia and cleft palate. It affects approximately 1 in 100 children born in the United States each year. Although fetal exposure to alcohol causes FASD virtually nothing of the genetics behind these ethanol-induced craniofacial defects is understood. The majority of the craniofacial skeleton is generated by cranial neural crest cells in part through complex interactions with epithelial tissues. These interactions are orchestrated by among others the Bone Morphogenetic Protein (Bmp) signaling pathway. My preliminary data demonstrates that Bmp signaling specific to the endoderm is required for lower jaw morphogenesis while Bmp signaling regulates palate morphogenesis in part through the transcription factor gata3. These results suggest a model where Bmp signaling regulates anterior craniofacial morphogenesis via multiple signaling pathways. Growing evidence supports that genetic predisposition plays a role in these ethanol-induced defects yet little is understood about these gene-ethanol interactions. The Eberhart lab has helped pioneer genetic screens to identify these ethanol-sensitive genetic loci. From these screens I have compiled a set of mutants with ethanol induced defects suggesting that ethanol interacts with a genetic hierarchy regulating anterior craniofacial development. First through a screen of available zebrafish mutants I found that several members of the Bmp signaling pathway exhibit ethanol-induced defects to the embryonic lower jaw and palate. Second in a forward genetic screen I recovered ethanol-sensitive mutants that phenocopy specific aspects of the Bmp phenotype. These findings support the hypothesis that Bmp signaling regulates a novel ethanol-sensitive pathway regulating morphogenesis of the anterior craniofacial skeleton. In Specific Aim 1 I will 1) determine how ethanol disrupts a Bmp mediated endoderm-oral ectoderm- neural crest pathway using 4D confocal analyses and 2) elucidate the target of ethanol action the Bmp pathway. In Specific Aim 2 I will 1) clone and characterize the ethanol sensitivity of au15 au24 and au25 2) analyze neural crest cell behaviors in ethanol-treated au15 mutants and 3) characterize the mechanism of ethanol action in au15 mutant embryos. In Specific Aim 3 I will a) clone and characterize au26 b) visualize palate morphogenesis in ethanol-treated Bmp mutants and au26 embryos and c) characterize the epistatic relationship between Bmp-pathway members au26 and gata3. Overall the work outlined in this proposal will provide insight into ethanol-sensitive pathways regulating anterior craniofacial development and the gene- ethanol interactions that underlie these pathways. Because of the conservation of gene function between zebrafish and humans this work will directly translate to studies of candidate genes in human populations and allow for better diagnosis and treatment of FASD.

project_terms:
Affect;Anterior;Bone Morphogenetic Proteins;Candidate Disease Gene;Cephalic;Child;Cleft Palate;Complex;Craniofacial Abnormalities;Data;Defect;Development;Diagnosis;Disease;Dysmorphology;Embryo;Endoderm;Epithelial;Ethanol;Etiology;Event;Exhibits;Fetal Alcohol Spectrum Disorder;GATA3 gene;Genes;Genetic;Genetic Epistasis;Genetic Predisposition to Disease;Genetic Screening;Human;Jaw;Maps;Mediating;Modeling;Morphogenesis;Neural Crest;Neural Crest Cell;Palate;Pathway interactions;Patients;Pattern;Phenocopy;Phenotype;Play;Population;Role;Signal Pathway;Signal Transduction;Signaling Protein;Skeleton;Testing;Tissues;Translating;United States;Ursidae Family;Vertebrates;Work;Zebrafish;alcohol exposure;alcohol sensitivity;cell behavior;craniofacial;craniofacial development;gene conservation;gene function;insight;member;mutant;novel;oral ectoderm;prenatal exposure;public health relevance;transcription factor;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The purpose of this proposal is to elucidate the genetics and mechanisms underlying the variability of defects found in patients with Fetal Alcohol Spectrum Disorders (FASD). Results obtained from this proposal will greatly increase our understanding of gene-ethanol interactions and the etiology of FASD.


application_id: 9707486
project_number: 3R01GM121660-02S1
project_title: Nucleophilic Halogenation Reagents
administering_ic: NIGMS
award_notice_date: 2018-09-14
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: GM
serial_number: 121660
suffix: S1
program_official: LEES, ROBERT G
project_start_date: 2016-12-06
project_end_date: 2021-11-30
contact_pi_person_id: 1979376
contact_pi: HAMMOND, GERALD B
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
A 1260 II UHPLC with 8-column switching valve a quaternary pump autosampler high sensitivity diode array (DAD) and 8 column switching valve is requested to replace an 18-year old Waters HPLC which cannot keep up with our current demands in the research area of halogenation reagents and conditions that include exploring stereoselective halogenation approaches and F18. The quote from the manufacturer is $ 59703.38

project_terms:
18 year old;Area;Award;Catalysis;Cells;Chemistry;Ensure;High Pressure Liquid Chromatography;Journals;Legal patent;Letters;Manufacturer Name;Paper;Physiologic pulse;Protocols documentation;Publications;Publishing;Pump;Reagent;Reporting;Research;Resolution;Sampling;Solvents;System;Technology;United States National Institutes of Health;Water;detector;flexibility;halogenation;interest;pressure;symposium

public_health_relevance:
In the first year of the NIH award my group produced six papers and a five conference presentations. described in our first year report last October. Since then we have published--in only 7 months--a total of six new papers in top-rated journals including one JACS one Angewandte one ACS Catalysis and one Organic Letters (all listed below). We have also submitted a patent application for a technology described in our JACS paper (publication #6). The fast-paced chemistry that we are engaged on has overrun the limits of our current HPLC Waters unit which was bought in 2004 (18 years ago). Especially now that we are interested in exploring the enantioselective applications of our halogenation protocols we want to purchase an Agilent HPLC system. It is a 1260 II UHPLC with 8-column switching valve a quaternary pump autosampler high sensitivity diode array (DAD) and 8 column switching valve. This unit delivers pressures up to 600 bar. Its pulse-free stable and well- mixed gradients ensure higher sensitivity and more reliable results . The unit has access to up to four solvents giving great flexibility in automated solvent blending for a wide range of research applications. The InfinityLab Poroshell 120 columns provide fast rugged high-resolution separations. High-sensitivity flow cells for the diode array detector will allow us to detect the weakest sample concentrations.


application_id: 9706954
project_number: 5R01NS095229-04
project_title: CNS Functions of Calpain 5
administering_ic: NINDS
award_notice_date: 2019-06-06
opportunity_number: PAS-15-029
application_type: 5
activity_code: R01
ic: NS
serial_number: 095229
program_official: RIDDLE, ROBERT D
project_start_date: 2016-09-01
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(02)S]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:Calpains are Ca2+-activated neutral (non-lysosomal) proteases implicated in neurodegenerationfollowing acute insults such as stroke and traumatic brain injury as well as in neurodegenerativedisorders such as Alzheimers disease. Calpain research in the CNS has focused almost exclusivelyon the classical calpains Calpains 1 and 2. Calpain 5 (CAPN5) which lacks the penta-EF handdomain of classical calpains is the 2nd most highly expressed calpain in the CNS. Calpain 5 hashomology to other calpains in the cysteine protease domain and also has a unique C2 domain at theC-terminus. C2 domains are involved in binding to membranes and lipids. Very little is knownregarding the functions and substrates of Calpain 5. The C. elegans orthologue of Calpain 5 Tra-3regulates transcriptional activity involved in sex determination. Tra-3 is also required forneurodegeneration induced by TDP-43 toxicity and for necrotic death of sensory neurons followingcalcium overload. At the subcellular level CAPN5 is found in nuclear and crude mitochondrialfractions and associated with promeylocytic nuclear bodies. The purpose of this proposal is gaininsight into the CNS functions of Calpain 5. Aim 1 will identify Calpain 5 binding partners andsubstrates using three complimentary techniques: tandem affinity purification; proximity dependentlocalization; and in vitro affinity capture with each technique paired with mass spectrometry forprotein identification. The binding partners and substrates will be evaluated under both basal andelevated intracellular calcium conditions. The role of the C2 domain in Ca2+ binding along withCAPN5 activation and localization will be evaluated in Aim 2. Aim 3 will explore the physiologicalfunctions of CAPN5 utilizing knockout cell lines generated using CRISPR/Cas-9 and conditionalknockout mice. Preliminary data support the feasibility of each Aim. Together these results willprovide essential information for deciphering the CNS function(s) of CAPN5.

project_terms:
Actins;Active Sites;Acute;Acute Promyelocytic Leukemia;Afferent Neurons;Affinity;Affinity Chromatography;Alzheimer's Disease;Basic Science;Binding;Binding Sites;Biotin;Brain;C2 Domain;CRISPR/Cas technology;Caenorhabditis elegans;Calcium;Calpain;Caspase;Cell Line;Cell Nucleus;Cell membrane;Cells;Cessation of life;Characteristics;Chronic;Cleaved cell;Computer Simulation;Cysteine;Cytokinesis;Data;Dynein ATPase;EF Hand Motifs;EF-Hand Domain;Family;Genes;Genetic;Genetic Transcription;Human;Impairment;In Vitro;Knock-out;Knockout Mice;Lipids;Long-Term Potentiation;Mass Spectrum Analysis;Membrane;Membrane Lipids;Messenger RNA;Methods;Microtubules;Mitochondria;Necrosis;Nerve Degeneration;Neurodegenerative Disorders;Neurosciences;Nomenclature;Nuclear;Pathologic;Pentas;Peptide Hydrolases;Phenotype;Phospholipids;Physiological;Property;Proprotein Convertase 1;Proprotein Convertase 2;Protease Domain;Protein Isoforms;Proteins;Research;Role;Signal Transduction;Site-Directed Mutagenesis;Spinal Cord;Stroke;Structure;Techniques;Toxic effect;Traumatic Brain Injury;Triad Acrylic Resin;alpha Actinin;alpha Tubulin;base;beta Tubulin;in vivo;inhibitor/antagonist;insight;interest;knock-down;member;migration;novel;overexpression;protein TDP-43;response;sensor;sex determination

public_health_relevance:
NarrativeCalpains are calcium-activated proteases which selectively cleave substrate proteins and areimplicated in neuronal degeneration associated with stroke traumatic brain injury and Alzheimersdisease. Calpain 5 is expressed in the brain at relatively high levels compared to the previouslystudied calpains 1 and 2 yet little is known regarding calpain 5s physiological and pathological roles.This basic science neuroscience proposal examines the binding partners/substrates of Calpain 5mechanisms of activation and consequences of genetic deletion to decipher its possible function(s)in the brain.


application_id: 9706232
project_number: 3P42ES007380-21S2
project_title: Chloro-Organic Degradation by Polymer Membrane Immobilized Iron-Based Particle Sy
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7485
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Project 5 - Bhattacharyya Ormsbee) Due to their relative chemical stability and ubiquitous nature chlorinated organic compounds such as polychlorinated biphenyls (PCBs) and trichloroethylene (TCE) continue to pose both remediation challenges and human health risks. At many Superfund sites past remediation efforts using traditional treatment strategies (e.g. reactive barriers six phase heating etc.) have proven to be highly costly and largely ineffective. Alternative strategies include both reductive and oxidative pathways for chloro-organic degradation to non-toxic compounds. The development of nanosized iron-based materials has brought important and promising techniques into the field of environmental remediation. In recent years zero-valent nanoscale metal (especially iron) particles have attracted growing attention in groundwater remediation of chlorinated solvents. For more rapid and complete reductive dechlorination a second metal is often added resulting in bimetallic nanoparticles. In the past utilization of such approaches at actual Superfund sites has been limited due to concerns about particle agglomeration or release into the environment. Project 5 will address the need for targeted remediation strategies by developing integrated cost-effective technologies which incorporate both reductive and oxidative strategies in order to allow the complete remediation of chlorinated organic compounds without the production of toxic byproducts Three specific aims are to: 1) create a porous common polymer membrane immobilized platform for synthesis of reactive and stable iron-based nanoparticles using environmentally safe approaches to prevent aggregation and loss of particles; 2) embed immobilized nanoparticles in responsive membrane domain to allow highly effective PCB and TCE dechlorination by both reductive and oxidative approaches; 3) determine whether PCB demineralization with reduction by bimetallic (iron and palladium) nanoparticles as a first step followed by oxidation with iron oxide nanoparticles immobilized in polymer membrane domain will eliminate the formation of toxic chlorine-substituted intermediates as verified by toxicity tests. To accomplish the aims a polymer/ membrane platform will be developed in both lab scale and full-scale for environmentally benign nanostructured iron synthesis and individual and combined technology strategies will be established to reduce the toxicity of chloro-organics (selected PCBs and chloroethylenes). The proposed approach should address the agglomeration and toxicity concerns associated with the use of bimetallic nanoparticles and allow for the complete breakdown of chlorinated organic compounds to nontoxic and biodegradable intermediates. The project will include collaborations with the U.S. Environmental Protection Agency's (EPA's) National Risk Management Research Laboratory focused on nanoparticle synthesis and characterization using EPA facilities. As in the past the project will work with diverse primary stakeholders at state and federal levels to implement the developed technologies at the Paducah Gaseous Diffusion Plant Kentucky largest Superfund site.

project_terms:
Address;Adsorption;Aftercare;Attention;Benign;Biological Sciences;Carbon;Chemicals;Chemistry;Chlorine;Collaborations;Development;Diffusion;Drug Metabolic Detoxication;Engineering;Environment;Environmental Health;Free Radicals;Funding;Generations;Health;Heating;High temperature of physical object;Human;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;Individual;Inflammatory;Iron;Kentucky;Knowledge;Laboratories;Laboratory Research;Lead;Manufacturer Name;Medical;Membrane;Metals;Methods;Modeling;Mono-S;Nanostructures;Nature;Outcome Study;Palladium;Pathway interactions;Phase;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Production;Public Health;Reaction;Research;Risk;Risk Management;Science;Scientist;Site;Soil;Solvents;Source;Structure;Superfund;System;Techniques;Technology;Temperature;Testing;Toxic effect;Toxicity Tests;Translational Research;Trichloroethylene;United States Environmental Protection Agency;Vinyl Chloride;Water;Work;aryl hydrocarbon receptor ligand;base;chemical stability;contaminated water;cost;cost effective;dechlorination;demineralization;design;drinking;drinking water;global environment;ground water;hazard;hydrodynamic flow;innovation;iron oxide;iron oxide nanoparticle;metal oxide;microbial;nanoparticle;nanoscale;nanosized;nanostructured;novel;nutrition;oxidation;particle;pollutant;prevent;remediation;scaffold;sensor;superfund chemical;superfund site;technology validation;treatment strategy

public_health_relevance:
PROJECT NARRATIVE The persistence of toxic pollutants at Superfund sites poses a major environmental public health problem and a serious need for environmental solutions to reduce risk. Our research is expected to lead to cost-effective technologies for remediation of chemicals known as PCBs and TCE that allow for their complete breakdown to nontoxic and biodegradable intermediates while eliminating the two primary concerns associated with the use of nanoparticle systems: their tendency to adhere to each other and their toxicity. Our approaches to develop new membrane-based materials to degrade toxic chemicals may lead to an advanced technology solution in the field of remediation science and engineering.


application_id: 9706231
project_number: 3P42ES007380-21S2
project_title: Biomimetic Magnetic Nanocomposites as a Platform Technology for the Capture and S
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7484
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Project 4 - Hilt Dziubla) Due to their relative chemical stability and pervasive contamination of the environment chlorinated organics such as polychlorinated biphenyls (PCBs) pose serious risks to human health. Given the lack of highly reliable rapid screening tools a convincing evidence base supports study of biological binding domains as a viable strategy for advances in PCB detection. Specifically novel nanomaterials will be developed and will result in a platform technology that allows for the inclusion of biomimetic domains into a variety of system designs facilitating the rapid detection of PCB congeners in the ppm levels needed for useful screening. Furthermore the biomimetic polymer coatings on the magnetic nanoparticles will allow for capture analysis remediation and release on demand. Despite a production ban in 1979 and decades of remediation efforts PCBs remain a persistent environmental contaminant. Gas chromatography mass spectrometry (GC-MS) remains the current standard for sensitivity and specificity in detecting PCBs in the environment. However GC-MS requires intricate time-consuming extraction and sample purification techniques. It has been reported that the binding domains of PCB-specific antibodies (e.g. S2B1) form sterically constrained highly aromatic (e.g. tryptophan tyrosine) pockets allowing for pi-pi bond stacking interactions. These same environments can also be seen in tests of PCB soil distribution (e.g. humin containing matter) and biodistribution (e.g. lipid rafts PCB-binding proteins). We hypothesize that synthetic biomimetic PCB-binding domains can be synthesized by incorporating phenolic and related moieties into polymeric coatings. In preliminary studies we showed that PCB binding was increased through the incorporation of phenolic moieties in our polymeric coatings. The overall goal of this project is to develop a magnetic nanocomposite platform that allows for the selective capture of PCB congeners with a range of affinities and selectivities. The specific aims follow: (1) synthesize and characterize physicochemical properties of magnetic nanocomposites (i.e. biomimetic polymeric networks coated on the surface of magnetic nanoparticles) with the ability to capture/release or capture/sense PCB congeners with tunable affinity and selectivity; (2) characterize the functionality of synthesized nanomaterials including binding capture/release and fluorescence sensing analysis; and (3) apply these novel nanomaterials for the selective capture and sensing of PCBs and mixtures including coplanar non-coplanar and mixed congener PCBs and mixtures (e.g. PCBs 126 153 118). The coatings will be engineered to have precise nanoscale thickness tunable affinity/selectivity and reversible binding using surface initiated polymerizations incorporating phenolic moieties and applying molecular imprinting approaches. These nanomaterials will have broader impact through their potential application in remediation and biomedical applications.

project_terms:
Address;Affinity;Antibodies;Binding;Binding Proteins;Biodistribution;Biological;Biomimetics;Characteristics;Chemistry;Coupled;Detection;Dioxins;Engineering;Environment;Environmental Health;Environmental Pollution;Excision;Flavonoids;Fluorescence;Goals;Health;Human;Kentucky;Light;Magnetic nanoparticles;Magnetism;Mass Fragmentography;Membrane Microdomains;Methods;Milk;Molecular;Phenols;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Process;Production;Property;Proteins;Reporting;Research;Resources;Risk;Sampling;Screening procedure;Sensitivity and Specificity;Soil;Solubility;Specificity;Superfund;Surface;System;Techniques;Technology;Testing;Thick;Time;Toxic effect;Tryptophan;Tyrosine;Universities;Work;aqueous;base;bisphenol A;chemical stability;design;disorder prevention;evidence base;exposed human population;exposure route;fundamental research;global environment;ground water;imprint;nanocomposite;nanomaterials;nanoscale;novel;novel strategies;nutrition;pi bond;pollutant;polyphenol;rapid detection;remediation;screening;superfund chemical;superfund site

public_health_relevance:
PROJECT NARRATIVE The selective capture and sensing of PCBs is critical for understanding environmental contamination by this class of toxic compounds and its impact on human health. The novel nanomaterials developed in this work will provide a solution to the problem widespread contamination at Superfund sites which poses serious global environmental health challenges. Addressing this fundamental research problem will directly impact disease prevention efforts.


application_id: 9706229
project_number: 3P42ES007380-21S2
project_title: Postnatal Complications of Perinatal Polychlorinated Biphenyl Exposure - Project
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7482
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Project 2 - Pearson Swanson) Polychlorinated biphenyls (PCBs) one of a number of chlorinated organic pollutants are highly lipid-soluble toxins that are characterized by relative chemical stability and prevalence in the environment. These traits are responsible for their widely recognized role as a source of serious environmental public health risks. PCBs have been shown to cross the placenta and enter breast milk and a recent paper suggests that prenatal organochlorine levels contribute to gender-specific obesity development in children. In a mouse model additional observations revealed that offspring exposed perinatally to PCB 126 a coplanar PCB that acts through the aryl hydrocarbon receptor had significantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Further mature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring from vehicle-treated dams. The principal investigator's group has shown that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long- term glucose homeostasis in offspring. The goal of the proposed research is to elucidate the potential long- term health complications and mechanisms of PCB toxicity during the critical periods of in utero and early postnatal life and to explore maternal exercise as a transgenerational intervention. Specific Aim 1 will establish the importance of the timing of perinatal PCB exposure (unexposed/in utero exposure/postnatal exposure/in utero + postnatal exposure) that precipitates impaired glucose tolerance in offspring. A subset of offspring will be fed a high fat diet to determine whether a 'second hit' will exacerbate the PCB-induced detriments. Specific Aim 2 will elucidate the mechanism of impaired glucose tolerance in offspring born to PCB-exposed dams. Specific Aim 3 will test if voluntary maternal exercise can be used as an intervention to protect adult offspring from the long-term effects of perinatal PCB exposure. The proposed studies will provide new etiological evidence supporting current observations that perinatal exposures to environmental PCBs are important contributors to the epidemic of diabetes in the United States. This work will also contribute innovative new insights to understanding the role of exercise in mitigating the environmental health impacts of PCB exposure by highlighting pregnancy as a sensitive period when environmental pollutants could have significant and long- lasting effects on offspring metabolism and when interventions could prove effective in ameliorating the detrimental health outcomes. Anticipated results are particularly significant in that they highlight early developmental stages i.e. fetal and neonatal as potential periods of particular vulnerability to lasting effects of toxic environmental insult from PCB contamination.

project_terms:
Adipose tissue;Adult;Adult Children;Agonist;Aryl Hydrocarbon Receptor;Attenuated;Beta Cell;Biochemical;Body Composition;Child;Chlorinated Hydrocarbons;Data;Development;Diabetes Mellitus;Discipline of Nursing;Dose;Environment;Environmental Health;Environmental Impact;Environmental Pollutants;Environmental Pollution;Epidemic;Etiology;Exercise;Exposure to;Fatty acid glycerol esters;Female;Fetal Liver;Fostering;Functional disorder;Funding;Gender;Glucose Clamp;Glucose Intolerance;Goals;Gold;Health;High Fat Diet;Human Milk;Impairment;Inflammation;Inflammatory;Insulin;Insulin Resistance;Intervention;Laboratories;Life;Life Cycle Stages;Lipids;Long-Term Effects;Measures;Messenger RNA;Metabolism;Methods;Molecular;Mus;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Paper;Partner in relationship;Perinatal;Perinatal Exposure;Phenotype;Placenta;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevalence;Principal Investigator;Public Health;Research;Risk;Role;Running;Serum;Source;Techniques;Testing;Thinness;Tissues;Toxic effect;Toxin;United States;Weaning;Work;blood glucose regulation;chemical stability;cost effective;critical period;cytokine;exposed human population;fasting glucose;fetal;glucose tolerance;healthy pregnancy;impaired glucose tolerance;improved;in utero;in vivo Model;innovation;insight;insulin sensitivity;insulin signaling;lifestyle intervention;mouse model;novel;nutrition;obesity development;offspring;perinatal complications;perinatal development;pollutant;postnatal;pregnant;prenatal;prenatal exposure;sedentary;superfund chemical;trait;trend

public_health_relevance:
PROJECT NARRATIVE Obesity and diabetes are at epidemic levels and the toxicity of environmental contaminants during perinatal development could be a significant contributor to these trends. The proposed studies will provide novel information on the detrimental impact that pollutants can have on maternal and offspring health and will test whether the lifestyle intervention maternal exercise can attenuate these effects.


application_id: 9706228
project_number: 3P42ES007380-21S2
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction - Project 1
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7481
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Project 1 - Hennig Morris) Due to their relative chemical stability and ubiquity in the environment chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) continue to pose significant environmental public health risks. The toxic insult from these highly lipid-soluble toxic compounds is known to correlate with a range of post-exposure human health impacts including endocrine disruption and vascular inflammation. In particular coplanar PCBs which act as an agonist of the aryl hydrocarbon receptor have been shown to exert particularly toxic effects on the endothelium and associated vasculature. Atherosclerosis a chronic inflammatory disease initiated by vascular endothelial cell dysfunction remains the leading cause of death in the United States. Exposure to Superfund chemicals such as persistent chlorinated organic pollutants (e.g. PCBs) has been implicated as a risk factor for the development of atherosclerosis. Furthermore PCB-induced toxicity has been linked to increased expression of caveolin-1 the major structural protein in caveolae membrane domains. Caveolae are particularly abundant in endothelial cells where they are believed to play a major role in the regulation of endothelial vesicular trafficking and cell signal transduction. PCBs are also known to affect the cellular redox status which may initiate antioxidant responses through nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. Increasing evidence suggests that diets high in plant-derived bioactive food components (e.g. polyphenols) and omega-3 lipids are associated with a reduced risk of chronic inflammatory diseases such as atherosclerosis. Current data suggest that endothelial cell dysfunction and inflammatory events induced by exposure to coplanar PCBs can be markedly downregulated by polyphenols such as flavonoids as well as by omega-3 polyunsaturated fatty acids. Preliminary data suggest that caveolae and cytosolic Nrf2 signaling are sensitized by dietary omega-3 lipids and polyphenols. We propose three specific aims to test the hypotheses that: 1) PCB-induced endothelial toxicity and associated inflammatory events are regulated through the crosstalk between caveolae and Nrf2 related proteins such as Keap1; 2) dietary protective components including polyphenols and omega-3 lipids sensitize Nrf2 and caveolae signaling pathways leading to a more effective anti-inflammatory cellular response against PCB insults; 3) dietary intervention in vivo can modify PCB-mediated initiation of inflammation and atherosclerosis through caveolae and/or Nrf2 signaling. Novel experimental methodologies including gene control constructs and bioanalytical technologies will be utilized to understand the interplay between Nrf2 and caveolae signaling. Results from our mechanistic studies will support the paradigm that healthful nutrition interventions may offer a powerful strategy to reduce disease risks associated with environmental toxic insults and to prevent inflammatory diseases such as atherosclerosis that have been linked to exposure to persistent chlorinated organic pollutants.

project_terms:
Address;Affect;Agonist;Anti-inflammatory;Antioxidants;Arterial Fatty Streak;Aryl Hydrocarbon Receptor;Atherosclerosis;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Catechin;Cause of Death;Caveolae;Caveolins;Cells;Chemicals;Chronic;Complement;Data;Development;Diet;Dietary Fats;Dietary Intervention;Dietary Polyphenol;Disease;Ecology;Endocrine disruption;Endothelial Cells;Endothelium;Environment;Environmental Health;Environmental Pollutants;Epigallocatechin Gallate;Erythroid;Event;Exposure to;Flavonoids;Foundations;Functional disorder;Genes;Green tea;Hazardous Waste Sites;Health;Health Food;Human;Hypertriglyceridemia;In Vitro;Inflammation;Inflammatory;Investigation;Kentucky;Knockout Mice;Link;Lipids;Mediating;Membrane;Methodology;Modeling;Nuclear;Nutritional;Nutritional status;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidation-Reduction;Plants;Play;Poisons;Polychlorinated Biphenyls;Preventive measure;Process;Proteins;Public Health;Regulation;Research;Risk;Risk Assessment;Risk Factors;Role;Severities;Signal Pathway;Signal Transduction;Small Interfering RNA;Structural Protein;Superfund;Technology;Testing;Time;Toxic effect;United States;Universities;Vascular Diseases;Vascular Endothelial Cell;Work;bioactive food component;caveolin 1;chemical stability;cost;design;disorder risk;exposed human population;genetic manipulation;global environment;heme oxygenase-1;in vivo;lipophilicity;mouse model;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;protective effect;remediation;response;stressor;superfund chemical;superfund site;toxicant;trafficking;vascular inflammation

public_health_relevance:
PROJECT NARRATIVE (Project 1 - Hennig Morris) This project explores connections between two major public health concerns: widespread contamination of the environment by a class of toxic chemical contaminants known as PCBs and vulnerability to one of the nation's leading health challenges vascular disease. The project also tests dietary interventions that may disrupt the disease processes initiated by exposure to PCBs and reduce the risk to people who reside near Superfund or other hazardous waste sites where PCBs are prevalent.


application_id: 9706226
project_number: 3P42ES007380-21S2
project_title: Community Engagement Core - Core D
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7479
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA 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
project_abstract:
PROJECT SUMMARY (Community Engagement Core - Gaetke Ormsbee) Responding to community needs UK-SRC's Community Engagement Core (CEC) has provided support and guidance through critical information on nutrition and environmental issues to meet the needs of individuals and communities affected by environmental pollutants. This purpose is underscored through the title of its activities Superfund Community Action through Nutrition (SCAN). During previous funding the CEC established a close collaboration with community groups in eastern and western Kentucky and SCAN activities endorsed by these two communities provided a new service resource for nutrition and scientific information. The aim of SCAN is to empower affected individuals and communities to take proactive steps toward their own health by drawing on the strength of the nutrition-related research from the UK-SRC. The specific aims of the CEC include: 1) establish trust with and assess the needs of affected individuals and communities with consideration of sensitive issues at the previously established site in Appalachia and a newly established third site in central Kentucky; 2) engage individuals communties health professionals trusted community leaders Kentucky Cooperative Extension agents Environmental Protection Agency and Agency for Toxic Substances and Disease Registry personnel and other partners to work together through bidirectional exchanges to guarantee effective communication and to build capacity in the affected communities to foster community participatory processes; 3) inform and translate the research information from UK-SRC researchers through community-requested activities developed by Registered Dietitians (RDs) and to evaluate outcome measures that demonstrate community sustainability and improved knowledge attitudes and health behaviors of the nutrition and environmental health focus; and 4) provide related community feedback outcomes and evaluations to UK-SRC's nutrition and environmental researchers in order to refine and develop safe evidenced-based nutrition and environmental health strategies that reduce the toxicity of PCB's and related compounds and improve public health. Exposure to Superfund chemicals has been shown to affect public health by contributing to an increased risk for chronic diseases especially in combination with poor diet. Through collaboration with the community and community partners the CEC's SCAN activities will empower affected individuals to make more informed decisions about their diet and health and will improve nutrition and environmental health knowledge and behaviors to serve all interested individuals families and communities and thereby enhance public health.

project_terms:
Affect;Appalachian Region;Area;Attitude;Chronic Disease;Collaborations;Communication;Communities;Community Actions;Community Services;County;Diet;Dietitian;Environmental Health;Environmental Pollutants;Evaluation;Exposure to;Family;Feedback;Food;Fostering;Funding;Hazardous Waste Sites;Health;Health Professional;Health Status;Health behavior;Human Resources;Individual;Kentucky;Knowledge;Life Style;Location;Methods;Nurses;Nutritional;Outcome;Outcome Measure;Outcomes Research;Physicians;Poisons;Polychlorinated Biphenyls;Population;Prevalence;Process;Public Health;Recommendation;Research;Research Personnel;Resources;Risk;Services;Site;Superfund;Toxic effect;Translating;Trust;United States Environmental Protection Agency;Work;base;design;disease registry;evidence base;health knowledge;improved;interest;nutrition;programs;response;superfund chemical

public_health_relevance:
PROJECT NARRATIVE (Community Engagement Core - Gaetke Ormsbee) Exposure to Superfund chemicals contributes to an increased risk for chronic diseases especially in combination with poor diet. Kentucky has an increased prevalence of hazardous waste sites chronic diseases and poor lifestyle choices. In response to exposed Kentucky community requests nutrition may be one method to improve health status and behavior and advance public health.


application_id: 9706225
project_number: 3P42ES007380-21S2
project_title: Research Translation Core - Core C
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7478
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Research Translation Core - Ormsbee Gaetke Hoover) To ensure optimal and effective translation of research outputs generated by the University of Kentucky Superfund Research Center (UK-SRC) the Research Translation Core (RTC) functions as the lead UK-SRC component responsible for external linkages and active communication with diverse relevant stakeholders. The UK-SRC addresses environmental health impacts of chlorinated organics focusing on polychlorinated biphenyls (PCBs) and trichloroethylene (TCE). The Center's five research projects are integrated around the study of specific PCBs and positive lifestyle modifications (e.g. nutrition) to tackle the four national Superfund Research Program (SRP) mandates. Specific aims explicitly address SRP program priorities. Thus the RTC will 1) work with UK-SRC projects and cores to develop an integrated program that translates program- and project-specific outcomes to appropriate stakeholders including NIEHS SRP staff and RTCs at other SRP centers nationally; translation mechanisms include electronic communication and participation in such SRP- wide activities as workshops seminars webinars and the annual meeting; 2) build on past successes to strengthen multidirectional agency partnerships including the U.S. Environmental Protection Agency's Region 4 and National Risk Management Research Laboratory Agency for Toxic Substances and Disease Registry U.S. Department of Energy via the Paducah Gaseous Diffusion Plant (PGDP) National Priorities List site the Kentucky Cabinet for Energy and the Environment and the Kentucky Cabinet for Health and Family Services; 3) develop targeted research translation projects that leverage existing university resources including the Center for Clinical and Translational Science the Cooperative Extension Service the Kentucky Water Resources Research Institute (an EPA-designated Center for Excellence for Watershed Management) the Kentucky Research Consortium for Energy and the Environment the Public Health Practice-Based Research Network Program and the Dissemination and Implementation Sciences Consortium. The RTC will also continue supporting UK-SRC project technology implementation at the PGDP; and 4) implement multidirectional strategies and best communication practices to disseminate program- and project-specific information to other end users. Communication channels include an interactive website a risk management workshop an expanded monthly seminar series and targeted print and online materials related to specific research projects and emerging findings. The RTC will partner with UK resources and with other SRP RTCs to ensure broad-based information dissemination to relevant stakeholders. With the UK-SRC Community Engagement Core the RTC will establish multidirectional relationships with two Superfund-impacted communities: 1) Dayhoit Kentucky in Appalachia home to a Kentucky NPL site and 2) Floyds Fork Watershed Community a six-county area in central Kentucky home to two NPL sites and near several others.

project_terms:
Address;Advisory Committees;Appalachian Region;Area;Cardiovascular system;Chemicals;Clinical Sciences;Collaborations;Communication;Communities;County;Decision Making;Department of Energy;Diffusion;Documentation;Educational workshop;Electronic Mail;Engineering;Ensure;Environment;Environment and Public Health;Environmental Health;Event;Exercise;Exposure to;Family;Fostering;Future;Goals;Health;Home environment;Housing;Human Resources;Information Dissemination;Interdisciplinary Study;Kentucky;Laboratory Research;Lead;Leadership;Life Style Modification;Maintenance;Medicine;Mentors;Mentorship;National Institute of Environmental Health Sciences;Outcome;Outcomes Research;Output;Pharmacology;Physiological;Plants;Poisons;Polychlorinated Biphenyls;Positioning Attribute;Process;Productivity;Program Development;Public Health;Public Health Practice;Public Policy;Reporting;Research;Research Activity;Research Infrastructure;Research Institute;Research Project Grants;Research Support;Resources;Risk;Risk Management;Role;Scientist;Series;Services;Site;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Translating;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;University resources;Water;Work;base;community center;disease registry;experience;health science research;implementation science;innovation;meetings;nano;new technology;nutrition;pollutant;practice-based research network;program dissemination;programs;success;superfund chemical;technology validation;web site;webinar

public_health_relevance:
PROJECT NARRATIVE (Research Translation Core - Ormsbee Gaetke Hoover) The Research Translation Core (RTC) uses multidirectional strategies and best communication practices to translate University of Kentucky Superfund Research Center research outcomes into decision-making public policy new technologies practice innovations and ultimately improvements in public health.


application_id: 9706224
project_number: 3P42ES007380-21S2
project_title: Research Support Core - Core B
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7477
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Research Support Core - Morris Stromberg) The Research Support Core (RSC) of the University of Kentucky Superfund Research Center (UK-SRC) provides vital access to expertise research resources and state-of-the-art instrumentation to researchers engaged in all aspects of the component biomedical and environmental science research projects. The RSC enhances the productivity quality and consistency of these projects by providing a formalized mechanism for access to expert investigators and professional staff and by enabling efficient use of expensive and sophisticated instrumentation that would otherwise be beyond the capabilities of individual laboratories to acquire and support. To reflect the evolving needs of the participating investigators the RSC has been reorganized to combine activities in systems biology and bioinformatics/ biostatistics into a single "Quantitative Biology" component that provides biostatistics support for experimental design and computational infrastructure for data management analysis and sharing. Our analytical capabilities have been greatly expanded and now constitute a "Bioanalytical" component that provides technologies for quantitation and structural analysis of toxins nutritional protectants and markers and mediators of oxidative stress and inflammation. In addition to their importance to the biomedical component projects these analytical capabilities are critical for validation of polychlorinated biphenyl (PCB) sensor/capture technologies monitoring mechanisms of PCB detoxification and remediation and evaluating toxicities associated with these approaches that are being developed by the non-biomedical projects. The RSC offers an additional range of analytical services that are of specific value to the biomedical projects is engaged in UK-SRC driven discovery research to identify biomarkers of PCB exposure and nutritional and lifestyle-based interventions that protect from these toxins and participates the full repertoire of UK-SRC translational and training/educational functions.

project_terms:
Address;Advanced Development;Animal Model;Animals;Area;Basic Science;Bioinformatics;Biological Markers;Biology;Biometry;Calibration;Cardiovascular Diseases;Cell model;Cells;Center for Translational Science Activities;Clinical;Clinical Research;Cultured Cells;Data;Data Analyses;Data Base Management;Data Set;Detection;Development;Dose;Drug Metabolic Detoxication;Ecology;Ensure;Experimental Designs;Funding;Gene Expression Profiling;Generations;Health Hazards;Health Services Research;High Pressure Liquid Chromatography;Individual;Inflammation;Informatics;Intervention;Investments;Kentucky;Laboratories;Life Style;Mass Fragmentography;Mass Spectrum Analysis;Mediator of activation protein;Metabolic;Metabolic Diseases;Methods;Monitor;Nutritional;Nutritional Study;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Polychlorinated Biphenyls;Productivity;Proteomics;Public Health;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Services;Superfund;Suspensions;Systems Biology;Technology;Toxic effect;Toxin;Training;Universities;Validation;base;biomarker discovery;biomarker identification;computer infrastructure;data acquisition;data management;design;diphenyl;experimental study;exposed human population;instrumentation;metabolomics;nutrition;programs;remediation;sensor;sensor technology;sharing data;small molecule;superfund chemical;translational scientist

public_health_relevance:
PROJECT NARRATIVE Polychorinated biphenyls pose a significant public health hazard. Researchers studying the effects of these toxins on cells and animals and devising methods and strategies for nutritional protection from these toxic effects or to sense and degrade these toxins require access to state of the art instrumentation and expertise for experiment design data acquisition storage and analysis. The Research Support Core addresses this critical need of our Superfund Basic Research Program investigators.


application_id: 9706222
project_number: 3P42ES007380-21S2
project_title: Administrative Core - Core A
administering_ic: NIEHS
award_notice_date: 2018-05-31
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_end_date: 2020-03-31
study_section: ZES1-LKB-K
subproject_number: 7476
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY (Administrative Core - Hennig Ormsbee Hoover) The overarching goal of the University of Kentucky Superfund Research Center (UK-SRC) is to reduce risk from exposure to environmentally persistent chlorinated organics which are prevalent at Superfund sites using polychlorinated biphenyls (PCBs) as a model pollutant. The UK-SRC proposes to address this goal through an integrated program of biomedical and environmental science research focused on pro-inflammatory health impacts of PCBs and innovations in environmental remediation technology. Further the Center uses the combined understandings from these two complementary areas of study to explore positive lifestyle practices (e.g. nutrition-based approaches) to modulate health effects as well as environmentally benign nano-based approaches to mitigate the environmental threat. To achieve these goals the Administrative Core provides high level coordination of transdisciplinary scientific interactions across biomedical and environmental science domains associated interdisciplinary research training and multi-directional translation efforts across diverse sectors-federal government state agencies the private sector and other stakeholders at community and individual levels. To provide an optimal support environment and the requisite infrastructure to accomplish the Center's goal we propose four specific aims to: 1) implement high level planning and coordination of research activities by implementing effective leadership identifying emerging research facilitating complementary approaches and establishing processes for dissemination translation and engagement; 2) integrate diverse cross-disciplinary areas of research by promoting intra- and extra-Center communication and fostering collaboration and cooperation across projects and cores; 3) provide effective fiscal management processes and oversight of core resources; 4) facilitate high quality management processes that promote continuing research productivity effective mentoring accurate documentation/reporting and capacity to meet future challenges. The focus of the Administrative Core on the establishment and maintenance of iterative program development processes along with multidirectional internal and external relationships positions our Center to contribute not only important scientific findings but also collaborative processes stakeholder-derived information and innovative endeavors to the national Superfund Research Program.

project_terms:
Address;Advisory Committees;Area;Benign;Cardiovascular system;Chemicals;Collaborations;Communication;Communities;Discipline;Documentation;Ecology;Educational workshop;Engineering;Ensure;Environment;Environmental Health;Environmental Pollution;Event;Exercise;Exposure to;Federal Government;Fostering;Future;Goals;Health;Housing;Human Resources;Individual;Inflammatory;Information Centers;Interdisciplinary Study;Kentucky;Leadership;Life Style;Maintenance;Medicine;Mentors;Mentorship;Modeling;National Institute of Environmental Health Sciences;Outcome;Output;Pharmacology;Physiological;Polychlorinated Biphenyls;Positioning Attribute;Private Sector;Process;Productivity;Program Development;Public Health;Reporting;Research;Research Activity;Research Infrastructure;Research Project Grants;Research Support;Research Training;Resources;Risk;Role;Science;Scientist;Superfund;Targeted Research;Technology;Toxic effect;Toxicology;Training;Translational Research;Translations;Universities;base;experience;health science research;innovation;meetings;nano;nutrition;pollutant;programs;remediation;superfund chemical;superfund site;training project

public_health_relevance:
PROJECT NARRATIVE (Administrative Core - Hennig Ormsbee Hoover) The Administrative Core of the University of Kentucky Superfund Research Program will continue to promote a set of approaches that apply principles of team science and rely on perspectives from different biomedical and environmental science disciplines. These approaches will address the problem of environmental contamination from a class of pollutants known as chlorinated organics. The goal will be to reduce risk from exposure to these compounds by studying their health effects and potential technical solutions in the environment.


application_id: 9705852
project_number: 5R01AG057290-03
project_title: Programming amylin secretion to slow brain aging - an animal model
administering_ic: NIA
award_notice_date: 2019-05-13
opportunity_number: RFA-AG-17-050
application_type: 5
activity_code: R01
ic: AG
serial_number: 057290
program_official: PEREZ MONTES, VIVIANA
project_start_date: 2017-09-15
project_end_date: 2022-04-30
study_section: ZAG1-ZIJ-6(A1)
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: THINAKARAN, GOPAL
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYProteostasis dysfunction of pancreatic -cells results in accumulation of oligomerized amylin within pancreaticislets which is a hallmark of type-2 diabetes. We recently showed that oligomerized amylin also incorporatesinto the brain blood vessel walls forms neuritic deposits and co-localizes with Alzheimer's disease (AD) -amyloid peptides (A) as mixed A-amylin plaques in brains of individuals with late-onset AD as well as familialearly-onset AD. It is unknown whether cerebral amylin deposits are a consequence of AD or type-2 diabetesor a hidden trigger of AD. Moreover we found that overexpressing human amylin within pancreatic islets inrats induces systemic amylin dyshomeostasis brain amylin accumulation microglia activation and behaviorchanges. Furthermore elevated human amylin in the periphery greatly accelerates behavior changes in a ratmodel of AD pathogenesis. These findings suggest the hypothesis that amylin dyshomeostasis in pancreaticislets and subsequent secretion of oligomerized amylin in the blood can affect the progression of AD bycompromising the ability of microglia to efficiently clear A and by inducing mixed A-amylin pathology. Thusameliorating amylin dyshomeostasis in the periphery can limit the progression of AD. The overarching goal ofthis proposal is to test our hypothesis and investigate molecular mechanisms underlying the interaction ofamylin with A pathology. We will accomplish this goal by characterizing novel transgenic mice with inducibleand reversible expression of human amylin in the pancreas (HuAmy line). We will carefully dissect proteostasisdysfunction of pancreatic -cells in the periphery and the consequent liability it imposes on the central nervoussystem. We will also cross HuAmy line and 85Dbo line to generate APP/PS1 transgenic mice with regulatedexpression of human amylin in the periphery. We predict that turning off the human amylin transgeneexpression at early time points during aging mitigates the disease progression in HuAmy:APP/PS1 mice bylimiting the blood-brain barrier injury and rescuing the ability of microglia to clear A. This investigation usingnovel regulated amylin expression represents the most direct in vivo approach to rigorously test theinvolvement of peripheral amylin in the biological pathways of AD pathogenesis. The completion of these aimswill elucidate the interplay of amylin dyshomeostasis with the progression of A pathology and whetherameliorating amylin dyshomeostasis in the periphery can reduce or reverse AD in a preclinical model. Webelieve that the proposed investigation fills significant gaps in our understanding of the molecular link betweentype-2 diabetes and AD.

project_terms:
APP-PS1;Affect;Age;Aging;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloidosis;Animal Model;Behavior;Biological;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Cerebrum;Data;Deposition;Development;Diabetes Mellitus;Disease Progression;Early Onset Familial Alzheimer's Disease;Feasibility Studies;Functional disorder;Genes;Goals;Heart;Heart failure;Hormones;Human;Impaired cognition;Individual;Injury;Insulin;Intravenous;Intravenous infusion procedures;Investigation;Islets of Langerhans;Kidney;Late Onset Alzheimer Disease;Link;Longevity;Mediating;Microglia;Molecular;Mus;Neuraxis;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pathogenesis;Pathology;Pericytes;Peripheral;Pre-Clinical Model;Protein Isoforms;Rattus;Structure of beta Cell of islet;Synapses;Testing;Time;Transgenes;Transgenic Mice;aging brain;amyloid formation;apolipoprotein E-4;behavior change;beta amyloid pathology;cognitive performance;design;diabetic patient;early onset;in vivo;islet amyloid polypeptide;mouse model;neural network;non-diabetic;novel;overexpression;proteostasis;transgene expression;transgenic model of alzheimer disease;uptake

public_health_relevance:
NarrativeRecent studies suggest that proteostasis dysfunction of pancreatic -cells is linked with Alzheimer's disease bythe brain accumulation of oligomerized amylin. Our proposed studies will elucidate the interplay of amylindyshomeostasis in the periphery with the progression of  amyloid pathology and whether ameliorating amylindyshomeostasis in the periphery can reduce or reverse Alzheimer's disease in a preclinical model.


application_id: 9703881
project_number: 5U01AI132817-03
administering_ic: NIAID
award_notice_date: 2019-05-03
opportunity_number: RFA-AI-16-042
application_type: 5
activity_code: U01
ic: AI
serial_number: 132817
program_official: KULKARNI, SHILPA S
project_start_date: 2017-06-20
project_end_date: 2020-05-31
study_section: ZAI1-TC-I(M1)
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: GARCIA, ANDRES J;YOLCU, ESMA S
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-06-01
project_title:
Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts

project_abstract:
PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide.Exogenous insulin treatment is the standard of care for T1D but often negatively affects the quality of life andis ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies showthat human islet allografts can restore long-term normoglycemia and insulin independence protect from severehypoglycemia and slow progression of microvascular lesions in immunosuppressed T1D patients. Howeverimmune rejection and continuous use of immunosuppression to control rejection are two major limitationsof clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survivaland also has significant adverse effects on the graft and graft recipients. Therefore the development of novelapproaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. Allogeneic islets are subject to rejection by both alloreactive and autoreactive T effector (Teff) cells. Animbalance in the frequency of pathogenic Teff and protective T regulatory (Treg) cells is the underlying causeof T1D and allogeneic islet graft rejection. Restoring the physiological Teff and Treg balance has significanttherapeutic potential. Approaches attempting to tilt the balance in favor of Treg cells have so far targeted eitherTeff or Treg cells individually for modulation with limited success. The primary goal of this application is totarget both cell types simultaneously for modulation for an outcome in favor of Treg cell expansion. This willbe achieved using innovative polyethylene glycol hydrogel particle platforms for graft-targeted deliveryand controlled presentation of two novel biologics serving as agonists of Fas and IL-2R receptors. Teffcells activated by antigens express Fas receptor and become sensitive to FasL-mediated apoptosis. IL-2Rsignaling preferentially sensitizes Teff cells to Fas-induced apoptosis and is also required for Treg cells(CD4+CD25+FoxP3+) generation expansion and survival. Therefore we hypothesize that the combined useof agonists of Fas and IL-2R will preferentially eliminate Teff cells and generate/expand Treg cells withinthe graft microenvironment resulting in induced-immune privilege and sustained survival and function of isletallograft in the absence of any immunosuppression. A set of preliminary data support this hypothesis andprovide strong scientific premise and feasibility for this application. This concept will be tested in threedifferent allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice spontaneously diabetic C57BL/6-to-NOD mice and human islets into humanized mice. Thesemodels will generate critical data relevant to the human setting. Furthermore proof-of-efficacy and theelucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of thisimmunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials forthe treatment of type 1 diabetes.

project_terms:
Acute;Adverse effects;Affect;Agonist;Allogenic;Antigens;Apoptosis;Apoptotic;Autoantigens;Autoimmune Diseases;Beta Cell;Binding;Biocompatible Materials;Biological;Biological Process;Biological Response Modifiers;C57BL/6 Mouse;CD8B1 gene;CD95 Antigens;Cell Death;Cell membrane;Cells;Chemicals;Chronic;Clinical;Clinical Treatment;Clinical Trials;Cloning;Complex;Data;Development;Engineering;Equilibrium;Eragrostis;FOXP3 gene;Failure;Formulation;Frequencies;Generations;Goals;Graft Rejection;Graft Survival;Homeostasis;Human;Hydrogels;Hyperglycemia;Hypoglycemia;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppression;Immunosuppressive Agents;Inbred BALB C Mice;Inbred NOD Mice;Individual;Innate Immune Response;Insulin;Insulin-Dependent Diabetes Mellitus;Interleukin-2;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Lesion;Life;Mediating;Membrane;Memory;Metabolic Control;Modeling;Outcome;Pathogenicity;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Physiological;Play;Polyethylene Glycols;Population;Pre-Clinical Model;Prevention Protocols;Protocols documentation;Quality of life;Rattus;Recurrence;Regulatory T-Lymphocyte;Research;Rodent;Role;Signal Pathway;Signal Transduction;Skin;Streptavidin;Surface;T memory cell;T-Lymphocyte;Testing;Therapeutic;Time;Translations;Treatment Protocols;Tumor Necrosis Factor Ligand Superfamily Member 6;Work;alternative treatment;autoreactivity;base;cell type;chronic autoimmune disease;controlled release;design;diabetic;effective therapy;efficacy testing;extracellular;graft function;humanized mouse;immunoregulation;immunosuppressed;improved;innovation;islet;islet allograft;mouse model;negative affect;nonhuman primate;novel;novel strategies;particle;prevent;receptor;response;standard of care;success;synergism;targeted delivery;therapeutic target;translation to humans

public_health_relevance:
PROJECT NARRATIVEType 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of the populationworldwide. Transplantation of pancreatic islets producing insulin has been shown to be an effective treatment.However graft recipients are required to take immunosuppressive drugs which has significant adverse effectsduring their life to control rejection. The primary objective of this proposal is to establish and test a graft-targeted immunomodulatory protocol delivered using advanced biomaterials that sustains long-term islet graftsurvival and function in the absence of any immunosuppression in various relevant pre-clinical modelsincluding a humanized mouse model. If effective this approach will have immediate and important implicationsfor the use of allogeneic islets for the treatment of T1D in humans.


application_id: 9703811
project_number: 5P50AA024337-04
project_title: Mechanisms of Alcohol-Induced Lung and Liver Injury
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8305
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
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: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Chronic ethanol abuse leads to increased susceptibility to acute lung injury (ALI) and mortality in the setting of sepsis. We believe that this is due in part to alterations in the expression of tissue remodeling genes that prime the lung to disrepair after injury. This is supported by our own findings showing that lungs harvested from rodents treated with ethanol show increased expression of fibronectin matrix metalloproteinases and transforming growth factor ; we also demonstrated activation of matrix remodeling in alcoholics. Together with changes in oxidative stress and epithelial cell dysfunction these alterations represent key features of what has been termed the alcoholic lung phenotype. Despite the above advances we still do not understand the mechanisms that lead to these changes nor the role of matrix remodeling in the alcoholic lung. Importantly the mechanisms by which these changes render the lung susceptible to disrepair after injury remain unclear. We hypothesize that chronic ethanol promotes redox stress that triggers extracellular matrix (ECM) remodeling resulting in the `re-pavement' of the lung with a `pro-inflammatory' ECM characterized by increased expression of fibronectin EDA and collagen V two molecules implicated in tissue disrepair. Upon injury of the alcoholic lung epithelial cells trying to populate denuded areas become exposed to this aberrant ECM resulting in increased permeability while incoming immune cells exposed to this ECM experience exaggerated activation. Together these processes enhance inflammation and epithelial cell dysfunction leading to disrepair and ultimately ALI. We have observed similar derangements in the aging lung and speculate that ethanol-induced redox stress promotes accelerated aging of the lung through epigenetic modifications that drive ECM remodeling. Our hypothesis is supported by several in vivo studies demonstrating a role for the ECM in the lung's response to injury. Second we showed that primary lung cells harvested from ethanol-treated animals deposit a pro-inflammatory matrix. Third we found that alveolar epithelial cells cultured on different matrices show alterations in their expression of claudins resulting in barrier dysfunction. Fourth like ethanol we found that aging also promotes ECM remodeling and this defect is associated with epigenetic histone modifications that drive fibronectin gene expression; we speculate that similar mechanisms are taking place here. Finally recent studies in our laboratory suggest that the above effects might be dependent on ethanol-induced redox stress and could potentially be ameliorated by dietary interventions targeting redox stress. We aim to test the hypothesis in specific aims designed to: 1) Examine the effects of ethanol-induced ECM remodeling on immune cells and epithelial cells in vitro and explore its role in susceptibility to ALI in vivo; 2) Examine ethanol- dependent gene-specific promoter-associated epigenetic modifications regulating ECM gene expression in lung fibroblasts; and 3) Investigate how ethanol-induced redox stress promotes ECM remodeling and determine the effect of anti-oxidant dietary interventions on ethanol-induced ECM remodeling and susceptibility to ALI.

project_terms:
Acute Lung Injury;Aging;Alcohol abuse;Alcohols;Alveolar;Animals;Antioxidants;Area;Cell surface;Cells;Chronic;Collagen;Complement Factor B;Cultured Cells;Defect;Deposition;Development;Dietary Intervention;Epigenetic Process;Epithelial Cells;Ethanol;Ethanol dependence;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Functional disorder;Gene Expression;Genes;Glycoproteins;Growth Factor;Harvest;Immune;In Vitro;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Laboratories;Lead;Lung;Matrix Metalloproteinases;Modeling;Modification;Mus;Nicotinic Receptors;Organ;Organ Transplantation;Oxidation-Reduction;Oxidative Stress;Permeability;Phenotype;Play;Predisposition;Process;Production;Rodent;Role;Sepsis;Stress;Testing;Tissues;Transforming Growth Factors;Work;alcohol effect;cytokine;design;experience;histone modification;in vivo;indium-bleomycin;injury and repair;liver injury;lung injury;monocyte;monolayer;mortality;nutrition;problem drinker;programs;promoter;response to injury;sensor


application_id: 9703810
project_number: 5P50AA024337-04
project_title: Sulforaphane-mediated epigenetic modulation of ethanol-induced apoptosis and teratogenesis
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8304
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Sulforaphane (SFN) is a chemical that is abundant in broccoli sprouts. Compelling evidence indicates that SFN or SFN-rich broccoli sprouts trigger the induction of antioxidant enzymes through activation of Nrf2 signaling and prevent cancer and other diseases. It was recently discovered that SFN can regulate gene expression through epigenetic mechanisms. We have recently demonstrated that SFN can significantly diminish ethanol- induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to elucidate the epigenetic mechanisms by which SFN epigenetically regulates the anti-apoptotic gene expression and prevent ethanol-induced apoptosis and to develop a safe and effective regimen to diminish the incidence and severity of FASD using SFN a safe nutraceutical. The central hypothesis of this project is that ethanol-induced epigenetic alterations lead to aberrant expression of the anti-apoptotic genes resulting in excessive apoptosis and malformations in embryos which can be prevented by epigenetic modulation elicited by SFN or SFN-rich broccoli sprout extract. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim 1: To identify the anti-apoptotic genes that are epigenetically silenced by ethanol and derepressed by SNF in ethanol-exposed NCCs and mouse embryos. Aim 2: To elucidate the mechanisms by which SFN epigenetically modulates the expression of the anti-apoptotic genes and apoptosis in ethanol- exposed NCCs and mouse embryos. Aim 3: To test the hypothesis that epigenetic modulation of the anti- apoptotic genes by maternal dietary SFN-rich broccoli sprout extract (BSE) represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. The proposed work is innovative because it focuses on a novel approach epigenetic modulation of the anti-apoptotic genes to preventing ethanol-induced teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent FASD through the use of bioactive compounds derived from a vegetable. The results from this study will be significant because they are expected to illustrate the potential of a practical nutraceutical-based therapeutic strategy for FASD.

project_terms:
Acetylation;Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Attenuated;Broccoli - dietary;Cell Death;Cells;Chemicals;Congenital Abnormality;Consumption;CpG Islands;DNA Modification Methylases;Data;Development;Diet;Disease;Disease model;Embryo;Epigenetic Process;Ethanol;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Gene Silencing;Genes;Goals;Histone Deacetylase;Incidence;Injury;Intake;Laboratories;Lead;Malignant Neoplasms;Mediating;Mental Retardation;Methylation;Modification;Mus;Neural Crest Cell;Nutraceutical;Oral;Organ;Pathogenesis;Pathway interactions;Population;Prevention;Promoter Regions;Regimen;Role;Severities;Signal Transduction;Sulforaphane;Testing;Therapeutic;Transcriptional Activation;Vegetables;Work;alcohol exposure;antioxidant enzyme;base;effective intervention;epigenetic regulation;histone modification;in vivo;innovation;malformation;non-genetic;novel strategies;novel therapeutics;nutrition;prevent;programs;promoter;response;teratogenesis


application_id: 9703809
project_number: 5P50AA024337-04
project_title: HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8303
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
There is increasing evidence that demonstrates a critical pathogenic role for the gut-liver axis in the development of alcoholic liver disease (ALD). The major goal of this proposal is to conduct studies that determine the mechanisms underlying chronic alcohol induced pathogenic changes in the gut-liver axis leading to ALD. Chronic alcohol consumption-mediated enteric microbiota (dysbiosis) and impairment of the gut barrier function leads to increased intestinal permeability and exposes the liver to gut-derived microbial products including endotoxin. The consequent hepatic steatosis and inflammation can in turn promote gut dysfunction. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiome and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Significantly the alcohol-induced intestinal and hepatic pathogenic changes were markedly attenuated by supplementation with the probiotic Lactobacillus rhamnosus Gorbach-Goldin (LGG).  There is gathering evidence and increasing interest regarding the contributory role of epigenetic mechanisms in the development of ALD. In this regard it has been observed that histone associated epigenetic modifications play a significant role in the development of hepatic pathology induced by chronic as well as binge alcohol exposure. Our recent work showed that binge alcohol treatment decreases hepatic class I II and IV HDACs with a sole increase in HDAC3 and a correspondent increase in the global hepatic histone H3 acetylation (H3Ac) status. Subsequently we demonstrated that increased HDAC3 plays a critical role in the binge alcohol-induced suppression of the carnitine palmitoyltransferase 1 (Cpt1a) gene expression and development of hepatic steatosis. Besides altered hepatic HDAC expression our recent preliminary data also show that chronic ethanol feeding leads to a significant increase in the intestinal HDAC1 expression. Accordingly the current proposal examines the unifying hypothesis that chronic alcohol induced alterations in the intestinal as well as hepatic HDACs and histone modifications constitute critical epigenetic mechanisms driving the abnormal gut-liver axis and liver disease. Importantly the proposal also pursues translational studies that examine the efficacy of nutrition based therapeutic interventions targeted at intestinal dysbiosis and HDAC inhibition in mitigating alcohol-induced gut-liver axis changes and liver disease. The specific aims of the proposal are: Aim 1 - Determine the effect of chronic alcohol on intestinal and hepatic HDAC expression and global histone modifications underlying gut-liver axis changes in ALD; Aim 2 - Determine the impact of alcohol-induced HDAC alterations on gene-specific histone modifications and consequent pathogenic expression affecting the gut-liver axis in ALD and; Aim 3 - Evaluate the efficacy of nutrition-based therapeutic interventions in ALD. We expect that the results of our study will provide critical molecular insights and facilitate the development of therapeutic interventions for ALD.

project_terms:
Acetylation;Affect;Alcoholic Liver Diseases;Alcohols;Attenuated;Automobile Driving;Bacteria;Butyrates;Carnitine Palmitoyltransferase I;Chronic;Data;Development;Diet;Endotoxemia;Endotoxins;Enteral;Epigenetic Process;Ethanol;Fatty Acids;Fatty Liver;Functional disorder;Gene Expression;Genes;Goals;Gram-Negative Bacteria;HDAC1 gene;HDAC3 gene;Hepatic;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Impairment;Inflammation;Injury;Intestinal permeability;Intestines;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Liver;Liver diseases;Mass Spectrum Analysis;Mediating;Modification;Molecular;Organ;Pathogenesis;Pathogenicity;Pathology;Permeability;Play;Prevention strategy;Probiotics;Prodrugs;Proteomics;Role;Testing;Therapeutic Intervention;Work;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;dysbiosis;epigenetic regulation;feeding;gut microbiome;gut microbiota;gut-liver axis;histone modification;insight;interest;lipid metabolism;metabolomics;microbial;nutrition;probiotic supplementation;programs;promoter;therapeutic development;translational study;treatment strategy;tributyrin


application_id: 9703808
project_number: 5P50AA024337-04
project_title: Role of Dietary Fat in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8302
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the US and worldwide. Although substantial progress has been made in ALD pathogenesis the specific mechanism(s) responsible for ALD development and progression remain incompletely understood. Importantly there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others demonstrated that dietary unsaturated fat rich in linoleic acid (LA) increased intestinal permeability to gut-derived endotoxins and exacerbated liver inflammation and injury in an experimental animal model of ALD. In addition our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs) specifically 9- and 13-hydroxy- octadecadienoic acids (9-and 13-HODEs) and concomitant up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) the key enzyme involved in the oxidation of LA. These findings suggest that OXLAMs which act as natural ligands to the transient receptor potential vanilloid 1 (TRPV1 subfamily V member 1) contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of interleukin-1 (IL-1) and interleukin-18 (IL-18) is an important pro- inflammatory response in ALD. Many factors are involved in inflammasome priming and activation network including gut-derived endotoxin lipopolysaccharide (LPS). These findings in conjunction with our preliminary data have led us to hypothesize that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol- mediated liver inflammation and injury via oxidized linoleic acid metabolites that induce gut barrier disruption and hepatic inflammasome activation. To address our hypothesis we propose the following four specific aims: Aim 1. Determine the role of dietary unsaturated fat specifically linoleic acid and its oxidation products in the development and/or progression of ALD. Aim 2. Assess whether hepatic inflammasome activation is mediated by OXLAMs-TRPV1-Ca2+ pathway in an animal model of ALD. Aim 3. Evaluate the molecular mechanism(s) by which dietary saturated fat attenuates and unsaturated fat exacerbates alcohol- mediated gut barrier disruption endotoxemia and liver injury. Aim 4. Explore the role of OXLAMs 12/15-LO and TRPV1 in monocyte inflammasome activation in human alcoholic hepatitis. The proposed studies will lead to a better understanding of the molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to better understand alcohol-diet interactions which may lead to identification of new drug targets and potential dietary interventions for treating ALD as well as help to explain why only some people who drink heavily develop clinically important ALD. This proposal extensively interacts with other projects pilots and cores and it incorporates the ULARC theme of nutrition and alcohol-induced organ injury.

project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Clinical;Consumption;Data;Development;Diet;Dietary Fats;Dietary Intervention;Down-Regulation;Endotoxemia;Endotoxins;Enzymes;Ethanol;Experimental Animal Model;FDA approved;Genetic;Heavy Drinking;Hepatic;Human;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Injury;Interleukin-1 beta;Interleukin-18;Intestinal permeability;Intestines;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Lipopolysaccharides;Mediating;Molecular;Morbidity - disease rate;Oral;Organ;Oxides;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Permeability;Pharmacology;Play;Production;Proteins;Role;Severities;Signal Pathway;Supplementation;TRPV1 gene;Testing;Tight Junctions;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;fecal metabolome;gut microbiome;human study;liver inflammation;liver injury;member;monocyte;mortality;new therapeutic target;nutrition;octadecadienoic acid;overexpression;oxidation;peripheral blood;prevent;programs;receptor;saturated fat


application_id: 9703807
project_number: 5P50AA024337-04
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8301
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
Abstract: The primary function of Omics Core is to provide members of the ULARC with the expertise resources and facilities needed for metabolomic proteomic and bioinformatic analyses of biological samples collected to study liver injury nutrition gut:liver interactions and liver:environment/toxicant/drug interactions. OMICS Core personnel will assist with the design of sample collection protocols will drive the development and the execution of novel and robust chromatographic methods for sample separation and mass spectrometric methods for the analysis of proteins peptides and metabolites with a goal of providing a greater understanding of the evolution of molecular mechanisms that correlate with or participate in liver dysfunction. The core will ensure uniformity and standardization in sample preparation method development instrument performance data collection data reporting and data sharing. The Core endeavors to contribute to the overall success and utility of the ULARC and to enhance the infrastructure and the technical and academic capabilities of the institution as a whole. In addition to its function as a service core we will also promote the education and training of the ULARC members with regards to state-ofthe-art Omics and Bioinformatics methods; with particular attention to the ULARC junior investigators.

project_terms:
Acids;Acrolein;Affinity;Alcoholic Liver Diseases;Alcohols;Animals;Attention;Attenuated;Automobile Driving;Bioinformatics;Biological;Biotin;Blood;Blood specimen;Body Weight;Cell Line;Cells;Chronic;Complex Mixtures;Curcumin;Data;Data Collection;Data Reporting;Data Set;Development;Drug Interactions;Embryo;Endotoxemia;Ensure;Environment;Epigenetic Process;Exposure to;Extracellular Matrix;Feces;Fibroblasts;Gas Chromatography;Ginger;Goals;Grapefruit;Hepatic;High Pressure Liquid Chromatography;Histone Acetylation;Histone Deacetylase;Histones;Human Resources;Inflammation;Infrastructure;Injury;Institution;Interleukin-2;Intestines;Lactobacillus casei rhamnosus;Liquid substance;Liver;Liver Dysfunction;Liver diseases;Lung;Lysine;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Methodology;Methods;Molecular;Molecular Evolution;Mus;Neural Crest Cell;Oral;Organ;Pathogenicity;Pattern;Peptides;Performance;Post-Translational Protein Processing;Preparation;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Research;Research Personnel;Resolution;Resources;Role;Sampling;Science;Services;Standardization;Sulforaphane;Techniques;Technology;Tissue Sample;Tissues;Training and Education;Transcriptional Regulation;Unsaturated Fats;Urine;alcohol effect;data sharing;design;exosome;histone methylation;histone modification;instrument;liquid chromatography mass spectrometry;liver injury;long chain fatty acid;male;member;metabolomics;method development;multiple reaction monitoring;nanoparticle;novel;nutrition;phosphoproteomics;programs;response;sample collection;saturated fat;success;time of flight mass spectrometry;toxicant;tributyrin;two-dimensional


application_id: 9703806
project_number: 5P50AA024337-04
project_title: Pilot Project Core
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8300
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN 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: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) was created to serve as a regional/national resource to investigate mechanisms of alcohol induced organ injury and to develop new agents/interventions to prevent/treat this organ injury both of which represent important unmet research needs. The theme of the center is unique among alcohol centers: the role of nutrition in the development/progression and potential prevention/treatment of alcohol-induced organ injury. The Pilots Core will contribute to this program by funding new projects dedicated to this theme of research. We will do this by supporting Young Investigators as well as recruiting Established Investigators who propose projects that represent a change in direction for their research. The goal of the Pilot Core is to provide support for promising clinical and translational research in alcohol-induced organ injury. This support will be targeted mainly at new investigators those newly entering alcohol clinical and translational research and alcohol clinical/translational investigators collaborating across departments and institutions. We will provide an environment that encourages development of pilot projects by providing alcohol researchers with the information resources and mentoring needed to perform innovative clinical/translational research that meets the demands of 21st century science. In addition we will improve the flow of information about existing and new opportunities and resources for pilot projects among University components and our affiliates. The ULARC will provide a clear entry point for investigators seeking to conduct alcohol research. We will reach our goal through the following Specific Aims: 1) To request potential pilot projects that coordinate with the overall theme of the ULARC: Nutrition and Alcohol-Induced Organ Injury; 2) To coordinate evaluation of new pilot project applications which conform to the criteria and goals of the ULARC pilot program; 3) To assist pilot project recipients to achieve extramural funding. This Pilot Program will build on UofL's already outstanding record of identifying promising pilot projects for support. Establishment of the ULARC and the Pilot Program will provide a significant boost to the currently available pilot program funding and greatly stimulate novel alcohol research at UofL.

project_terms:
Address;Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Awareness;Chronic Disease;Clinical;Clinical Research;Development;Educational Status;Environment;Evaluation;Extramural Activities;Funding;Goals;Health;Heart Diseases;Individual;Injury;Institution;Intervention;Kentucky;Lung diseases;Malignant Neoplasms;Mentors;Mission;Modeling;New Agents;Obesity;Organ;Patients;Peer Review;Pilot Projects;Prevention;Research;Research Personnel;Resources;Role;Rural;Schools;Science;Secure;Stroke;Study Section;Substance abuse problem;Translational Research;United States National Institutes of Health;Universities;alcohol abuse therapy;alcohol research;base;black lung;health disparity;improved;innovation;medically underserved;novel;nutrition;prevent;programs;recruit;translational scientist


application_id: 9703805
project_number: 5P50AA024337-04
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8308
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
budget_end_date: 2020-04-30
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) is a multidisciplinary group of investigators focusing on nutrition gut flora/intestinal dysfunction and alcohol-induced organ injury and therapeutic interventions. The ULARC investigators come from 13 departments across 6 schools. The Administrative Core will provide oversight and coordination to the ULARC. The Administrative Core will support education opportunities a biostatistician and a tissue handling/archiving technician. The PI will be assisted by a the Steering and Program Advisory committees and a part-time assistant. The Specific Aims of the Administrative Core are to: 1) provide a formal governance structure for the coordination implementation direction and prioritization of activities including budget issues and resolving any conflicts as they arise ensuring the quality of all functions and evaluating progress; 2) provide a mechanism to replace any key individuals who may leave; 3) provide educational/training opportunities for students at all levels and junior faculty members; 4) provide biostatistical support for investigators; 5) provide `chain of custody' tissue/sample handling and storage; and 6) disseminate pertinent information to the scientific and lay community. All projects pilots and cores will be using the Administrative Core.

project_terms:
Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Archives;Area;Arts;Basic Science;Bioinformatics;Biometry;Budgets;Cancer Center;Clinical;Clinical Investigator;Collaborations;Communities;Conflict (Psychology);Consultations;Country;Development;Education;Engineering;Ensure;Epigenetic Process;Faculty;Functional disorder;Funding;Grant;Health;Health Sciences;Individual;Injury;International;Intervention;Intestines;Lead;Leadership;Letters;Medicine;Organ;Pilot Projects;Proteomics;Public Health Nursing;Reporting;Research;Research Personnel;Research Proposals;Resources;Role;Schools;Science;Social Work;Specialized Center;Structure;Students;Therapeutic Intervention;Time;Tissue Sample;Tissues;Universities;alcohol research;body system;cohesion;gut microbiota;high school;innovation;interest;medical schools;member;metabolomics;multidisciplinary;next generation;novel;nutrition;programs;training opportunity


application_id: 9703803
project_number: 5P50AA024337-04
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2019-04-17
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
program_official: DUNTY, JR, WILLIAM
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville Alcohol Research Center (ULARC) was created to serve as a regional/national resource to investigate mechanisms of alcohol induced organ injury and to develop new agents/interventions to prevent/treat this organ injury both of which represent important unmet research needs. The theme of the center is unique among alcohol centers: the role of nutrition and alcohol-induced organ injury. The approach is highly translational. Our investigators include faculty from 13 departments and 6 colleges. The Specific Aims of the ULARC are to:  1) facilitate interdisciplinary approaches and serve as a regional/national resource for the study of nutrition and alcohol-induced organ injury; 
2) provide a robust pilot project program and comprehensive education and research training in order to develop the next generation of alcohol investigators; and  3) develop potential therapeutic targets/interventions for alcohol induced organ injury based on the mechanistic research of the ULARC and translate knowledge/interventions to the community.  We will explore interactions of nutrition and alcohol abuse in the development of alcohol-induced organ dysfunction and we will evaluate diverse potential nutritional therapeutic interventions. Project  (McClain/Kirpich) evaluates the role of dietary unsaturated fat in the development/progression of alcoholic liver disease. Project 2 (Barve/Feng) evaluates alcohol-induced alterations in the gut-liver axis. They study the role of histone deacetylases (HDACs) in both the intestine and liver in gut-barrier dysfunction and steatohepatitis and the role of probiotics and dietary HDAC inhibitor in preventing/treating experimental ALD. Project 3 (Chen/Arteel) determines mechanisms by which maternal alcohol consumption causes mental retardation in the offspring. They evaluate epigenetic mechanisms by which alcohol induces apoptosis and teratogenesis and by which the nutraceutical sulforaphane provides epigenetic protection. Project 4 (Roman/Watson) evaluates mechanisms by which alcohol causes increased susceptibility to acute lung injury. They postulate that chronic alcohol intake triggers extracellular matrix remodeling resulting in "repavement" of lung tissue with a proinflammatory extracelluar matrix and that this process can be modulated by dietary intervention. We propose 3 pilots that evaluate nutrition:alcohol interactions on the A) liver B) immune system and C) the gut:liver axis and we have a novel "omics" core (metabolomics/proteomics) that will be utilized by all projects and pilots as well as
outside alcohol investigators/centers. Together these projects form a cohesive and interactive approach to investigate the effects of nutrition and nutritional interventions on alcohol-induced organ injury.

project_terms:
Acute Lung Injury;Alcohol Nutrition;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Apoptosis;Area;Award;Biomedical Engineering;Carnosine;Cause of Death;Chronic;Clinical Research;Collaborations;Communities;Development;Diet;Dietary Intervention;Education;Epigenetic Process;Extracellular Matrix;FDA approved;Faculty;Functional disorder;Funding;Goals;Health Care Costs;Histone Deacetylase;Histone Deacetylase Inhibitor;Immune system;Industry;Injury;Institution;Intervention;Intestines;Knowledge;Laboratories;Lead;Lipids;Liver;Mental Retardation;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;New Agents;Nutraceutical;Nutritional;Organ;Pilot Projects;Predisposition;Prevention;Probiotics;Process;Proteomics;Research;Research Personnel;Research Training;Resources;Rewards;Role;S-Adenosylmethionine;Steatohepatitis;Structure of parenchyma of lung;Sulforaphane;Therapeutic Intervention;Training and Education;Translating;Translational Research;United States;United States National Institutes of Health;Universities;Unsaturated Fats;alcohol abuse therapy;alcohol intervention;alcohol research;base;cohesion;college;gut-liver axis;high school;improved;interdisciplinary approach;interest;metabolomics;mortality;multidisciplinary;new therapeutic target;next generation;novel;nutrition;offspring;prevent;programs;public health relevance;success;teratogenesis;therapeutic target

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


application_id: 9702519
project_number: 1R01DA047952-01
administering_ic: NIDA
award_notice_date: 2018-09-25
opportunity_number: PA-18-345
application_type: 1
activity_code: R01
ic: DA
serial_number: 047952
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2018-09-30
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1 AARR-K (92)]
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: 2018-09-30
project_terms:
Abstinence;Address;Adverse effects;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 usage;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;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 setting;telehealth;treatment services;uptake;viral RNA;virology


application_id: 9702417
project_number: 261201800013I-0-26100001-1
project_title: IGF::OT::IGF Core Infrastructure Support for Surveillance Epidemiology and End Results (SEER)
administering_ic: NCI
project_start_date: 2018-05-01
project_end_date: 2019-04-30
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_terms:
Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Pattern;Population;Prevalence;Research Infrastructure;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;trend


application_id: 9702081
project_number: 5R34MH111783-03
project_title: Validation of an Implementation Strategy of COMPASS for School Trainers of Children with Autism
administering_ic: NIMH
award_notice_date: 2019-05-15
opportunity_number: RFA-MH-16-410
application_type: 5
activity_code: R34
ic: MH
serial_number: 111783
program_official: PINTELLO, DENISE
project_start_date: 2017-08-15
project_end_date: 2020-07-31
study_section: ZMH1-ERB-K(03)
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractWe seek to conduct a pilot effectiveness trial within an implementation trial for improving educational outcomesof children with autism spectrum disorder (ASD). Modeled after a Hybrid Trial Type 2 design [1] our study aimsto (a) to create a valid and locally adapted implementation training strategy leveraging the mechanismsunderlying the intervention effects and delivered in priority educational settings located in urban andunderserved rural contexts while also (b) considering implementation and maintenance factors impactingtraining sensitivity to mechanisms and adoption/uptake of COMPASS. The study addresses a significantresearch-to-practice gap that less than 10% of educational strategies for children with ASD are based onevidence [2 3]. Importantly consultation methods have a multiplier effect in the efficient and broaddissemination of best practices. This proposal responds to recommendations from the Interagency AutismCoordinating Committee for studies that utilize implementation science to test methods to improveimplementation of evidence-based treatments (p.41) and develop and evaluate quality measures to helpmonitor progress in improving care and outcomes for people with ASD (p.41) [4]. Our approach aligns withrecommendations from the Institute of Medicine framework for establishing evidence based standards [5] andthe goals of this RFA for effectiveness research on therapeutic interventions with previously demonstratedefficacy for use in community settings. The proposed study builds on two completed NIH funded randomizedcontrolled studies (RCTs) [6 7] a recently published treatment manual [8] and a monograph-length scientificreview [9]. The RCTs provided strong support for the efficacy of consulting delivered by the research team toassist public school special educators and parents via face-to-face interactions and through videoconferencingtechnology [10]. High quality ecological assessments research-informed goal development and guideddecision-making for individualizing evidence-based interventions for children with ASD are accomplished usingthe consultation intervention the Collaborative Model for Promoting Competence and Success (COMPASS)[8]. COMPASS consists of an initial parent-teacher session (3 hours) occurring near the start of the schoolyear followed by four 1-hour teacher coaching sessions evenly spaced through the rest of the school year.COMPASS assists in creating (1) individualized educationally appropriate well-constructed psychometrically-sensitive goals and (2) effective educational plans to meet the goals. Goals and teaching plans take intoaccount the personalized context within which the evidence based interventions will be delivered. Theobjectives of the current proposal are to evaluate the effectiveness of training local consultants/trainersincluding how well the training engages the mechanisms of change (e.g. fidelity) that have been identified andreplicated in two RCTs [67]. The long-term goal is to improve the quality of services and overall functional andsocial outcomes of children with ASD when COMPASS is delivered by practitioners. Our aims are framed withthe Replicating Effective Programs (REP) [11] Framework for implementation in community settings.

project_terms:
Address;Adherence;Administrator;Adoption;Assessment tool;Behavior;Child;Competence;Consult;Consultations;Decision Making;Development;Educational process of instructing;Effectiveness;Evidence based intervention;Evidence based treatment;Feedback;Fibrinogen;Funding;Goals;Grant;Hour;Hybrids;Institute of Medicine (U.S.);Intervention;Knowledge;Length;Maintenance;Manuals;Measures;Methods;Modeling;Monitor;Monograph;Outcome;Parents;Protocols documentation;Psychometrics;Publishing;Randomized Controlled Trials;Recommendation;Research;Rest;Rural;Schools;Services;Technology;Testing;Therapeutic Intervention;Time;Training;Translations;United States National Institutes of Health;Use Effectiveness;Validation;Videoconferencing;autism spectrum disorder;autistic children;base;care outcomes;combat;community setting;design;effectiveness research;effectiveness trial;evidence base;implementation science;implementation strategy;implementation trial;improved;intervention effect;programs;research to practice;rural underserved;satisfaction;social;success;teacher;uptake;urban underserved;usability

public_health_relevance:
NarrativeThis application is pilot research that responds to the Interagency Autism Coordinating Committee for studiesthat utilize implementation science to test methods to improve implementation of evidence-based treatments.High quality ecological assessments research-informed goal development and decision-making forindividualizing evidence-based interventions for children with ASD is accomplished using the consultationintervention called the Collaborative Model for Promoting Competence and Success (COMPASS). Specificallywe will create a valid and locally adapted COMPASS training package; pilot the trainer package; and identifyimplementation and maintenance factors impacting training ongoing quality (including mechanisms) andadoption/uptake of COMPASS when delivered by nonexperts.


application_id: 9702074
project_number: 5R01HL131526-03
project_title: ASK1 and Ventilator-Induced Lung Injury
administering_ic: NHLBI
award_notice_date: 2018-12-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131526
program_official: ZHOU, GUOFEI
project_start_date: 2016-12-15
project_end_date: 2020-11-30
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER 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
project_abstract:
Acute Respiratory Distress Syndrome (ARDS) is a severe form of acute lung injury with very high mortality andfew therapeutic options. Patients with acute lung injury are often initially treated with oxygen by mask and ifthe disease progresses they will be mechanically ventilated with high levels of oxygen (typically 50 to 100%).Although both mechanical ventilation and hyperoxia (HO) can independently cause injury the combination ofthe two has been shown to accelerate and cause more extensive lung injury than either condition alone. Thereis a critical need for understanding these mechanisms in order to develop strategies to reduce or preventventilator-induced lung injury (VILI). The long term goal is to improve understanding of the mechanisms bywhich the combination of exposure to high levels of oxygen (HO) and overdistention (or stretch) of lungscontributes to VILI. The overall objective of this application is to demonstrate that apoptosis signal regulatingkinase-1 (ASK1) is a central mediator of HO-induced exacerbation of VILI. The central hypothesis of thisapplication is that HO-induced activation of ASK1 promotes VILI by enhancing cell death through p38-mediated apoptosis and increased inflammation and by preventing cell survival through suppression ofextracellular signal-regulated kinase- (ERK1/2)-mediated pathways. These mechanisms will be investigatedusing ASK1-deficient mice in a clinically relevant mouse model with pre-exposure to HO (24 hr) followed bymechanical ventilation with high tidal volume. We will also investigate these mechanisms in mice with lunginjury caused by LPS or influenza virus prior to exposure to HO and mechanical ventilation in order to modelthe clinical scenario of ARDS. In addition primary cultures of alveolar type II epithelial cells and macrophagesas well as cell lines with knockdown of ASK1 and other key mediators will be subjected to HO and cyclicstretch. Aim 1 will test the hypothesis that HO/VILI is exacerbated by ASK1-induced activation of p38 thatpromotes stretch-induced apoptosis via inhibition of survivin and through activation of the inflammasome. Aim2 will test the hypothesis that ASK1 activation prevents ERK1/2-mediated pro-survival pathways includingexpression of survivin and Nrf2-mediated production of antioxidant enzymes. These studies will elucidate newsignaling pathways involved in HO-induced exacerbation of VILI.

project_terms:
Acute Lung Injury;Adult Respiratory Distress Syndrome;Alveolar;Animal Model;Apoptosis;Apoptosis Inhibitor;Apoptotic;Cell Death;Cell Line;Cell Survival;Cells;Clinical;Disease;Epithelial;Epithelial Cells;Exposure to;Extracellular Signal Regulated Kinases;Genetic Transcription;Goals;Hyperoxia;Infection;Inflammasome;Inflammation;Influenza;Injury;Investigation;JUN gene;Lead;Life;Lipopolysaccharides;Lung;MAP Kinase Gene;MAP Kinase Kinase Kinase;MAP3K5 gene;MAPK14 gene;MAPK8 gene;Masks;Mechanical Ventilators;Mechanical ventilation;Mechanics;Mediating;Mediator of activation protein;Mitogen-Activated Protein Kinases;Modeling;Mus;Oxidative Stress;Oxygen;Pathway interactions;Patients;Periodicity;Phosphothreonine;Production;Public Health;Reactive Oxygen Species;Research;Role;Severities;Signal Pathway;Signal Transduction;Stretching;Structure of parenchyma of lung;TXN gene;Testing;Therapeutic;Therapeutic Intervention;Tidal Volume;Tissues;Ventilator;Ventilator-induced lung injury;Viral;Work;antioxidant enzyme;clinically relevant;improved;influenzavirus;knock-down;lung injury;macrophage;mortality;mouse model;novel;novel therapeutic intervention;novel therapeutics;prevent;response;survivin;targeted treatment

public_health_relevance:
The proposed project is relevant to public health because ventilator-induced lung injury contributes to themortality of patients with the acute respiratory distress syndrome a devastating disease which results insignificant loss of life. The proposed studies will investigate the mechanisms of how high levels of oxygencontribute to this increased injury and will identify potential targets for therapeutic intervention to reduce injury.


application_id: 9701854
project_number: 5R01HL131647-04
project_title: Regulation of Metabolic Genes in the Heart
administering_ic: NHLBI
award_notice_date: 2019-04-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131647
program_official: WONG, RENEE P
project_start_date: 2016-06-01
project_end_date: 2021-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project AbstractProfound derangements in pathophysiology occur during heart failure including alterations in thecardiomyocyte's ability to coordinate metabolic cues. Glucose represents the quintessential substrate formetabolism. Yet not all glucose is dedicated to the production of ATP; a fraction of intracellular glucose isshunted into several accessory pathways such as the Hexosamine Biosynthetic Pathway which forms themonosaccharide donor for the post-translational modification known as O-linked--N-acetylglucosamine (O-GlcNAc). The PI's laboratory has identified O-GlcNAcylation as an important event in the failing heart and O-GlcNAcase (OGA) is a key regulator of O-GlcNAc removal from targets. Despite significant insights related tothe phenomenology of O-GlcNAc in acute myocardial ischemia and heart failure almost nothing is knownabout the regulation of the O-GlcNAc enzymes (OGA and OGT) in the heart or other tissues. The presentproposal will reduce significantly this critical gap in knowledge. To this end the present proposal will: i) Identifytranscriptional and post-transcriptional regulators of OGA expression; again nothing is known currentlyregarding such regulation in the cardiomyocyte. In addition to in vivo studies experiments will be performed inisolated cells and cell lines using common molecular biology techniques (e.g. promoter mutations transcriptionfactor binding transduction). ii) Using a loss-of-function approach the project will determine the impact ofOGA suppression during heart failure. Studies will incorporate tissue-specific inducible cre-lox-mediateddeletion of the OGA gene in cardiomyocytes. The PI will use genetically modified surgically operated micecoupled with state-of-the-art physiologic assessment of cardiac function. iii) Mechanistic inquiries will focus onmitochondria to understand how OGA suppression attenuates the severity of heart failure. The PI will performvarious analyses of mitochondrial function including bioenergetics assays along with protein chemistry todetermine how suppression of OGA improves mitochondrial function. The overarching hypothesis holds thatthat OGA suppression attenuates heart failure through preservation of mitochondrial respiratory integrity.Although not the direct near-time goal of this project the results could eventually contribute to new potentialtreatment options for heart failure and because of the potential involvement of O-GlcNAcylation in severaldiseases will contribute to new directions in studies of diabetes Alzheimer's aging and vascular diseases.

project_terms:
Ablation;Accounting;Acute;Address;Aging;Alzheimer's Disease;Area;Attenuated;Binding;Bioenergetics;Biological;Biological Assay;Biology;Cardiac Myocytes;Cell Line;Cell physiology;Collaborations;Coupled;Cues;Diabetes Mellitus;Disease;Elements;Enzymes;Event;Excision;Functional disorder;Gene Expression Regulation;Genes;Genetic Transcription;Glucose;Goals;Heart;Heart failure;Hexosamines;Hypertrophy;Infarction;Knowledge;Laboratories;Life;Link;Mediating;Metabolic;Metabolism;MicroRNAs;Mitochondria;Molecular;Molecular Biology Techniques;Monosaccharides;Mus;Mutation;Myocardial Ischemia;Myocardium;Neurodegenerative Disorders;O-GlcNAc transferase;Operative Surgical Procedures;Outcome;Pathway interactions;Physiological;Positioning Attribute;Post-Translational Protein Processing;Production;Protein Chemistry;Proteins;Recording of previous events;Regulation;Research Personnel;Respiratory physiology;Role;Severities;Signal Transduction;Stress;System;Testing;Therapeutic;Time;Tissues;Vascular Diseases;Ventricular Function;Work;authority;experience;experimental study;heart function;human disease;improved;in vivo;innovation;insight;interest;loss of function;novel;peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase;phenomenological models;preservation;promoter;respiratory;response;synergism;tool;transcription factor;vector;virtual

public_health_relevance:
Project NarrativeThis project will determine the role of a unique metabolism-related signal in the failing heart. This project willalso provide new insights into the molecular regulation of genes also involved in neurodegenerative diseasesdiabetes and other diseases. This project will produce broadly applicable basic biological insights.


application_id: 9701282
project_number: 5R01NS097722-03
project_title: Neurovascular astrocyte dysfunction in VCID
administering_ic: NINDS
award_notice_date: 2019-06-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 097722
program_official: CORRIVEAU, RODERICK A
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behindAlzheimer's disease (AD). In addition VCID is a frequent co-morbidity with AD complicating the diagnosis andtreatment of AD for a significant proportion of AD patients. Despite its prevalence VCID remains relativelyunderstudied compared to AD and little is known about the molecular mechanisms underlying the cognitivedysfunction resulting from cerebrovascular disease. In part this is due to the multiple pathological processesdisrupting neurovascular networks that can result in VaD. We have previously shown that astrocytic end-feet are significantly impacted in the presence ofcerebral amyloid angiopathy (CAA) with decreased contact of astrocytic end-feet with the vasculature. Furtherthese morphological changes in the astrocyte were associated with decreased expression of aquaporin 4Kir4.1 and BK channels at the astrocytic end-feet. We have developed a model of VCID through the inductionof hyperhomocysteinemia (HHcy). We have shown that this model in wildtype mice is associated with multiplemicrohemorrhages reduced blood flow neuroinflammation and cognitive impairment. We now have intriguingpreliminary data that indicates these same pathological changes in the astrocytes that we observed with CAAalso occur in our HHcy model of VCID. In this research proposal we will use the HHcy model of VCID. We will test the hypothesis thatastrocyte end-foot disruption contributes to neuronal dysfunction and that the activation of MMP9 inthe HHcy model is critical to the disruption of the astrocytic end-feet. We have developed 3 specific aims.Aim 1. Test the hypothesis that astrocytic end-foot disruption leads to neuronal dysfunction and impairedpotassium homeostasis.Aim 2. Test the hypothesis that MMP9 is an essential mediator of astrocyte end-foot detachment from thecerebrovasculature with VCID.Aim 3. Test the hypothesis that astrocytic end-foot disruption is a common pathological characteristic ofcerebrovascular pathologies of VCID.

project_terms:
Alzheimer's Disease;Astrocytes;Autopsy;Basal lamina;Biochemical;Blood flow;Brain;Cerebral Amyloid Angiopathy;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrovascular system;Characteristics;Comorbidity;Data;Dementia;Diagnosis;Dystroglycan;Electrophysiology (science);Environment;Enzymes;Extracellular Matrix;Family;Functional disorder;Gene Expression;Glial Fibrillary Acidic Protein;Histologic;Homeostasis;Human;Hyperhomocysteinemia;Impaired cognition;Impairment;Inhibition of Matrix Metalloproteinases Pathway;Interleukin-1 beta;Knockout Mice;MMP9 gene;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measures;Mediator of activation protein;Methods;Modeling;Molecular;Morphology;Mus;Neuroglia;Neuronal Dysfunction;Neurons;Pathologic;Pathologic Processes;Pathology;Patients;Pharmacology;Pilot Projects;Potassium;Prevalence;Proteins;Research Proposals;Role;TNF gene;Testing;Time;Tissues;aquaporin 4;behavioral outcome;cerebrovascular pathology;foot;human tissue;large-conductance calcium-activated potassium channels;mouse model;neuroinflammation;neurovascular;protein expression;vascular cognitive impairment and dementia

public_health_relevance:
Project NarrativeVascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementiabehind Alzheimer's disease (AD) and frequently occurs as a co-morbidity with AD. Astrocytes are glial cellsthat are critical for both controlling blood flow in the brain and maintaining an optimal environment for theneurons to function properly. We will determine the involvement of astrocytes in the progression of VCID.


application_id: 9701278
project_number: 5R03HD095098-02
project_title: The Function of Progesterone Receptor in Human Ovulatory Follicles
administering_ic: NICHD
award_notice_date: 2019-05-07
opportunity_number: PA-16-162
application_type: 5
activity_code: R03
ic: HD
serial_number: 095098
program_official: TAYMANS, SUSAN
project_start_date: 2018-05-22
project_end_date: 2021-04-30
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract We seek to understand the mechanisms underlying ovulation and luteal formation in the human bydetermining the function of key ovulatory mediators progesterone (P4) and progesterone receptor (PGR) inhuman periovulatory follicles. The understanding of P4/PGR-mediated cellular events underlying ovulation andluteal formation has strong translational potential because P4 and its antagonists have been used ascontraceptives and the modulation of P4 levels is one of most common practices to aid or prevent femalefertility. The increase in P4 production and PGR expression in periovulatory follicles after the LH surge hasbeen found to be crucial for successful ovulation in many species. For instance Pgr knockout mice fail toovulate. The inhibition of P4 synthesis and PGR action blocked ovulation and/or luteal function in studies usingrodents sheep and non-human primates. However there are very few reports of PGR expression in thehuman ovary and virtually no experimental data on the mechanism(s) of P4/PGR's action in humanperiovulatory follicles. In the present proposal we hypothesize that PGR induced by the LH surge inperiovulatory follicles plays a crucial role in ovulation and/or luteal formation by regulating the expression ofkey ovulatory and/or luteal genes in women. To test this hypothesis we will utilize a unique in vivo model thatallows the collection of timed human periovulatory follicles from normally cycling women and a primary humangranulosa cell culture model in which the LH-induced increase in the expression of PGR and other keyovulatory genes in vivo can be mimicked in vitro. We proposed first to unveil potential downstream targetgenes of P4/PGR using a primary human granulosa cell culture model (Specific Aim #1). Secondly we willdetermine the expression pattern of PGR-downstream target genes in preovulatory follicles obtained before theLH surge periovulatory follicles obtained at defined hours after hCG administration and post-ovulatory folliclesfrom normally cycling women (Specific Aim #2). This study will be the first to document the comprehensiveexpression pattern of key and novel ovulatory genes in human periovulatory follicles during the ovulatoryperiod in vivo and identify P4/PGR-target genes to delineate the mechanisms by which P4/PGR mediates theovulatory process in humans.

project_terms:
AREG gene;Amphiregulin;Cell Culture Techniques;Cell model;Collection;Complex;Contraceptive Agents;Data;Development;Epiregulin;Event;Expression Profiling;Failure;Fertility;Genes;Gonadotropins;Hormones;Hour;Human;Human Chorionic Gonadotropin;Immunohistochemistry;In Situ Hybridization;In Vitro;Knockout Mice;Laboratories;Luteinization;Mediating;Mediator of activation protein;Mifepristone;Modeling;Ovarian;Ovary;Ovulation;PTGS2 gene;Pathologic;Pathway interactions;Pattern;Physiology;Play;Process;Production;Progesterone;Progesterone Receptors;Prostaglandin-Endoperoxide Synthase;Prostaglandins;RNA;Rattus;Reporting;Reproductive Health;Rodent;Role;Sheep;Small Interfering RNA;Testing;Time;Woman;corpus luteum;design;emergency contraception;female fertility;granulosa cell;in vitro Model;in vivo;in vivo Model;insight;next generation sequencing;nonhuman primate;novel;prevent;receptor;receptor expression;transcriptome sequencing;virtual

public_health_relevance:
NARRATIVE Successful ovulation and subsequent corpus luteum formation and development areessential for female fertility and the failure of these processes results in pathological conditionsin women. In the present proposal we will characterize for the first time the expression profile ofkey ovulatory genes in timed human periovulatory follicles and explore the mechanisms bywhich PGR coordinates the ovulatory process in women. Information derived from the presentproposal will provide novel insights into the mechanisms involved in ovulation and lutealformation in humans and can be applied for promoting and inhibiting the critical facet of ovarianphysiology thereby allowing us to better manage fertility in women.


application_id: 9701217
project_number: 5R01GM113087-05
project_title: Deciphering the molecular mechanisms underlying active scaffolding
administering_ic: NIGMS
award_notice_date: 2019-05-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 113087
program_official: KODURI, SAILAJA
project_start_date: 2015-08-01
project_end_date: 2021-05-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway plays an essential role in several critical steps of embryonic development and tumor progression. It also controls critical cellular functions such as apoptosis motility and differentiation. Kinases and phosphatases of this pathway have been extensively studied and targeted therapeutically. However the mechanisms that determine the signal specificity and orchestrate the diverse biological outcomes of ERK1/2 signaling are still poorly understood. Scaffold proteins are key players in the ERK1/2 signaling pathway that are thought to integrate incoming signals and deliver signaling specificity and yet their role in signal propagation and the mechanisms of their action are still unknown. The long-term goal of our research is to reveal how scaffold proteins are involved in the biological processes regulated by the ERK1/2 cascade. In this way new therapeutic strategies can be developed to more specifically target this cascade without affecting other essential biological functions.  The objective of this proposal is to determine the mechanisms underlying the ability of the key scaffold protein Shoc2 to regulate ERK1/2-mediated cell motility. Shoc2 is essential for embryonic development and a critical regulator of ERK1/2 activity. We have shown that depletion of Shoc2 in zebrafish results in defects in hematopoiesis. We also found that Shoc2 integrates endocytic and ubiquitin machineries to regulate ERK1/2 signaling. Based on this preliminary data the central hypothesis of this proposal is that Shoc2 creates a signaling hub that regulates ERK's developmental signals in a spatio-temporal manner.  Our hypothesis will be tested by pursuing three specific aims: Aim 1 will determine the spatio-temporal organization and dynamics of Shoc2 scaffold complexes. Aim 2 will reveal the molecular mechanism by which the E3 ligase HUWE1 controls Shoc2 function and assembly of the Shoc2 scaffold complexes. Aim 3 will determine the signaling events mediated through the Shoc2 scaffold complexes that control embryonic development. The proposed Aims therefore are expected to provide a detailed understanding of how Shoc2 is involved in determining the specificity of ERK1/2 signaling outcomes. These studies will employ state-of-the-art innovative microscopy genetic molecular and cellular techniques and will provide critical insights into our understanding of the spatial-temporal control of signaling by scaffold proteins. This research has significance for contributing to the advancement of novel therapeutic strategies and biomarker innovations for developmental disorders and cancer progression. Thus the proposed studies are relevant to the NIH's mission to increase understanding of biological processes and to lay the foundation for advances in disease diagnosis treatment and prevention.

project_terms:
Address;Affect;Apoptosis;Biochemical;Biological;Biological Markers;Biological Process;Blood;Cell Adhesion;Cell membrane;Cell model;Cell physiology;Cells;Cognitive deficits;Complex;Cultured Cells;Data;Defect;Development;Disease;Effectiveness;Embryo;Embryonic Development;Endocytosis;Endosomes;Ensure;Event;Face;Fluorescence Resonance Energy Transfer;Foundations;Genetic;Genetic Models;Goals;Growth;Heart Abnormalities;Hematopoiesis;Hematopoietic;Lead;Link;MAP Kinase Gene;MAPK3 gene;MEKs;Mediating;Microscopy;Mission;Modeling;Molecular;Mus;Mutation;Outcome;Pathology;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiological;Play;Prevention;Prognostic Marker;Protein Biochemistry;Proto-Oncogene Proteins c-raf;Ras/Raf;Regulation;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Spatial Distribution;Specificity;Study models;System;Techniques;Testing;Ubiquitin;Ubiquitination;United States National Institutes of Health;Work;Zebrafish;base;cell motility;cellular transduction;chromophore;developmental disease;disease diagnosis;imaging approach;imaging study;in vivo;innovation;insight;novel;novel therapeutic intervention;novel therapeutics;public health relevance;scaffold;spatiotemporal;targeted treatment;therapeutic development;transmission process;tumor;tumor progression;ubiquitin-protein ligase;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Deregulation of the MAPK signaling cascade is found in 30% of all tumors and multiple cardiac abnormalities and virtually every component of the cascade is target for therapeutic development. The effective targeting of this pathway in disease relies upon a clear understanding of all the intricacies in modulating numerous signaling components. Understanding the molecular mechanisms underlying the role of Shoc2 in MAPK signaling propagation potentially may lead to the development of specific prognostic markers and will enhance the effectiveness of targeted treatment.


application_id: 9701182
project_number: 5R01DK048498-24
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2019-06-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2020-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The mammalian intestinal mucosa undergoes a process of continual renewal characterized by active proliferation of stem cells localized near the base of the crypts; progression of these cells up the crypt-villus axis with cessation of proliferation; and subsequent differentiation into one of the four primary cell types (i.e. enterocytes goblet cells Paneth cells and enteroendocrine cells). An imbalance in this highly-regimented and orderly process within the crypts is associated with a number of common intestinal pathologies (e.g. colorectal cancer and inflammatory bowel disease [IBD]) which are associated with significant morbidity and mortality. Delineating the molecular factors regulating intestinal proliferation and differentiation is crucial to our understanding of not only normal gutdevelopment and adaptation but also aberrant gut growth. With the support of this grant we have shown the importance of the PI3K/Akt/mTOR pathway in the regulation of intestinal cell proliferation and differentiation. In addition we have shown the differential effects of various NFAT isoforms which integrate and cooperate with the PI3K/mTOR pathway to maintain intestinal homeostasis. As an extension to our published results our recent findings have demonstrated a novel metabolomic profile associated with intestinal cell differentiation and found that the ketogenic enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) and its product -hydroxybutyrate (HB) an endogenous inhibitor of histone deacetylases (HDACs) are increased with differentiation. In addition inhibition of mTOR Complex 1 (mTORC1) increases HMGCS2 expression in vitro and in vivo and moreover HB induces intestinal cell differentiation. Finally we have shown that HB increases the expression of the sirtuin proteins that contribute to intestinal cell differentiation; mTOR interacts with and regulates the expressio and deacetylase activity of the sirtuin proteins. Based on our recently published and preliminary findings we have further refined our central hypothesis to state that intestinal cell proliferatio and differentiation are regulated by PI3K/Akt/mTOR signaling pathway acting on critical downstream proteins (e.g. HMGCS2 and sirtuin proteins); a novel interaction between these pathways may exist that further adds to the intricate but highly regimented regulation of intestinal homeostasis. To examine our central hypothesis we have planned experiments with the following Specific Aims: 1) to delineate mTOR-mediated metabolic reprogramming in intestinal cell proliferation and differentiation; 2) to define the role of HMGCS2/HB in mediatin the effects of mTOR in the intestine; 3) to determine whether sirtuin proteins act cooperatively with HMGCS2/HB to maintain intestinal homeostasis. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Atrophic;Biochemistry;Biometry;Cell Differentiation process;Cell Proliferation;Cell model;Cells;Colorectal Cancer;Complex;Deacetylase;Development;Enterocytes;Enteroendocrine Cell;Enzymes;Event;Excision;FRAP1 gene;Glycolysis;Goals;Goblet Cells;Grant;Growth;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;In Vitro;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Ketone Bodies;Lead;Maintenance;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Mus;Operative Surgical Procedures;Organoids;Paneth Cells;Pathology;Pathway interactions;Phenotype;Play;Process;Protein Isoforms;Proteins;Publishing;Regulation;Role;Signal Pathway;Signal Transduction;Sirtuins;Stem cells;Stress;System;Testing;Time;Transgenic Mice;Tuberous sclerosis protein complex;Villus;base;beta-Hydroxybutyrate;cell type;clinically relevant;design;experimental study;in vivo;insight;intestinal homeostasis;ketogenesis;ketogentic;mTOR Signaling Pathway;mTOR inhibition;metabolomics;migration;mortality;mouse model;multidisciplinary;novel;novel therapeutic intervention;nuclear factors of activated T-cells;public health relevance;stable isotope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to this critical function are poorly understood. Our recent findings have identified novel roles for components of the mTOR/HMGCS2 and sirtuin signaling pathways in intestinal homeostasis. Delineating the cellular factors and signaling pathways regulating these processes is crucial to our understanding of not only normal gut development and maturation but also the effects of surgical resection and stress on intestinal adaptation and survival and the aberrant gut growth that can occur with deregulation of these normal processes.


application_id: 9700296
project_number: 3R01AG033649-09S1
project_title: A healthy brain aging strategy to restore insulin signaling and Ca homeostasis
administering_ic: NIA
award_notice_date: 2018-08-03
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: AG
serial_number: 033649
suffix: S1
program_official: WISE, BRADLEY C
project_start_date: 2018-08-15
project_end_date: 2019-07-31
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTPeripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility todementing neurodegenerative disorders such as Alzheimer's disease. However the pathways and mechanismsunderlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearlydefined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes whichmaintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well recognized mechanism contributing to neurologic dysfunction andcognitive decline and we and others have extensively characterized this dysfunction in brain structures importantfor learning and memory. Interestingly peripheral tissues that are insulin resistant also show calcium dysregulationand provide supporting evidence for a similar relationship in the brain.In the prior funding cycle we identified a previously unrecognized link between metabolic dysregulation and alteredcalcium signaling in hippocampal neurons. Together these findings provide support for the notion thatovercoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronalcalcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging.Specifically we will 1) utilize intranasal insulin delivery to increase insulin availability at the brain insulin receptor invivo 2) increase insulin receptor signaling in the brain via AAV-mediated expression of a constitutively activehuman insulin receptor mutant ( subunit) and 3) increase endogenous insulin receptor trafficking through the useof a novel pharmacologic strategy. Using these approaches in the F344 rat model of aging we will investigatecognitive functions using different behavioral paradigms. In hippocampal tissue from these animals we will usesingle cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependentpotentials and calcium imaging) and complement these studies with molecular/biochemical assays. To determinewhether increasing insulin in the brain affects other pathways independent of Ca2+ we will also quantify p-Aktsignaling tyrosine phosphorylation glucose homeostasis (glucose imaging) and adiponectin levels.Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 millionpeople and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed todetermine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helpsto maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and mayhave significant impact for the aging population especially for those at increased risk for neurodegenerativediseases such as Alzheimer's disease. This work is clinically-oriented and directly addresses one of the missions ofthe NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.

project_terms:
Accounting;Address;Affect;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Paradigm;Biochemical;Biological Assay;Brain;Calcium;Calcium Signaling;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical;Clinical Research;Complement;Dementia;Diabetes Mellitus;Disease;Dorsal;Elderly;Electrophysiology (science);Epidemic;Event;Exhibits;Formulation;Functional disorder;Funding;Gap Junctions;Glucose;Healthcare Systems;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Image;Imaging Techniques;Impaired cognition;Inbred F344 Rats;Insulin;Insulin Receptor;Insulin Resistance;Intervention;Kinetics;Learning;Ligands;Link;Measures;Mediating;Memory;Metabolic;Metabolic dysfunction;Mission;Modeling;Modification;Molecular;Neurodegenerative Disorders;Neurologic Dysfunctions;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Measure;Pathologic;Pathway interactions;Patients;Peripheral;Pharmacology;Physiological;Positioning Attribute;Predisposition;Process;Receptor Signaling;Regulation;Research;Risk;Role;Satiation;Signal Transduction;Slice;Structure;Synapses;Techniques;Testing;Time;Tissues;Tyrosine Phosphorylation;Viral;Visceral;Work;adeno-associated viral vector;adiponectin;age related;aged;aging brain;aging population;animal tissue;base;blood glucose regulation;clinical effect;clinically relevant;cognitive function;cognitive performance;cognitive process;design;feeding;improved;in vivo;innovation;insight;insulin sensitivity;insulin signaling;male;morris water maze;mutant;neuronal excitability;novel;novel therapeutics;pre-clinical research;receptor;response;sensory cortex;sigma-2 receptor;statistics;trafficking;treatment strategy

public_health_relevance:
PROJECT NARRATIVEOur work will test if the mechanism of insulin actions in the brain modulates calcium-related functions inside cells.We will focus on one area of the brain that is known for its role in memory function the hippocampus. We proposenew ways to increase insulin signals in the brain.


application_id: 9700234
project_number: 5R01NS092552-02
project_title: Contribution of adult neurogenesis to epileptogenesis and recovery after TBI
administering_ic: NINDS
award_notice_date: 2019-04-30
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 092552
program_official: CHURN, SEVERN BORDEN
project_start_date: 2018-06-01
project_end_date: 2023-05-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: SAATMAN, KATHRYN E
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMore than one million people are treated medically each year in the United States after sustaining a braininjury and traumatic brain injury (TBI) is often accompanied by the delayed development of posttraumaticepilepsy (PTE) for which there are few effective therapies. Although clinical association between TBI andepilepsy is well documented treatments designed to prevent PTE have been largely unsuccessful. Among themost promising antiepileptogenic treatments reported to date center on inhibition of the mammalian(mechanistic) target of rapamycin (mTOR) pathway. mTOR is activated after TBI and seizures and it's activityregulates a variety of cellular activities including growth and proliferation especially in developing neurons.Inhibiting mTOR activity has shown promise for altering the progression of epileptogenesis in rodent models ofepilepsy including PTE but several caveats have also been acknowledged specifically: Suppression ofmTOR post-TBI has been proposed to prevent epileptogenesis whereas mTOR activation has been proposedas a means of improving cognitive recovery after TBI in patients. The mechanisms by which mTORmodulation exerts its anti-epileptogenic effects are not known and the contribution of newborn neurons andsynaptic reorganization in the dentate gyrus to epileptogenesis and cognition are controversial. PreventingPTE is hampered by these fundamental knowledge gaps. This proposal will use the controlled cortical impact(CCI) model of TBI which results in cell loss increased neurogenesis and synaptic reorganization in thedentate gyrus and delayed development of spontaneous seizures (i.e. epileptogenesis) to study the impact ofnewborn neurons on synaptic excitability changes in the dentate gyrus. The effects of both negative andpositive regulation of mTOR on epileptogenesis and cognitive recovery will also be determined in the context ofneurogenesis after brain injury. The overarching hypotheses are that adult born neurons contribute to synapticreorganization after TBI and that mTOR activity-dependent regulation of neurogenesis alters epileptogenesisand post-TBI cognitive recovery. A combination of electrophysiological histological and behavioral techniquesutilizing optogenetic and chemogenetic modification of adult born neurons will be used to address three aims:1) Determine the functional synaptic organization of adult born DGCs after TBI; 2) Determine effects of mTORmodulation on neurogenesis and synaptic connectivity in the dentate gyrus after TBI; and 3) Determine howadult born DGCs contribute to functional recovery and seizures after TBI. A mechanistic understanding of howadult born neurons contribute to DGC circuitry and how mTOR modulation alters the circuitry of these neuronsafter CCI will be developed in the context of both cognitive recovery after TBI and development of PTE. Abetter understanding of the contribution of adult born neurons to recovery and epileptogenesis after TBI willfacilitate the development of treatments to prevent PTE.

project_terms:
Address;Adult;Affect;Antiepileptogenic;Behavior;Behavioral;Brain;Brain Injuries;Cells;Cessation of life;Clinical;Cognition;Coupled;Development;Disease;Disease Progression;Down-Regulation;Electrophysiology (science);Epilepsy;Epileptogenesis;FRAP1 gene;Growth;Hippocampus (Brain);Histologic;In Vitro;Injury;Knowledge;Medical;Modeling;Modification;Mus;Neurons;Newborn Infant;Outcome;Pathway interactions;Patients;Post-Traumatic Epilepsy;Recovery;Recovery of Function;Regulation;Reporting;Risk;Rodent Model;Role;Seizures;Sirolimus;Site;Structure;Synapses;Techniques;Temporal Lobe Epilepsy;Testing;Therapeutic;Time;Traumatic Brain Injury;Traumatic Brain Injury recovery;United States;Up-Regulation;adult neurogenesis;base;behavioral outcome;cognitive development;cognitive function;cognitive recovery;controlled cortical impact;dentate gyrus;effective therapy;experimental study;functional outcomes;granule cell;improved;mossy fiber;mouse model;neural network;neurogenesis;newborn neuron;optogenetics;prevent;therapeutic target;therapy design;therapy development

public_health_relevance:
Project Narrative.After brain injury synaptic reorganization specifically involving newborn neurons in the dentate gyrus may beinvolved in the development of posttraumatic epilepsy and the increase in adult neurogenesis after brain injuryis modulated by increasing or decreasing mTOR function. The function of adult born neurons after brain injuryis incompletely described hampering development of potential post-injury therapies based on mTORmodulation. Experiments in this proposal will examine how neurons born after brain injury integrate intohippocampal circuitry and contribute to post-injury recovery or pottraumatic epilepsy in order to better exploitthe promising mTOR therapeutic pathway to both improve recovery and prevent development of epilepsy afterbrain injury.


application_id: 9700062
project_number: 5R03AI135592-02
project_title: Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant Candidates
administering_ic: NIAID
award_notice_date: 2019-03-22
opportunity_number: PA-16-162
application_type: 5
activity_code: R03
ic: AI
serial_number: 135592
program_official: KEHN, PATRICIA J
project_start_date: 2018-05-18
project_end_date: 2020-12-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 7732443
contact_pi: MARTI, FRANCESC
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:
Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant CandidatesABSTRACTMore than two-thirds of adults in the United States are currently considered obese. The epidemic is particularlyacute in Kentucky (ranked fifth highest state in the US) as well as in Appalachian counties in adjacent statesthat make up the University of Kentucky Transplant Centers service area. In 2016 this center evaluated nearly1000 patients with end-stage renal disease (ESRD) of which 54.2% had a body mass index (BMI) equal orgreater than 30 Kg/m2 (obese status). Obesity is an increasingly common comorbidity in patients with chronicrenal diseases. In kidney transplant patients it has been associated with delayed graft function acute rejectionepisodes and graft loss. Acute cellular rejection occurs through immunologic mechanisms that include theadaptive immune response mediated by T cells. A growing body of evidence recognizes the balance betweengraft-reactive effector cells and graft-protective suppressor regulatory T cells (Tregs) as the ultimatedeterminant of long-term allograft survival. Our Transplant Center is developing a novel clinical protocol usingexpanded autologous Treg infusions to induce tolerance in renal transplant recipients with the ultimate goal ofenhancing long-term allograft function preventing rejection and reducing the overall toxicity of currentimmunosuppressive regimens. Circulating Treg cells are reduced in number and function in obese patients.Therefore the generation of sufficient numbers of clinically competent suppressive Treg cells from these obesepatients is especially challenging. In addition how the obese microenvironment may alter the functionalcompetency of adoptively transferred Treg is not known. In order to characterize the association betweenobesity-related parameters and the functional integrity of Tregs this study will (1) optimize the conditions ofprimary Treg cell expansion isolated from obese potential transplant recipients and (2) determine the tissuedistribution functional progress and lineage stability of adoptive transferred Tregs in obese recipients. Wehypothesize that the ex-vivo activation and expansion of obese Treg cells will overcome cell-intrinsicalterations and extrinsic pro-inflammatory signals associated with obesity. In Specific Aim 1 we will measurebaseline levels of Treg cells in peripheral blood from obese (BMI 35) and non-obese (BMI <25) ESRDpatients. We will also purify the Treg cells expand them ex-vivo and verify their cell phenotype expansionrates suppressor activity metabolic profile and linage stability. We will compare the data generated fromobese and non-obese patients and perform a multivariable logistic regression analysis with the parameterscollected to determine independent predictors of Treg cell expansion and function. In Specific Aim 2 we willuse a mouse model to evaluate in vivo the functional proficiency of adoptively transferred Treg cells into obeserecipients. The results will (1) characterize the population of Treg cells (baseline levels) (2) determine thefeasibility of expanding functionally competent and stable Treg cells from obese patients and (3) establish thein vivo influence of obese environment to the functional status of adoptively transferred Treg cells.

project_terms:
Acute;Address;Adoptive Cell Transfers;Adoptive Immunotherapy;Adoptive Transfer;Adult;Affect;Allografting;Appalachian Region;Area;Autologous;Blood;Body mass index;Cell Count;Cells;Cessation of life;Chronic Kidney Failure;Clinical;Clinical Data;Clinical Investigator;Clinical Protocols;Collaborations;Communities;Comorbidity;Competence;County;Data;Dependence;Development;Diet;Drug or chemical Tissue Distribution;Effector Cell;End stage renal failure;Energy-Generating Resources;Environment;Epidemic;Equilibrium;FOXP3 gene;Generations;Glycolysis;Goals;Graft Survival;Health Service Area;Immune;Immunologics;Immunology;Immunosuppressive Agents;Impairment;Incidence;Inflammatory;Infusion procedures;Insulin-Dependent Diabetes Mellitus;Kentucky;Kidney;Kidney Transplantation;Life;Logistic Regressions;Measures;Mediating;Mitochondria;Modeling;Morbidity - disease rate;Mouse Strains;Non obese;Obese Mice;Obesity;Ohio;Organ;Outcome;Overweight;Oxidative Phosphorylation;Patients;Perioperative complication;Pharmaceutical Preparations;Phenotype;Population;Proteins;Publishing;Quality of life;Regimen;Regression Analysis;Regulatory T-Lymphocyte;Reporting;Research;Risk Factors;Savings;Signal Transduction;Solid;Surveys;Survival Rate;T-Lymphocyte;Tennessee;Testing;Therapeutic;Toxic effect;Transplant Recipients;Transplantation;Transplantation Surgery;United States;Universities;Validation;Weight;West Virginia;adaptive immune response;allograft rejection;base;delayed graft function;dosage;functional status;improved;in vivo;metabolic profile;mortality;mouse model;multidisciplinary;novel;novel therapeutic intervention;perioperative mortality;peripheral blood;pre-clinical;prevent;programs;promoter;public health relevance;side effect;transplant centers

public_health_relevance:
Function and Stability of Expanded Regulatory T cells in Obese Renal Transplant CandidatesPROJECT NARRATIVEPUBLIC HEALTH RELEVANCE: This project will characterize the functional competency of Treg cellsin obese and develop the optimal conditions for the pre-clinical validation of expanded obese Tregs.


application_id: 9699185
project_number: 261201300013I-5-26100005-4
administering_ic: NCI
project_start_date: 2015-05-01
project_end_date: 2018-04-30
contact_pi_person_id: 15482999
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_title:
IGF::OT::IGF CORE INFRASTRUCTURE SUPPORT FOR SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PERIOD OF PERFORMANCE: 05/01/2015 TO 04/30/2018

project_abstract:
The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. The SEER Program has among its objectives: 1. To assemble and report on a periodic basis estimates of cancer incidence especially among the following key cancer sites: breast cancer lung cancer colorectal cancer prostate cancer pancreatic cancer and urinary bladder cancer. 2. To monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3. To provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 4. To identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 5. To serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as problems related to the operation of the SEER Program.

project_terms:
Cancer Burden;Cancer Control;Cancer Etiology;Cancer Patient;Colorectal Cancer;Diagnosis;Disease;Geography;Incidence;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Monitor;National Cancer Institute;National Cancer Program;Patients;Performance;Periodicity;Population;Reporting;Research Infrastructure;Resources;SEER Program;Social Characteristics;Subgroup;Time;Treatment-Related Cancer;United States;cancer risk;cancer site;cancer therapy;malignant breast neoplasm;operation;response;trend


application_id: 9698436
project_number: 5R21NS098170-02
project_title: HIF-1/p38 MAPK pathway in rotational acceleration-deceleration neonatal brain injury
administering_ic: NINDS
award_notice_date: 2019-04-30
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: NS
serial_number: 098170
program_official: AWWAD, HIBAH OMAR
project_start_date: 2018-05-15
project_end_date: 2021-10-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9256836
contact_pi: CAI, JUN
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Shaken baby syndrome (SBS) or shaken impact syndrome is a form of abusive head injury (AHT) inwhich a child is subjected to severe repetitive rotational acceleration-deceleration (RAD) forces without bluntimpact to the head. Approximately 25 percent of SBS victims die as a result of their injuries. Survivors maysuffer permanent physical neurological and mental disabilities. Little is known about the etiologypathophysiological implications and underlying mechanisms and preventive/therapeutic interventions arelacking. The preliminary findings in a neonatal mouse model of RAD injury (RADi) show that RADi in thedeveloping brain results in [global cerebral blood hypoperfusion] cerebral accumulation of hypoxia-induciblefactor-1 (HIF-1) and activation of its downstream target molecules such as [glucose transporter 1 (Glut 1)nuclear factor like 2 (Nrf2)] heme oxygenase-1 (HO-1) and aquaporin 4 (AQP4). [At the later stage HIF-1 issignificantly down-regulated with activation of p38 mitogen-activated protein kinase (MAPK) followed byneuronal degeneration and behavioral deficits. Surprisingly daily acute intermittent hypoxia (dAIH) post-conditioning intervention promotes accumulation of HIF-1 inhibition of p38 phosphorylation and recovery ofcognitive function in RADi mice.] To date knowledge of the HIF-1 signaling pathway in the central nervoussystem (CNS) is still limited and controversial. The precise role of HIF-1 signaling has never been explored inSBS and relevant animal models. In this proposal it is hypothesized that neuronal activation of HIF-1 signalingplays a [neuroprotective role via inhibiting p38 MAPK activation] following RADi in developing brains. Theprecise function of HIF-1 [and its effect on p38 MAPK signaling] will be identified in the neonatal RADi mousewith neuron-specific HIF-1 disruption or forced expression just induced before RADi. Furthermore [inter-regulation of HIF-1 and p38 MAPK as well as their therapeutic potentials will be investigated in sham andRADi mice administrated with vehicle solution prolyl-4-hydroxylase (PHD) inhibitor and p38 MAPK inhibitorrespectively.] Effects of HIF-1[/p38 MAPK pathways] on RADi brain will be assessed by quantifyingcardiorespiratory function brain water content gene expression neuronal degeneration and apoptosis[cerebral blood perfusion magnetic resonance spectroscopy] and behavior. These findings will likely elucidatethe underlying pathological mechanism(s) of RADi and functional deficits in SBS and suggest early-stageinterventions to treat SBS-related neurological and/or psychological sequelae.

project_terms:
Acceleration;Acute;Address;Animal Model;Apoptosis;Behavior;Behavioral;Blood;Brain;Brain Edema;Brain Injuries;Brain-Derived Neurotrophic Factor;Cerebral cortex;Cerebrum;Child;Cognition;Deceleration;Etiology;Gene Expression;HIF1A gene;Head;Hippocampus (Brain);Hypoxia;Hypoxia Inducible Factor;Injury;Intervention;Knowledge;Laboratory Diagnosis;MAPK14 gene;Magnetic Resonance Spectroscopy;Mediating;Mitogen-Activated Protein Kinase Inhibitor;Molecular Target;Mus;Natural regeneration;Neonatal;Neonatal Brain Injury;Nerve Degeneration;Neuraxis;Neurologic;Neuronal Hypoxia;Neuronal Plasticity;Neurons;Nuclear;Pathologic;Pathway interactions;Phosphorylation;Play;Preventive;Procollagen-Proline Dioxygenase;Property;Psyche structure;Regulation;Reporting;Role;Rotation;SB 203580;SLC2A1 gene;Shaken baby syndrome;Signal Pathway;Signal Transduction;Spinal cord injury;Survivors;Tamoxifen;Testing;Therapeutic;Therapeutic Intervention;Time;Traumatic Brain Injury;Up-Regulation;Water;aquaporin 4;blood perfusion;clinical application;cognitive function;cognitive recovery;conditioning;disability;experimental study;functional restoration;gain of function;heme oxygenase-1;hypoperfusion;hypoxia inducible factor 1;inhibitor/antagonist;mitogen-activated protein kinase p38;mouse model;nervous system disorder;neuron apoptosis;neuroprotection;novel;novel strategies;prevent;psychologic;relating to nervous system;therapeutic target

public_health_relevance:
Project Narrative Little is known about the etiology pathophysiological implications and the underlying mechanisms ofshaken baby syndrome (SBS). The precise laboratory diagnosis and preventive/therapeutic interventions arelacking. The proposed project will identify the [neuroprotective role] of HIF-1 signaling in the developing brainusing a novel neonatal mouse model of repetitive rotational acceleration-deceleration brain injury which mayreveal the pathological mechanism(s) of SBS and potential therapeutic target(s) to prevent functionalneurologic decline facilitate de novo regeneration and restore function (especially for cognition) followingbrain injury.


application_id: 9697907
project_number: 3R01ES027881-02S1
project_title: Air Pollution Circadian Rhythm Disruption and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2018-05-15
opportunity_number: PA-16-160
application_type: 3
activity_code: R01
ic: ES
serial_number: 027881
suffix: S1
program_official: SCHUG, THADDEUS
project_start_date: 2018-05-17
project_end_date: 2019-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
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:
AbstractExposure to ambient air pollution has been linked to annually 7 million premature deathsworldwide and 200000 in the US and the global burden of air pollution is likely to increase dueto increasing urbanization and industrialization. Extensive research has shown that exposure toparticulate air pollution and specifically fine particulates (PM2.5) increase the risk ofcardiovascular disease and diabetes. However despite this extensive evidence it is unclearhow PM2.5 exposure increases the cardiometabolic risk and which susceptible states increasethe sensitivity to vascular and cardiometabolic injury due to PM2.5 exposure. In our proposedstudies we attempt to disentangle the mechanism leading to the toxicity of PM2.5 by testing thenovel hypothesis that PM2.5 disrupts vascular circadian rhythms and that this contributes to thedevelopment of cardiometabolic disease in a new susceptibility state of circadian dyssynchrony.This hypothesis is supported by our preliminary data showing that that exposure to concentratedambient PM2.5 (CAP) alters the rhythmic expression of clock genes in the murine aorta andincreases insulin resistance in mice with the disturbed light/dark cycle (circadian dyssynchrony).As this models a real-world scenario in which individuals with disturbed light cycle (e.g. due tolight pollution sleep deprivation) are exposed to air pollution it is of high relevance to ourmodern urban 24 h lifestyle associated with air and light pollution and changes in sleepbehavior. Successful completion of this project will identify new targets of and novelsusceptibility states (circadian dyssynchrony and chronotoxicity) for PM2.5 toxicity. Results oftheses studies will be of significance in understanding the adverse health effects originated fromour modern lifestyle and could ultimately lead to the development of evidence-based guidelinesand policies to minimize the cardiometabolic effects of urbanization and pollutant exposure.

project_terms:
ARNTL gene;Aerosols;Affect;Air;Air Pollution;Animal Model;Aorta;Attenuated;Behavior;Biochemical Process;Biological;Biological Availability;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Characteristics;Circadian Rhythms;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Eating;Exposure to;Gene Expression;Genes;Goals;Health;Human;Individual;Industrialization;Injury;Insulin Resistance;Knockout Mice;Laboratories;Lead;Life Style;Light;Link;Lung;Mediating;Metabolism;Modeling;Modernization;Mus;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Oxidation-Reduction;Oxidative Stress;Particulate;Periodicity;Peripheral;Phase;Physiological Processes;Policies;Pollution;Post-Translational Protein Processing;Predisposition;Prevention strategy;Research;Sleep;Sleep Deprivation;System;Testing;Toxic effect;Transcriptional Regulation;Urbanization;Work;air filter;ambient air pollution;atherogenesis;base;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;chemical property;diabetes risk;epidemiologic data;evidence based guidelines;mortality;mouse model;novel;overexpression;particle;physical property;pollutant;premature;prevent;response

public_health_relevance:
NarrativeGoal of this project is to test the novel hypothesis that air pollution exposure a major healthconcern worldwide that increase the risk of cardiovascular disease and diabetes disruptsvascular circadian rhythms and that this exacerbates cardiometabolic injury in the newsusceptibility state of circadian dyssynchrony. Results of this project will be of significance inunderstanding and preventing the adverse health effects originated from air pollution exposure.


application_id: 9697856
project_number: 5R01HL130174-04
project_title: Metabolic optimization of cell therapy
administering_ic: NHLBI
award_notice_date: 2019-05-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 130174
program_official: SCHWARTZ, LISA
project_start_date: 2016-06-01
project_end_date: 2021-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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:
ABSTRACTType 2 diabetes is an independent risk factor for the development of heart failure. It contributes to adversecardiac remodeling and it increases heart failure mortality. While cell therapy offers promise for treating heartfailure in nondiabetic patients the efficacy of cell therapy in diabetic hearts remains uncertain. Our preliminarystudies show that diabetes impairs cardiac progenitor cell (CPC) growth survival and differentiation and thatCPCs isolated from diabetic hearts fail to promote myocardial recovery after myocardial infarction (MI). We findthat CPCs express Glut1 and that their rate of glucose utilization increases in the presence of high extracellularglucose independently of insulin. Moreover CPCs isolated from diabetic mice exhibit a marked and sustainedincrease in aerobic glycolysis accompanied by an elevated level of 6-phophofructo-2-kinase/fructose-26-bisphosphatase 3a phosphofructokinase 2 isoform known to sustain high rates of glycolysis. Our studiesalso show that increased glycolytic activity in diabetic CPCs is associated with lower glucose-derived carbonflux through the pentose phosphate and hexosamine biosynthetic pathways but higher flux through theglycerolipid biosynthetic pathway. These results indicate that high rates of glycolysis in CPCs alter the activityof ancillary pathways of glucose metabolism which are important for biosynthetic reactions maintaining redoxbalance and for resistance to stress. That such changes in glucose metabolism affect CPC function isindicated by our observation that increasing glycolysis at the PFK step is sufficient to decrease CPCproliferation in vitro. Informed by these observations we suspect that diabetic dysfunction in CPCs is at leastin part caused by a dysregulation of glucose metabolism and that correcting this metabolic defect will be aviable approach to optimize cell therapy for the diabetic heart. We propose to test the hypothesis that diabetesleads to an increase in the glycolytic activity in CPCs which diminishes flux through key ancillary pathways ofglucose metabolism. This metabolic dysregulation decreases CPC proliferation survival and secretory activityand impairs the capacity of CPCs to promote myocardial repair. To test this hypothesis we will: (1) examinehow diabetes affects CPC competence and therapy; (2) elucidate the role of glucose metabolism in mediatingCPC dysfunction in diabetes; and (3) determine whether rescuing defects in glucose metabolism improves celltherapy in the diabetic heart. Successful completion of the project will provide new understanding of themetabolic pathways that regulate stem/progenitor cell function and how they affect the outcomes of celltherapy for heart failure. These findings would facilitate the optimization of cell therapy protocols and informongoing and future cell therapy trials for the treatment of heart failure in both nondiabetic and diabetic patients.

project_terms:
6-Phosphofructo-2-kinase;Affect;Attenuated;Biochemical;Carbon;Cardiac;Cause of Death;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplantation;Cell Transplants;Cell physiology;Cells;Cicatrix;Clinical Treatment;Competence;Defect;Development;Diabetes Mellitus;Diabetic mouse;Enzymes;Equilibrium;Exhibits;Fatty acid glycerol esters;Fibrosis;Fructose-26-bisphosphatase;Functional disorder;Future;Glucose;Glycolysis;Heart;Heart failure;Hexosamines;Impairment;In Vitro;Inflammation;Injury;Insulin;Intervention;Measurement;Mediating;Metabolic;Metabolic Pathway;Modeling;Mus;Myocardial;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Oxidation-Reduction;Pathway interactions;Patients;Pentosephosphate Pathway;Pentosephosphates;Pharmacology;Phosphoric Monoester Hydrolases;Phosphotransferases;Property;Protein Isoforms;Protocols documentation;Radiolabeled;Reaction;Recovery;Resistance;Risk Factors;Role;Stem cell transplant;Stem cells;Stress;Testing;Tissues;Tracer;Transplantation;aerobic glycolysis;cardiogenesis;cell growth;cellular transduction;db/db mouse;diabetic;diabetic patient;extracellular;glucose metabolism;heart function;impaired capacity;improved;inhibitor/antagonist;metabolomics;mortality;non-diabetic;novel therapeutic intervention;repaired;stable isotope;stem

public_health_relevance:
PROJECT NARRATIVEHeart failure is a leading cause of death and is prominent in patients with diabetes. In this project we willexamine the mechanisms by which diabetes impairs cell therapy and how cell therapy can be improved toameliorate heart failure. These studies could lay the groundwork for the development of novel therapeuticinterventions to improve cardiac function in both nondiabetic and diabetic patients with heart failure.


application_id: 9697739
project_number: 5R03AG059107-02
project_title: Dementia and Physical Disablement Processes among Aging Latinos
administering_ic: NIA
award_notice_date: 2019-06-19
opportunity_number: PA-16-162
application_type: 5
activity_code: R03
ic: AG
serial_number: 059107
program_official: BANDIERA, FRANK
project_start_date: 2018-06-01
project_end_date: 2021-05-31
study_section: Social Sciences and Population Studies A Study Section[SSPA]
contact_pi_person_id: 11167033
contact_pi: ROTE, SUNSHINE MARIE
other_pis: Not Applicable
congressional_district: 03
department: NONE
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 SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Dementia and Physical Disablement Processes among Aging LatinosProject SummaryThe Latino population is rapidly aging and by 2050 will represent over 20% of the older adult population in theU.S. At the same time the burden of dementia in the older Latino population is expected to increase from around200000 cases in 2000 to as many as 1.3 million cases in 2050 with many more suffering from milder degreesof cognitive impairment. A further stress on the Latino and specifically Mexican-origin population is high povertyrates. Close to 27% of older Mexican Americans in the U.S. live below the poverty line which is over double therate for older adults in general (Administration for Community Living 2014). Disparities in dementia raise seriouspublic health concerns; yet there have been surprisingly few longitudinal studies on the role of dementia andcognitive impairment for physical disablement processes in the Mexican-origin population. Understanding howdementia shapes physical disablement pathways and identifying factors that slow down or speed up disablementwill lead to a better understanding at which point geriatric public health intervention is most needed. We proposeto employ a longitudinal cohort study of 3050 older Mexican-origin individuals the 1993/94-2016/17 HispanicEstablished Populations for the Epidemiologic Studies of the Elderly (H-EPESE). First we will use nine wavesof survey data to 1) describe the long-term patterns of dementia and cognitive impairment for a prospectivecohort of older Mexican Americans. Growth Mixture Modeling (GMM) is used for this part of the analysis. Thenwe will 2) estimate the role of dementia and cognitive impairment for changes in physical disablement processesover twenty years of study data. Finally we will 3) assess differences in dementia-related physical disablementwithin the group by gender socioeconomic status and sociocultural factors. The proposed research will lead toa better understanding of long-term health change for Mexican Americans in late life and an estimation of howmany Mexican Americans with dementia need support in late life. Ultimately our objective is to develop andevaluate a new empirical model to describe long-term patterns of dementia for physical disablement processesthat can be replicated with other segments of the aging population to determine the extent of need for specializedlong-term support services.

project_terms:
Acculturation;Activities of Daily Living;Affect;Age;Aging;Alzheimer's Disease;Area;Bathing;Caregivers;Cohort Studies;Communities;Cultural Backgrounds;Data;Dementia;Diagnosis;Eating;Elderly;Family;Gender;Gills;Growth;Health;Heterogeneity;Hispanics;Household;Immigration;Impaired cognition;Impairment;Individual;Intervention;Interview;Knowledge;Latino;Life Cycle Stages;Life Expectancy;Long-Term Care;Longitudinal Studies;Longitudinal cohort study;Maintenance;Mexican;Mexican Americans;Modeling;Nature;Pathway interactions;Patient Self-Report;Patients;Pattern;Performance;Physical shape;Physically Handicapped;Policies;Population;Population Intervention;Poverty;Prevalence;Process;Prospective cohort;Public Health;Recording of previous events;Research;Research Design;Role;Self Care;Services;Socioeconomic Status;Source;Speed;Sterile coverings;Stress;Subgroup;Surveys;Symptoms;Theoretical model;Time;Transportation;aging population;base;care costs;care systems;cognitive ability;cognitive disability;community living;dementia care;dementia risk;disability;epidemiology study;ethnic disparity;experience;high risk;human old age (65+);innovation;instrumental activity of daily living;mental state;middle age;migration;novel;programs;public health intervention;sociodemographics;socioeconomics

public_health_relevance:
Project NarrativeCurrently little is known about the nature of dementia-specific physical disablement processes for the rapidlygrowing and rapidly aging Mexican American population. We propose to utilize data from a cohort study ofMexican Americans and develop an innovative research design to examine heterogeneity in physicaldisablement processes and the role of dementia as these disablement processes unfold. The proposed studywill advance knowledge of dementia-related physical disablement in the aging Latino population in the U.S. andhighlight segments of this population that would greatly benefit from effective policy and program initiatives.


application_id: 9697686
project_number: 5F31AG055233-03
administering_ic: NIA
award_notice_date: 2019-04-25
opportunity_number: PA-16-309
application_type: 5
activity_code: F31
ic: AG
serial_number: 055233
program_official: NIELSEN, LISBETH
project_start_date: 2017-05-14
project_end_date: 2020-05-13
study_section: Special Emphasis Panel[ZRG1-F16-L(20)L]
contact_pi_person_id: 14276080
contact_pi: OLTMANNS, JOSHUA R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-14
project_title:
A longitudinal investigation of maladaptive personality traits asreported by the self and others in the prediction of physical health

project_abstract:
Compared to traditional DSM personality disorder (PD) diagnostic categories dimensional representations ofPD provide a more comprehensive framework from which to understand and conceptualize maladaptivepersonality functioning (Clark 2007; Widiger & Trull 2007) consistent with the RDoC emphasis ondimensional models relative to traditional DSM syndromes. The five-factor model (FFM) of personality is widelyregarded as the leading dimensional model of personality and is supported by an extensive amount ofempirical support spanning over 30 years. The FFM consists of 30 lower-order facet scales (as conceptualizedby McCrae and Costa 2003) from which both high and low levels can be used to describe PD. FFMdescriptions of PD have been shown to account for the variance of all ten categorical DSM PD types (Livesley2001; Miller 2012). In addition personality science has demonstrated that "normal" range domains and facetsof the FFM significantly predict disease and mortality (Dixon-Gordon Whalen Layden & Chapman 2015;Friedman & Kern 2014; Smith & Mackenzie 2006). However symptoms of personality disorder have evenlarger associations with health outcomes (Gleason Weinstein Balsis & Oltmanns 2014). Recently FFM-based dimensional measures of PD have been developed (Widiger Lynam Miller & Oltmanns 2012)providing an exciting opportunity to measure PD within the comprehensive framework of the FFM. The presentline of research will incorporate this novel analytic and conceptual approach into an ongoing longitudinal studyof a representative sample of 1630 older adults in the St. Louis area. FFM-PD measures of neuroticismconscientiousness and extraversion (the Five-Factor Borderline Obsessive-Compulsive and AvoidantInventories respectively) which are most frequently associated with health (Smith Williams & Segerstrom2015) will be employed. Structural Equation Modeling will be used to compare the predictive and incrementalvalidity of FFM PD measures with and over DSM PD measures and normal personality measures in thelongitudinal prediction of self- and informant-reported general health status major disease (including cancerdiabetes and lung and heart disease) biological markers of stress and inflammation (e.g. cortisol interleukin-6 tumor necrosis factor- and C reactive protein) and mortality. The dimensional FFM PD measurementperspective will provide incremental validity over traditional measures of PD and normal personality measuresin the prediction of these both subjective and objective measures of health. Results will be imperative todeveloping a comprehensive framework for understanding the longitudinal relationship between maladaptivePD traits and risk of physical disease and mortality in older adults. This proposal will provide the PI with theopportunity to unite two cutting-edge personality research laboratories while advancing knowledge about therelationship between personality and health and developing research skills and clinical training that willfacilitate the goal of conducting and disseminating personality research as an academic professor.

project_terms:
Area;Biological Markers;Borderline Personality Disorder;C-reactive protein;Categories;Classification;Clinical;Clinical Treatment;Development;Diabetes Mellitus;Diagnostic;Dimensions;Disease;Elderly;Equation;Equipment and supply inventories;Evaluation;Goals;Health;Health Services;Health Status;Health behavior;Heart Diseases;Hydrocortisone;Individual;Inflammation;Interleukin-6;Intervention;Investigation;Knowledge;Laboratory Research;Link;Literature;Longevity;Longitudinal Studies;Lung diseases;Malignant Neoplasms;Measurement;Measures;Methodology;Methods;Modeling;Neurotic Disorders;Normal Range;Obsessive compulsive behavior;Obsessive-Compulsive Personality;Outcome;Patient Self-Report;Personality;Personality Assessment;Personality Disorders;Personality Traits;Prevention;Process;Property;Psychometrics;Reporting;Research;Research Domain Criteria;Risk;Sampling;Science;Stress;Structure;Symptoms;Syndrome;System;TNF gene;Testing;Time;Training;Variant;base;immune function;informant;longitudinal dataset;mortality;novel;physical conditioning;professor;service providers;skills;stress reactivity;tool;trait

public_health_relevance:
The present study examines the usefulness of a dimensional model of maladaptive personality traits incomparison to DSM personality disorder types for the prediction of important subjectively and objectivelymeasured health outcomes (such as physical disease stress reactivity health functioning and mortality) in anongoing longitudinal study of a representative sample of older adults in St. Louis. The goal of the project is todevelop scientific understanding of the relationships between maladaptive personality traits and health acrosstime. Implications of the present research include providing a more comprehensive knowledge of theconnection between personality and health testing the utility of a dimensional model of personality disorderand ultimately informing recent developing clinical treatments of maladaptive personality traits that couldpotentially reduce the long-term risk of deleterious health problems for many individuals.


application_id: 9696365
project_number: 5R01DK108056-04
project_title: Inflammation in human obesity and type 2 diabetes
administering_ic: NIDDK
award_notice_date: 2019-03-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 108056
program_official: ABRAHAM, KRISTIN M
project_start_date: 2018-04-01
project_end_date: 2021-03-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: LAUFFENBURGER, DOUGLAS A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammation is generally required for the development of insulin resistance in obese animals consistent with demonstrations that inflammation predisposes obese people to be metabolically unhealthy. In contrast obese people with negligible inflammation are often metabolically healthy. The role of inflammation as an accelerator of obesity-associated metabolic decline indicates that an inflammatory signature can predict the transition from obese/metabolically healthy to obese/insulin resistant/type 2 diabetes (T2D). Our proposed work will comprehensively define inflammatory signature(s) during T2D etiology and pathogenesis to fill critical gaps in 1. Identifying people most likely to transition to T2D in response to obesity; 2. Pinpointing treatments to new targets thus improve the currently modest efficacy of anti-inflammatory drugs in T2D; and 3. Using targeted therapies to uncouple obesity from inflammatory-mediated complications such as T2D and cardiovascular disease. We have used a multivariate mathematical approach to identify a previously unappreciated inflammatory signature that differentiates obese/non-T2D obese/pre-T2D and obese/T2D subjects. This signature includes multiple T cell cytokines many of which are preferentially produced by the Th17 or Th1 T cell subsets. Our identification of a human T cell inflammatory signature coupled with the proposed extention of the analyses to additional putative sources of "diabetogenic" inflammation provide unique opportunities to address important outstanding questions in the relationship between inflammation and T2D pathogenesis. We will test the hypothesis that a T cell signature that distinguishes T2D from non-T2D subjects is a predictive biomarker for T2D pathogenesis through a longitudinal multiple-PI project involving experts in human immunometabolism cytokine network modeling and clinical research in obesity. The possibility that a cytokine signature validated by the proposed work will identify people who require more intensive monitoring intervention or new anti-inflammatory drugs to delay or prevent obesity-associated T2D has tremendous potential to change clinical practice emphasizing both the impact and the urgency of the project.

project_terms:
Address;Affect;Agreement;Animals;Anti-inflammatory;Biological Markers;Blood;Boston;Cardiovascular Diseases;Categories;Cell physiology;Cells;Chronic;Clinic;Clinical;Clinical Research;Clinical Trials;Coupled;Cytokine Network Pathway;Development;Disease;Etiology;Future;Genes;Health;Human;Immune;Individual;Inflammation;Inflammatory;Insulin Resistance;Intervention;Logistic Regressions;Measures;Mediating;Medical center;Metabolic;Minority;Modeling;Modification;Monitor;Mus;Myeloid Cells;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Pathogenesis;Pathogenicity;Pharmaceutical Preparations;Plasma;Play;Population;Positioning Attribute;Prediabetes syndrome;Regression Analysis;Research;Role;Route;Sampling;Source;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Thinness;Time;Validation;Work;clinical practice;cytokine;diabetogenic;follow-up;glycemic control;improved;longitudinal analysis;mathematical methods;monocyte;network models;predictive marker;predictive signature;prevent;public health relevance;recruit;response;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The role of inflammation in the development and prediction of type 2 diabetes (T2D) is an important outstanding question in the clinics. We will take advantage of samples from our minority-rich clinical population to define and validate inflammatory networks critical for T2D development and longitudinal analyses will add predictive power. Identification of key inflammatory networks in human T2D will pave the way for more effective use of anti-inflammatory treatments to treat or delay T2D.


application_id: 9696165
project_number: 3R01AG027297-10S1
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2018-06-08
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: AG
serial_number: 027297
suffix: S1
program_official: WISE, BRADLEY C
project_start_date: 2006-09-01
project_end_date: 2018-07-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The experiments in this project use innovative gene delivery techniques and a multipronged approach to assess the fundamental role of astrocyte activation in neurologic function in an intact mouse model of Alzheimer's disease (AD). Studies use adeno-associated virus vectors (AAV) bearing the astrocyte-specific promoter Gfa2 to target the protein phosphatase calcineurin (CN) and NFAT transcription factors in astrocytes of wild-type and APP/PS1 mice. AAV-Gfa2 vectors are bilaterally delivered to the hippocampus at different ages/disease stages and mice are assessed on different AD biomarkers. In Aim 1 cognitive status is assessed using the active avoidance task while synaptic function is evaluated using hippocampal slice electrophysiology and Western blot measures of synaptic proteins. In Aim 2 hippocampal glutamate regulation is investigated using ceramic enzyme-based microelectrode arrays and measures of glutamate transporter levels. In Aim 3 levels of glial activation and neuroinflammation are determined with immunohistochemical (IHC) analyses and assessment of cytokine levels using Multiplex ELISAs. In Aim 4 IHC is used to determine the extent of A deposition while ELISAs are used to quantify levels of A40 and A42 in soluble and insoluble hippocampal tissue fractions and Westerns used to assess BACE protein expression. AAV-Gfa2 vectors encode either potent inhibitors or activators of CN/NFAT signaling and therefore will determine the necessity and sufficiency of this astrocytic pathway in driving and/or maintaining neurologic dysfunction in AD mice. These studies provide a highly novel approach to the study of activated astrocytes and could have a major impact on the development of treatment strategies for AD and other neurodegenerative conditions.

project_terms:
APP-PS1;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Animals;Astrocytes;Automobile Driving;Avoidance Learning;Behavior;Behavioral;Bilateral;Biochemical Process;Biological Assay;Biological Markers;Brain;Brain Diseases;Calcineurin;Cells;Ceramics;Cognitive;Data;Dependence;Dependovirus;Deposition;Disease;Electrodes;Electrophysiology (science);Enzyme-Linked Immunosorbent Assay;Enzymes;Funding;Gene Delivery;Glial Fibrillary Acidic Protein;Glutamate Receptor;Glutamate Transporter;Glutamates;Hippocampus (Brain);Human;Hypertrophy;Impaired cognition;Impairment;Implant;In Vitro;Inflammatory;Ipsilateral;Label;Measurement;Measures;Methods;Microelectrodes;Microglia;Mus;NFAT Pathway;Nerve Degeneration;Nervous System Physiology;Neurodegenerative Disorders;Neurologic Dysfunctions;Outcome Measure;Pathologic;Pathology;Pathway interactions;Phenotype;Process;Production;Protein phosphatase;Proteins;Reaction;Regulation;Resolution;Rodent Model;Role;Signal Transduction;Slice;Synapses;Synaptic plasticity;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Mice;Transgenic Organisms;Western Blotting;Wild Type Mouse;abeta deposition;adeno-associated viral vector;aging brain;amyloid pathology;astrogliosis;base;beta-site APP cleaving enzyme 1;calcineurin phosphatase;cytokine;experimental study;functional outcomes;glial activation;glutamatergic signaling;improved;in vivo;inhibitor/antagonist;innovation;interest;mouse model;multi-electrode arrays;neuroinflammation;neuropathology;neuroprotection;novel strategies;prevent;promoter;protein expression;relating to nervous system;response;synaptic function;therapy development;transcription factor;treatment strategy;vector

public_health_relevance:
Increasing evidence implicates activated astrocytes in a variety of neurodegenerative conditions including Alzheimer's disease (AD). However these cells are difficult to target selectively with therapeutics. In this project we use cutting-edge adeno associated virus vectors to selectively prevent astrocyte activation and improve neurologic function in intact AD model mice. This approach could emerge as a new treatment strategy for AD and other neurodegenerative disorders.


application_id: 9695971
project_number: 5R01CA207538-03
project_title: Addressing ELSI Issues in Unregulated Health Research Using Mobile Devices
administering_ic: NCI
award_notice_date: 2019-04-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 207538
program_official: CAGA-ANAN, EMILIE CHARLISSE F
project_start_date: 2017-05-04
project_end_date: 2021-04-30
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: WILBANKS, JOHN
congressional_district: 03
department: SOCIAL SCIENCES
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 SUMMARYHealth research using mobile devices such as smartphones and tablets is becoming more common. Newhardware and software can transform a mobile device into a sophisticated data collection and analyticalplatform. These technologies are fundamentally changing health research because the recruitment datacollection and data sharing are conducted online without any face-to-face interaction between researchers andresearch participants.Increasingly this research also is being conducted by researchers who do not receive any federal funding andare not subject to the Common Rule the FDA research regulations and the HIPAA Privacy Rule. Yetunregulated health research using mobile devices raises numerous important ethical issues including externalreview recruitment inclusion and exclusion criteria informed consent privacy and security incidental findingsand data sharing.This project has the following three aims:Aim 1: Conduct in-depth qualitative interviews to elicit thought leaders' perspectives on the risks andappropriate protections for participants in unregulated health research using mobile devices.Aim 2: Develop a detailed analysis of the ELSI issues through a series of 4 meetings by a diverseexpert working group and use a consensus-building methodology to develop recommendations.Aim 3: Devise and implement educational programs and translation of the consensusrecommendations. Sub-aim 3-1: Because app developers play a key role in mobile health innovations we will hold 2 workshops exclusively for app developers on ethical issues in designing mobile health apps with video highlights posted on the internet. Sub-aim 3-2: We will hold a conference in Washington DC on policy issues of interest to the NIH FDA OHRP FTC Congressional staffs state governments professional organizations researchers IRBs patient groups and other stakeholders. Sub-aim 3-3: Members of the working group will draft 20 articles containing consensus policy recommendations for publication in a special symposium issue of the Journal of Law Medicine &Ethics. Sub-aim 3-4: We will present our findings and recommendations at meetings of consumers professionals and policy makers.

project_terms:
Address;Categories;Cellular Phone;Child;Computer software;Consensus;Data;Data Analytics;Data Collection;Educational workshop;Ensure;Ethical Issues;Ethics;Exclusion Criteria;Funding;Government Agencies;Grant;Health;Health Insurance Portability and Accountability Act;Health Technology;Incidental Findings;Informed Consent;Institutional Review Boards;Internet;Interview;Journals;Laws;Measures;Medicine;Methodology;Mobile Health Application;Nonprofit Organizations;Participant;Patients;Play;Policies;Policy Maker;Precision Medicine Initiative;Privacy;Professional Organizations;Publications;Recommendation;Regulation;Research;Research Ethics;Research Personnel;Risk;Security;Series;State Government;Tablets;Technology;Translations;United States National Institutes of Health;Washington;cancer care;citizen science;common rule;data sharing;design;handheld mobile device;inclusion criteria;innovation;interest;mHealth;meetings;member;novel;patient advocacy group;programs;recruit;symposium;welfare;working group

public_health_relevance:
PROJECT NARRATIVEHealth research using mobile devices such as smartphones and tablets is becoming increasingly common.Because some of this research is not subject to the federal research regulations it raises novel ethical andpolicy issues such as independent review informed consent and privacy. The proposed study will developand disseminate recommendations for the ethical conduct of this emerging research.


application_id: 9694520
project_number: 5F32DE027277-03
project_title: Retinoic Acid Signaling in Salivary Gland Organogenesis
administering_ic: NIDCR
award_notice_date: 2019-05-15
opportunity_number: PA-16-307
application_type: 5
activity_code: F32
ic: DE
serial_number: 027277
program_official: FRIEDEN, LESLIE A
project_start_date: 2017-07-01
project_end_date: 2020-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11005944
contact_pi: METZLER, MELISSA A
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:
AbstractUnderstanding how an embryo builds an organ during development is essential to inform studies intoregenerating tissue in vitro. There is currently a clinical need to regenerate salivary glands for patients whohave suffered permanent gland damage due to radiation therapy or autoimmune disease. The resulting chronicxerostomia (dry mouth) leads to a sharp decline in oral health and quality of life. The ability to constructfunctioning gland for these patients would restore saliva to the oral cavity which includes many beneficialcomponents involved in functions such as antimicrobial protection pH balance digestion lubrication andremineralization. Many current studies in salivary gland development have elucidated the signaling molecules necessaryfor several important processes such as branching morphogenesis lumen formation cell differentiation andprogenitor cell maintenance. Studies in the field have also shown that early salivary gland development isdependent on both the epithelium and enervation from the closely associated parasympathetic ganglion (PSG).However very little is known about the earliest stages of gland development and no studies have been doneon the signaling molecules needed to control salivary gland initiation or PSG formation. The gap in knowledgeis likely due to the lack of experimental models for the earliest phases of gland organogenesis. In preparation for this proposal I have established a novel ex vivo culture system utilizing mouseembryo tissues to assay salivary gland initiation. This is an important development for the field in that it allowsresearchers to answer questions they could not before. With this system I have generated preliminary datashowing that RA signaling is required for submandibular gland (SMG) initiation and development of theparasympathetic ganglion (PSG). Blocking RA signaling represses gland bud initiation and converselysupplementation with retinol (vitamin A) enhances initiation. Moreover I have identified that the size of theinitial PSG is reduced with a fewer number of cells when RA signaling is blocked. In this proposal I willinvestigate the role of vitamin A metabolism by the retinol oxidizing enzyme RDH10 in initiation of the SMGepithelium and the role of RA signaling on PSG formation.

project_terms:
All-Trans-Retinol;Alleles;Autoimmune Diseases;Biological Assay;Biomedical Research;Cell Differentiation process;Cell Maintenance;Cells;Chemicals;Chronic;Clinical;Communication;Data;Development;Digestion;Embryo;Embryonic Development;Enzymes;Epithelial;Epithelium;Equilibrium;Experimental Models;Future;Gene Expression;Genes;Gland;Growth;In Vitro;Investigation;Kidney;Knock-out;Knowledge;LacZ Genes;Ligands;Lubrication;Lung;Mandible;Mediating;Metabolism;Monitor;Morphogenesis;Mus;Natural regeneration;Nerve;Neural Crest;Neurons;Nuclear Family;Nuclear Receptors;Oral cavity;Oral health;Organ;Organogenesis;Oxides;Pancreas;Patients;Phase;Physical condensation;Preparation;Process;Production;Quality of life;Radiation therapy;Reaction;Reporter;Research;Research Personnel;Retinoic Acid Receptor;Retinol Metabolism Pathway;Role;Saliva;Salivary;Salivary Glands;Schwann Cells;Signal Transduction;Signaling Molecule;Stem cells;Structure of parasympathetic ganglion;Submandibular gland;Supplementation;Surface;System;Testing;Tissues;Training;Transgenic Organisms;Tretinoin;Vitamin A;Xerostomia;antimicrobial;career;chorda tympani;embryo tissue;experience;gland development;hindbrain;in vitro Assay;inhibitor/antagonist;innovation;migration;neuron development;neuronal survival;novel;oxidation;remineralization;salivary assay

public_health_relevance:
Project NarrativeUnderstanding how an embryo builds an organ during development is essential to inform studies intoregenerating tissue in vitro. I have developed a novel assay for submandibular salivary gland initiation andearly formation of the associated parasympathetic ganglion two previously unstudied stages in salivary glanddevelopment. Using this assay I will investigate the essential role of vitamin A metabolism and retinoic acidsignaling in these processes.


application_id: 9692496
project_number: 5R01AG033649-10
project_title: A healthy brain aging strategy to restore insulin signaling and Ca homeostasis
administering_ic: NIA
award_notice_date: 2019-04-03
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: WISE, BRADLEY C
project_start_date: 2009-04-01
project_end_date: 2021-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
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):    Peripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility to dementing neurodegenerative disorders such as Alzheimer's disease. However the pathways and mechanisms underlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearly defined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes which maintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well-recognized mechanism contributing to neurologic dysfunction and cognitive decline and we and others have extensively characterized this dysfunction in brain structures important for learning and memory. Interestingly peripheral tissues that are insulin resistant also show calcium dysregulation and provide supporting evidence for a similar relationship in the brain. In the prior funding cycle weidentified a previously unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Together these findings provide support for the notion that overcoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronal calcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging. Specifically we will 1) utilize intranasal insulin delivery to increas insulin availability at the brain insulin receptor in vivo 2) increase insulin receptor signaling n the brain via AAV-mediated expression of a constitutively active human insulin receptor mutant ( subunit) and 3) increase endogenous insulin receptor trafficking through the use of a novel pharmacologic strategy. Using these approaches in the F344 rat model of aging we will investigate cognitive functions using different behavioral paradigms. In hippocampal tissue from these animals we will use single cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependent potentials and calcium imaging) and complement these studies with molecular/biochemical assays. To determine whether increasing insulin in the brain affects other pathways independent of Ca2+ we will also quantify p-Akt signaling tyrosine phosphorylation glucose homeostasis (glucose imaging) and adiponectin levels. Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed to determine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helps to maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and may have significant impact for the aging population especially for those at increased risk for neurodegenerative diseases such as Alzheimer's disease. This work is clinically-oriented and directly addresses one of the missions of the NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.

project_terms:
Accounting;Address;Affect;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Paradigm;Biochemical;Biological;Biological Assay;Brain;Calcium;Calcium Signaling;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical;Clinical Research;Complement;Dementia;Diabetes Mellitus;Disease;Dorsal;Elderly;Electrophysiology (science);Epidemic;Event;Exhibits;Formulation;Functional disorder;Funding;Gap Junctions;Glucose;Healthcare Systems;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Image;Imaging Techniques;Impaired cognition;Inbred F344 Rats;Insulin;Insulin Receptor;Insulin Resistance;Intervention;Kinetics;Learning;Ligands;Link;Measures;Mediating;Memory;Metabolic;Metabolic dysfunction;Mission;Modeling;Modification;Molecular;Neurodegenerative Disorders;Neurologic Dysfunctions;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Measure;Pathologic;Pathway interactions;Patients;Peripheral;Pharmacology;Physiological;Positioning Attribute;Predisposition;Process;Receptor Signaling;Regulation;Research;Risk;Role;Satiation;Signal Transduction;Slice;Structure;Synapses;Techniques;Testing;Time;Tissues;Tyrosine Phosphorylation;Viral;Visceral;Work;adeno-associated viral vector;adiponectin;age related;aged;aging brain;aging population;animal tissue;base;blood glucose regulation;clinical effect;clinically relevant;cognitive function;cognitive performance;cognitive process;design;feeding;improved;in vivo;innovation;insight;insulin sensitivity;insulin signaling;male;morris water maze;mutant;neuronal excitability;novel;novel therapeutics;pre-clinical research;public health relevance;receptor;response;sensory cortex;sigma-2 receptor;statistics;trafficking;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    Our work will test if the mechanism of insulin actions in the brain modulates calcium-related functions inside cells. We will focus on one area of the brain that is known for its role in memoryfunction the hippocampus. We propose new ways to increase insulin signals in the brain.


application_id: 9691971
project_number: 5R01HL122676-05
project_title: Cardiovascular Toxicity of Tobacco Products and Constituents
administering_ic: NHLBI
award_notice_date: 2019-04-30
opportunity_number: RFA-OD-13-011
application_type: 5
activity_code: R01
ic: HL
serial_number: 122676
program_official: ITURRIAGA, ERIN
project_start_date: 2015-07-01
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZRG1-AARR-J(56)R]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
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): Cardiovascular Toxicity of Tobacco Products The Family Smoking Prevention and Tobacco Control Act grants the FDA the authority to regulate tobacco products to protect public health. However to set standards for tobacco products it is important to know which components of conventional new and emerging tobacco products induce cardiovascular injury so as to provide toxicity thresholds for harmful and potentially harmful constituents (HPHC) in tobacco products. However to identify HPHC toxicity it is important to determine how this toxicity could be identified and associated with disease risk and what assays best compare the toxic properties of different tobacco products. Although for toxicological profiling a high-throughput in vitro method is preferable CVD is a complex disease that develops from the dysfunction of several organ systems. Therefore the cardiovascular toxicity of tobacco products cannot be estimated in simple in vitro systems. Hence we will use an animal model and determine the relative toxicity of major HPHCs in cigarette smoke and electronic cigarette aerosol determine the toxicity profile of individual HPHCs specifically aldehydes and assess how the toxicity of an individual HPHC is modified by other HPHCs and nicotine. To validate this toxicity profile in humans we will examine the relationship between exposure to different HPHCs and cardiovascular toxicity in a well-characterized cohort. Successful completion of this project will lead to quantitative and rigorous evaluation of the cardiovascular toxicity of the major HPHCs in tobacco products and to the validation of an association between exposure to individual HPHCs and cardiovascular toxicity in humans. These findings will provide new information regarding the contribution of individual aldehydes in HPHC mixtures to the cardiovascular toxicity of tobacco smoke and as such will be useful in developing informed threshold limits and the policies needed to regulate HPHC levels in cigarettes electronic cigarettes smokeless tobacco as well as in other emerging tobacco-derived products.

project_terms:
Acetaldehyde;Acrolein;Address;Adult;Aerosols;Affect;Aldehydes;Animal Model;Animals;Biological Assay;Biological Markers;C57BL/6 Mouse;Cardiovascular Diseases;Cardiovascular system;Chronic Disease;Cigarette;Complex;Complex Mixtures;Cotinine;Creatinine;Data;Disease;Dose;Dyslipidemias;Electronic cigarette;Evaluation;Exposure to;Family Smoking Prevention and Tobacco Control Act;Female;Formaldehyde;Functional disorder;Future;Grant;Guidelines;Human;In Vitro;Individual;Injury;Insulin Resistance;Knowledge;Lead;Lipids;Measures;Mediating;Metabolism;Methods;Modification;Mus;Nicotine;Plasma;Policies;Property;Public Health;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoker;Smoking;System;Thrombosis;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Toxicology;Validation;Variant;authority;body system;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;cohort;disorder risk;environmental tobacco smoke exposure;experimental study;male;non-smoker;preventable death;primary endpoint;primary outcome;public health relevance;response;secondary endpoint;secondary outcome;smokeless tobacco use;tobacco exposure;tobacco products;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular Toxicity of Tobacco Products Project Narrative Although the rates of smoking have declined in the recent past nearly 1 billion people continue to smoke and cigarette smoking remains the most important cause of preventable deaths worldwide. Smoking and the use of tobacco products are associated with increased risk of developing multiple chronic diseases; however roughly half of all smoking-related illnesses are due to cardiovascular disease (CVD). Cigarette smoking and potentially the use of smokeless tobacco are associated with an increase in CVD risk factors. Nonetheless tobacco constituents that mediate the cardiovascular toxicity of tobacco use remain unknown and therefore it is unclear how tobacco products could be regulated to reduce cardiovascular injury or how Potential Reduced Exposure Tobacco Products (PREPs) such as electronic cigarettes could be evaluated for cardiovascular toxicity. This project will address this gap in knowledge regarding the toxicity of harmful and potentially harmful constituents (HPHCs) in tobacco products.


application_id: 9691832
project_number: 5R01AG055449-03
project_title: Contributions of Alzheimer's Pathology and Cerebrovascular Factors to Cognitive Aging
administering_ic: NIA
award_notice_date: 2019-05-13
opportunity_number: PAR-15-357
application_type: 5
activity_code: R01
ic: AG
serial_number: 055449
program_official: WAGSTER, MOLLY V
project_start_date: 2017-09-15
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alzheimer's disease is associated with the accumulation of pathological markers [amyloid-beta(A) and tau] brain atrophy and a progressive loss of memory functions. However a significantproportion of individuals with AD pathology do not develop cognitive impairment indicatingcontributions of other factors to clinical AD. Increasing evidence suggests that factors stronglylinked with brain aging such as cerebrovascular alterations and declines in executive functioncontribute to clinical AD. This link is not straightforward though as the effects of AD pathologyand vascular alterations can be moderated by cognitive reserve and brain resilience. Our recentresults suggest that levels of A and tau in cerebrospinal fluid (CSF) and cerebrovasculardeclines associated with white matter hyperintensities (WMHs) are differentially related topatterns of executive function in cognitively normal older adults. In addition our results suggestthat some of the patterns appear modifiable based on positive lifestyle variables. This proposalseeks to define the interplay between AD pathology cerebrovascular-related alterations andcognitive reserve that distinguish normal brain aging from AD-like cognitive declines. Wepropose to study of 120 cognitively normal older adults using measures of CSF A p-tau and t-tau neuroimaging measures including event-related fMRI multiple structural imaging measures.Structural neuroimaging measures will include volumetric measures FLAIR imaging forquantification of WMH volumes and diffusion tensor imaging for quantification of regionallydistributed white matter abnormalities. A subset of participants will complete the same CSF andimaging measures approximately 3 years later. We aim to (1) dissociate effects of AD pathologyand brain aging on functional compensation (2) identify the separate and synergistic effects ofAD pathology and cerebrovascular markers on cognitive declines over time and (3) identifyreserve factors that moderate relationships between vascular and AD pathology markers oncognition. We will test hypotheses that AD pathology and cerebrovascular factors synergisticallyinteract to predict AD-like cognitive declines. We will also test the hypothesis that reservefactors will offset the effects of some of these pathological and vascular changes on cognitivefunctions via mechanisms of brain maintenance or plastic functional brain reorganization oflarge-scale brain functional networks in some older adults.

project_terms:
Affect;Aging;Alzheimer's Disease;Alzheimers disease biomarker;Amyloid beta-Protein;Biological Markers;Blood Vessels;Brain;Brain region;Brain scan;Cerebrospinal Fluid;Clinical;Cognition;Cognitive;Cognitive aging;Development;Diffusion Magnetic Resonance Imaging;Elderly;Event;Financial compensation;Functional Magnetic Resonance Imaging;Goals;Health;Hippocampus (Brain);Image;Impaired cognition;Individual;Intercept;Intervention;Life Style;Linear Regressions;Link;Magnetic Resonance Imaging;Maintenance;Measures;Memory Loss;Modeling;Neurocognitive;Neuropsychological Tests;Outcome Study;Participant;Pathologic;Pathology;Pathway interactions;Pattern;Performance;Regression Analysis;Running;Short-Term Memory;Structure;System;Testing;Time;Visit;White Matter Hyperintensity;aging brain;base;behavior measurement;brain health;cerebral atrophy;cerebrovascular;clinical development;cognitive function;cognitive performance;cognitive reserve;executive function;frontal lobe;gray matter;hippocampal atrophy;indexing;lifestyle factors;neuroimaging;neuromechanism;prevent;rate of change;resilience;response;tau Proteins;tau-1;white matter

public_health_relevance:
Overall this project will begin to disentangle the relative contributions of Alzheimer's pathologyand brain aging to the development of clinical Alzheimer's disease and identify factors that maypromote optimal cognitive aging.


application_id: 9691830
project_number: 5R01AG054459-03
project_title: Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model
administering_ic: NIA
award_notice_date: 2019-05-02
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 054459
program_official: WAGSTER, MOLLY V
project_start_date: 2017-07-01
project_end_date: 2022-04-30
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryApolipoprotein 4 (APOE4) allele is the strongest genetic risk factor for Alzheimers disease (AD).Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop vascularmetabolic and structural deficits decades before the aggregation of beta-amyloid (A) and neurofibrillary tautangles. Interventions that can restore these deficits to normal would be critical to potentially prevent thedevelopment of AD related neuropathology and cognitive impairment. The rationale of the study is to use thestate-of-the-art in vivo MRI methods to identify a potential intervention Rapamcyin for AD prevention in amouse model that overexpresses human A via 5 familial-AD mutations and expresses human APOE4(E4FAD). The central hypothesis is that multi-modal MRI can be used as surrogate markers to assess efficacyof Rapamycin for restoring brain vascular metabolic and structural functions in mice that carry APOE4 genes.We will also validate our MRI results by comparison with biochemical assays and finally compare withbehavioral outcomes. The hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis thatRapamycin restores neurovascular functions; 2) Test the hypothesis that Rapamycin protects neurometabolicfunctions; and 3) Test the hypothesis that Rapamycin preserves structural and cognitive functions. The projectis innovative because it employs cutting-edge multi-disciplinary novel technology to focus on earlyinterventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers. Theproject is significant because with validation these multimodal MRI methods will dramatically enhance futureresearch for identifying potential therapeutics using animal models in the fields related to AD and other age-related neurodegenerative disorders. We can also translate our approach to future human studies because allthe MRI methods used in the proposal are readily able to be used in humans. Because Rapamycin is FDA-approved the findings from the study will also provide valuable information and may pave a way for futureRapamycin clinical trials to prevent dementia for pre-symptomatic APOE4 carriers.!

project_terms:
Aftercare;Alleles;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Animal Model;Animals;Apolipoproteins;Biochemical;Biological Assay;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrovascular Circulation;Clinical Trials;Cognitive;Dementia;Development;Diet;Dietary Intervention;Disease Progression;Early Intervention;Effectiveness;FDA approved;FRAP1 gene;Functional disorder;Future;Genes;Goals;Human;Impaired cognition;Impairment;Inflammation;Intervention;Magnetic Resonance Imaging;Measurement;Memory;Metabolic;Methods;Mitochondria;Molecular;Mus;Mutation;Myelin;Neurons;Oligodendroglia;Pathology;Pharmacology;Public Health;Radial;Reporting;Research;Sirolimus;Structure;Surrogate Markers;Synapses;Technology;Testing;Therapeutic Uses;Transgenic Mice;Translating;Treatment Efficacy;Validation;abeta accumulation;age related neurodegeneration;arm;base;behavior test;behavioral outcome;brain tissue;cerebrovascular;cognitive function;cohort;density;familial Alzheimer disease;feeding;flexibility;genetic risk factor;glucose metabolism;gray matter;human model;imaging study;improved;in vivo;inhibitor/antagonist;innovation;mouse development;mouse model;multidisciplinary;multimodality;nanoparticle;neuroimaging;neuroinflammation;neuropathology;neurovascular;new technology;novel;object recognition;outcome prediction;overexpression;preservation;prevent;tau aggregation;time use;tool;water maze;white matter

public_health_relevance:
NarrativeThe proposed research is relevant to public health because we will use multi-modal MRI as surrogate markersto assess efficacy of Rapamycin for restoring brain vascular metabolic and structural functions in mice thatcarry APOE4 genes the strongest genetic risk factor for Alzheimer's disease (AD). Because MRI methods arereadily able to be used in humans and Rapamycin is FDA-approved the findings from the study will providevaluable information and may pave a way for future Rapamycin clinical trials to prevent AD for pre-symptomatic APOE4 carriers.


application_id: 9691147
project_number: 5R21AI136821-02
administering_ic: NIAID
award_notice_date: 2019-04-12
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 136821
program_official: PESCE, JOHN T
project_start_date: 2018-05-01
project_end_date: 2021-04-30
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-05-01
project_title:
Gender-dependent innate IL-10 production as a key pathogenic factor to promote toxoplasmic encephalitis

project_abstract:
Reactivation of chronic infection with Toxoplasma gondii in the brains of immunocompromised individualsresults in development of life-threatening toxoplasmic encephalitis (TE). To improve prevention andmanagement of TE it is important to understand the immunopathogenesis of the disease. Epidemiologicalstudies showed significantly higher incidence of TE in female AIDS patients than male patients. Our previousstudies in ADIS patients revealed the presence of a susceptibility marker gene to development of TE within theMHC complex suggesting that the pathogenic immune responses predisposing the patients to reactivation of T.gondii infection are involved in the pathogenesis of TE. Consistent with the observation in AIDS patients ourpreliminary studies uncovered that female mice are more susceptible to reactivation of cerebral T. gondiiinfection than males. However the mechanisms of the pathogenic immune responses that predispose femalesto developing TE are unknown. In this regard our preliminary studies suggested that IL-10 overly produced byinnate immune cells in the brain of female mice suppresses the protective innate immune responses andskews cerebral T cell responses from the protective Th1-type to suppressive IL-10-dominant profile to facilitatereactivation of T. gondii infection. Thus the goal of this project is to elucidate the crucial pathogenic roles ofgender-dependent production of IL-10 by cerebral innate immune cells to down-regulate both protective innateand T cell-mediated immunity in the brain and increase susceptibility to TE. In the first aim we will determinethe pathogenic activities of IL-10 produced by each of brain-resident and infiltrating blood-derived innateimmune cell populations on the protective innate immunity in the brain to facilitate reactivation of T. gondiiinfection in a gender-dependent manner. We will infect male and female SCID mice with depletion of IL-10production in the different innate cell populations in the brain and determine the effects of the innate IL-10depletion on cerebral expression of IL-12 IFN- and IFN--mediated effector molecules and tachyzoite growthduring reactivation of the infection. We will also determine the identity of the major producer of the pathogenicinnate IL-10 in the brain during reactivation of the infection. The second aim is to determine whether thegender-dependent cerebral innate IL-10 production alters T cell recruitment and/or development in the brainand skews T cell cytokine production from IFN-- to IL-10-dominant profile to facilitate reactivation of T. gondiiinfection. We will transfer immune T cells to the infected SCID mice with depletion of IL-10 in the differentinnate cell populations described in Aim 1 and determine changes in numbers of sub-populations of CD4+ andCD8+ T cells that produce either IFN- or IL-10 or both in their brains expression of IFN--mediated protectiveeffector molecules and cerebral tachyzoite growth during the course of the infection. These studies willgenerate the novel and critical information that allow us to begin understanding the mechanisms of thepathogenic immunity that promotes reactivation of cerebral T. gondii infection in a gender-dependent manner.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Animals;Blood;Brain;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cell Count;Cells;Cellular Immunity;Cerebrum;Chronic;Complex;Development;Disease;FOXP3 gene;Female;Gender;Genes;Goals;Growth;Haplotypes;Host resistance;Immune;Immune response;Immunity;Immunocompetent;Immunocompromised Host;Immunosuppressive Agents;Incidence;Individual;Infection;Innate Immune Response;Interferon Type II;Interleukin-10;Interleukin-12;Life;Mediating;Messenger RNA;Methods;Mus;Natural Immunity;Organ;Pathogenesis;Pathogenicity;Patients;Play;Population;Predisposition;Prevention;Production;Regulatory T-Lymphocyte;Reporting;Research;Resistance;Role;SCID Mice;Spleen;T cell response;T-Cell Development;T-Lymphocyte;Toxoplasma gondii;Toxoplasmosis;Virulence Factors;Wild Type Mouse;base;chronic infection;cytokine;epidemiology study;improved;male;microbial;novel;recruit;toxoplasmic encephalitis;transcription factor

public_health_relevance:
Reactivation of chronic infection with Toxoplasma gondii in the brain causes life-threatening toxoplasmic encephalitis (TE) in immunocompromised individuals. Theproposed studies are aimed to uncover the pathogenic roles of gender-dependentproduction of IL-10 by cerebral innate cells to increase susceptibility to development ofTE. These studies will provide the cutting-edge information that dramatically improvesour understanding of the regulatory mechanisms of host resistance against TE andassists in developing a novel method(s) to improve prevention and treatment of TE bysuppressing the innate IL-10-mediated pathogenic mechanisms.


application_id: 9691082
project_number: 5R01AA015407-15
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2019-04-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
program_official: AKBAR, MOHAMMED
project_start_date: 2004-12-01
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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:
Ethanol is a neuroteratogen and alcohol consumption during pregnancy causes Fetal Alcohol SpectrumDisorders (FASD). FASD are currently the leading cause of mental retardation in North America. The mostdevastating effect of developmental exposure to ethanol is the loss of CNS neurons which underlie manybehavioral deficits observed in FASD. We demonstrated that ethanol caused both oxidative stress andendoplasmic reticulum (ER) stress in the developing brain. We showed that ethanol induced the expression ofmonocyte chemoattractant protein-1 (MCP-1) and a specific ER stress-inducible protein mesencephalicastrocyte-derived neurotrophic factor (MANF). Our studies suggested that both MCP-1 and MANF wereinvolved in ethanol-induced ER stress and neuron death. The central hypothesis for this proposal is thatethanol-induced neurodegeneration in the developing brain is mediated by the interplay of oxidative stress andER stress. Three corollary hypotheses will be tested: 1) ethanol-mediated oxidative stress causes an earlyneuron death; the second phase of neuron death is mainly mediated by ethanol-induced ER stress or acombined action of both oxidative stress and ER stress; 2) the oxidative stress-induced neuron death is mainlyregulated by the mitochondrial intrinsic apoptotic pathway; while the ER stress-induced neuron death ismediated by the GSK3/calpain/caspase7/12 pathway; 3) activation of MCP-1 mediated signaling potentiatesethanol-induced ER stress and promotes an ER stress-initiated apoptotic program in neurons; contrarilyMANF is a neuroprotective protein which alleviates ethanol-induced ER stress and neuron death. We proposethree specific aims to test these hypotheses. Specific Aim 1 will test the hypothesis that ethanol-inducedneuron death is caused by the interplay of oxidative stress and ER stress in vitro. Specific Aim 2 willdetermine the role of MCP-1 signaling and MANF in ethanol-induced ER stress and neuron death in thedeveloping brain. Specific Aim 3 will determine whether simultaneous inhibition of oxidative stress and ERstress offers maximal protection and improves behavioral deficits in mice. As a unit this proposal willsystematically investigate the interplay of oxidative stress and ER stress and assess their contribution toethanol-induced neuron death. This study will therefore not only provide novel insight into the mechanisms ofethanol-induced damage to the developing CNS but also identify specific targets for developing effectivetherapeutic strategies.

project_terms:
Apoptotic;Astrocytes;Attention;Behavior;Behavioral;Biological Models;Brain;CCL2 gene;Calpain;Complex;Development;Equilibrium;Ethanol;Fetal Alcohol Spectrum Disorder;Funding;Hour;Hyperactive behavior;In Vitro;Learning;Mediating;Mediator of activation protein;Memory;Mental Retardation;Mitochondria;Modeling;Molecular;Motor;Mus;Neonatal Alcohol Exposure;Nerve Degeneration;Neuraxis;Neurons;North America;Oxidative Stress;Pathway interactions;Phase;Play;Proteins;Research;Role;Signal Pathway;Signal Transduction;Testing;Third Pregnancy Trimester;Time;Treatment Efficacy;alcohol behavior;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;endoplasmic reticulum stress;improved;in vitro Model;in vivo Model;insight;monocyte chemoattractant protein 1 receptor;neuron loss;neuroteratogen;neurotoxicity;neurotrophic factor;novel;novel therapeutic intervention;postnatal;prenatal;programs

public_health_relevance:
Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD). Bothoxidative stress and endoplasmic reticulum (ER) stress contributes to ethanol neurotoxicity. The study willexplore the underlying mechanisms and develop a new therapeutic approach by targeting both oxidative stressand ER stress.


application_id: 9690846
project_number: 5R01NS070899-10
project_title: Regulation signaling and dynamics of glucan phosphatases
administering_ic: NINDS
award_notice_date: 2019-04-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 070899
program_official: LEENDERS, MIRIAM
project_start_date: 2010-07-01
project_end_date: 2020-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this project is to utilize the unique window into cellular metabolism that Lafora disease offers to define both normal glycogen metabolism and disease implications when the process is disrupted. Lafora disease (LD) one of five major progressive myoclonic epilepsies is a fatal recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic hyperphosphorylated water-insoluble glycogen-like particles called Lafora bodies. These inclusions occur throughout the body but disease results from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. LD is the result of loss of function mutations or mutations that cause aberrant function in either of the genes encoding the glucan phosphatase laforin or E3 ubiquitin ligase malin.  We established laforin as the founding member of the glucan phosphatase family i.e. phosphatases that dephosphorylate glycogen or starch. A laforin structure is needed to determine how reversible glycogen phosphorylation impacts glycogen metabolism and define why laforin mutations result in LD. We also demonstrated that malin is an E3 ubiquitin ligase and reported that malin ubiquitinates proteins involved in glycogen synthesis. However malin does not promote degradation of these enzymes and it has remained unknown as to how malin impacts glycogen metabolism and why mutations in malin result in LD. While mutations in the laforin or malin gene result in LD it is increasingly recognized that multiple mechanisms lead to LD and that a spectrum of mutations yields different degrees of disease progression. Because our work has defined the molecular function of laforin and malin we are uniquely poised to define the clinical biochemistry of LD mutations in both laforin and malin. Therefore we propose to: 1. Determine the structural mechanism of laforin. We will utilize X-ray crystallography combined with structure-guided mutagenesis and functional assays to determine how laforin binds to glycogen how phosphorylated glycogen is dephosphorylated laforin's role in glycogen metabolism and laforin's role in LD. 2. Define the role of malin in LD and glycogen metabolism. Using multiple methods we have identified malin substrates and established the type of ubiquitination as well as defined the consequences of ubiquitination for one substrate. We will define the signaling events that drive ubiquitination of malin substrates the dynamics of the events the functional consequences and how misregulation leads to LD. We will utilize cell culture and mouse models to determine the role of malin in glycogen metabolism and LD. 3. Translate current insights into patient-specific diagnosis and treatment. LD results from both missense mutations as well as Premature Termination Codons. Our initial analysis revealed that not all point mutations abolish activity. We will utilize our biochemical tools to define mutation specific mechanisms for laforin and malin LD mutations and explore therapeutic options using our recently developed bioassay.

project_terms:
Acute;Affect;Aminoglycosides;Binding;Biochemical;Biochemistry;Biological Assay;Biology;Carbohydrates;Cell Culture Techniques;Cells;Cellular Metabolic Process;Cellular Structures;Clinical;Complex;Comprehension;Diagnosis;Disease;Disease Progression;Energy Metabolism;Enzymes;Epilepsy;Event;Family;Fibroblasts;Genes;Glucans;Glycogen;Glycogen Phosphorylase;Glycogen Storage Disease;Goals;Inherited;Knockout Mice;Lafora Disease;Lead;Life;Link;Liver;Metabolism;Methods;Missense Mutation;Modeling;Molecular;Muscle;Mutagenesis;Mutation;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Point Mutation;Process;Progressive Myoclonic Epilepsies;Proteins;Proteome;Protocols documentation;Regulation;Reporting;Role;Signal Transduction;Starch;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Tissues;Translating;Ubiquitin;Ubiquitination;Water;Work;X-Ray Crystallography;biochemical tools;cell type;design;disease-causing mutation;gene product;glycogen metabolism;in vivo;insight;loss of function mutation;member;mouse model;neuron apoptosis;neurotoxicity;novel;novel therapeutics;particle;potency testing;premature;public health relevance;screening;tool;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The focus of our work is to determine how mutations in either of two gene products lead to the fatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intertwined events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better comprehension of these complex events and will allow us to translate our insights into diagnoses bioassays and treatments.


application_id: 9690716
project_number: 5R01GM077422-10
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2019-04-19
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: GM
serial_number: 077422
program_official: SAKALIAN, MICHAEL
project_start_date: 2007-02-01
project_end_date: 2021-04-30
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: TRENT, JOHN O
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:
We seek a second renewal for our program to refine and apply an integrated virtual and actual screeningplatform for the discovery of new lead compounds to inhibit telomerase. Progress during the current fundingperiod was outstanding and we have achieved most of the specific aims proposed. During the next fundingperiod we will focus on the discovery of lead compounds that bind selectively to biologically important higher-order telomeric DNA quadruplexes and targeting the single strand telomere:POT1 interface. Telomerase hasbeen identified as a target for over 20 years but there are no approved drugs that inhibit its activity so newapproaches are required. We will inhibit POT1 (Protection of Telomere 1) a protein essential for telomeraseactivity by targeting the telomeric DNA substrate and by directly targeting the POT1 telomeric DNA bindingfunction. We now propose fundamental studies that will continue to develop and refine our integratedscreening platform. Nucleic acids remain underrepresented targets for small molecule therapeutic agents. There is mountingevidence to indicate that non-B DNA structures play prominent roles in gene expression and especially in thefunction of telomeres. Targeting these structural elements is an attractive and innovative strategy for thedevelopment of new therapeutic agents. The higher-order DNA quadruplex structures formed by the singlestrand of the human telomere remain a very poorly and improperly investigated target as traditional structuralbiology approaches have been unsuccessful. We have used a combination of computational modeling andexperimental biophysics to derive consistent structural models for telomeric DNA sequences of up to 192bases or eight quadruplex repeats in the current grant period. The higher-order quadruplex stackinginterfaces thus represent a new target for small molecule stabilization of telomeric DNA. This stabilizationshould inhibit telomerase by locking the substrate DNA in an unusable form. An even more under representedtarget than non-B DNA is the nucleic acid-protein interaction particularly single stranded DNA:proteincomplexes as exist with POT1. We will target both the DNA substrate and the DNA-binding function of POT1which could lead to synergistic inhibition of telomerase. This is a natural progression from our current fundingperiod where we targeted biologically relevant quadruplex structures to telomere-like higher-order quadruplexnucleic acid structures and the telomere ssDNA binding protein POT1 which is essential for telomeric DNAreplication. The Specific Aims are: 1) Targeting higher-order telomeric quadruplex structures using integratedvirtual and actual screens; 2) Characterizing the specific interactions of POT1 with higher-order quadruplexes;3) Targeting POT1 using integrated virtual and actual screens; 4) Characterizing the biological properties ofhigher-order G-quadruplexes and POT1 binding agents.!

project_terms:
Binding;Binding Proteins;Biological;Biological Assay;Biophysics;Characteristics;Computer Simulation;DNA;DNA Binding;DNA Sequence;DNA Structure;DNA biosynthesis;Development;Drug Design;Elements;Face;Funding;G-Quartets;Gene Expression;Genome;Grant;Human;Kinetics;Laboratories;Lead;Measures;Methods;Modeling;Molecular Conformation;Nucleic Acids;Nucleotides;Oligonucleotides;Pathway interactions;Pharmaceutical Preparations;Play;Positioning Attribute;Property;Proteins;Recombinants;Role;Series;Single-Stranded DNA;Source;Structural Models;Structure;Telomerase;Telomerase inhibition;Therapeutic Agents;Thermodynamics;Validation;base;biophysical properties;biophysical techniques;design;innovation;new therapeutic target;novel;novel lead compound;novel strategies;novel therapeutics;nucleic acid structure;programs;protein complex;quadruplex DNA;screening;small molecule;small molecule inhibitor;small molecule therapeutics;structural biology;telomere;virtual

public_health_relevance:
This project will refine and apply an integrated computational and experimental screening platform for thediscovery of new drugs that target specific structures of functional importance within the genome. The currentfunding period for this project was successful and productive and we will continue our efforts. Several noveltelomeric functionally important quadruplex structures were characterized. We will characterize the interactionsof these with their protein partner and use this information to target both.


application_id: 9690550
project_number: 5R21AI135345-02
project_title: HDAC6 regulation of beta-catenin and endothelial adherens junctions in sepsis
administering_ic: NIAID
award_notice_date: 2019-03-15
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 135345
program_official: MINNICOZZI, MICHAEL
project_start_date: 2018-05-01
project_end_date: 2021-04-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummarySepsis a systemic inflammatory response syndrome is a life-threatening disease with highmorbidity and mortality. Sepsis is often triggered by bacterial infection. Excessive inflammatoryresponses lead to vascular injury in sepsis including increased vascular permeability and edema.Identifying novel therapeutic targets that can help control sepsis-induced vascular injury iscrucial to treat this devastating disease. Endothelial barrier dysfunction contributes to thepathogenesis of multi-organ failure in sepsis. Acetylation and deacetylation of cell-cell junctionand cytoskeleton proteins may serve as an important mechanism to control the dynamics ofendothelial barrier integrity. HDAC6 a deacetylase primarily localized in the cytoplasm hasbeen reported to modulate non-nuclear protein function through deacetylation. -catenin is anendogenous substrate for HDAC6. -catenin is a key component of adherens junction complex.-catenin interacts with VE-Cadherin at cell-cell junctions to maintain endothelial barrier integrity.In this project we will investigate HDAC6 regulation of -catenin and endothelial adherensjunctions in sepsis. In our preliminary studies we demonstrated that HDAC6 knockdown orselective HDAC6 inhibition prevented TNF- induced endothelial cell barrier disruption andincreased -catenin acetylation in endothelial cells which was associated with increasedmembrane localization of -catenin and stabilization of adherens junctions. Furthermore in amouse model of polymicrobial sepsis HDAC6 inhibition was able to prevent sepsis-induceddeacetylation of -catenin in lung tissues which was associated with the protection of adherensjunctions and reduced pulmonary edema. In the proposed studies we will investigate molecularmechanisms of HDAC6 regulation of endothelial adherens junctions in sepsis using inducibleendothelial-specific HDAC6 knockout mice. We will also assess the therapeutic potential ofnovel HDAC6 inhibitors in the protection of endothelial adherens junctions during sepsis.

project_terms:
Acetylation;Adherens Junction;Bacterial Infections;Blood Vessels;Cells;Cessation of life;Clinical Research;Clinical Trials;Complex;Cytoplasm;Cytoskeleton;Data;Deacetylase;Deacetylation;Disease;Edema;Endothelial Cells;Endothelium;Failure;Functional disorder;Future;HDAC6 gene;Human;Inflammatory;Inflammatory Response;Injury;Intercellular Junctions;Knockout Mice;Lead;Life;Lung;Mediating;Membrane;Molecular;Morbidity - disease rate;Mus;Operative Surgical Procedures;Pathogenesis;Proteins;Pulmonary Edema;Regulation;Reporting;Role;Sepsis;Structure of parenchyma of lung;Systemic Inflammatory Response Syndrome;TNF gene;Testing;Therapeutic;Therapeutic Effect;Vascular Permeabilities;beta catenin;cadherin 5;experimental study;inhibitor/antagonist;knock-down;mortality;mouse model;new therapeutic target;novel;novel therapeutics;polymicrobial sepsis;prevent;protective effect;protein function

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of HDAC6 in sepsis-inducedendothelial adherens junction dysfunction. We will also validate the therapeutic potential of HDAC6inhibition against vascular injury in sepsis. The proposed studies will provide important information forfuture clinical studies.


application_id: 9690052
project_number: 5R01ES029378-02
project_title: EGFR and angiogenesis in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2019-04-08
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 029378
program_official: REINLIB, LESLIE J
project_start_date: 2018-05-01
project_end_date: 2019-08-22
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cr(VI)-containing compounds are well-established environmental carcinogens. Most mechanisticinvestigations of Cr(VI)-induced carcinogenesis focus on oxidative stress and various cellular responsesleading to malignant cell transformation the first stage of metal-induced carcinogenesis. The development ofmalignantly transformed cells into tumors in which angiogenesis is required is the second stage. Thisapplication focuses on this second stage in particular the role of epidermal growth factor receptor (EGFR)signaling in angiogenesis and tumorigenesis of Cr(VI)-transformed cells. Our previous studies have found thatchronic exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) causes malignant cell transformation.Our preliminary studies have shown that EGFR is constitutively activated in Cr(VI)-transformed cells in lungtissues from Cr(VI)-exposed animals and in lung tumor tissues from non-smoking workers exposed to Cr(VI).Our preliminary studies have also shown that EGFR phosphorylates p62 at serine349 (S349) that p62upregulates nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) and that Nrf2 upregulates bothNAD(P)H:quinone oxidoreductase 1 (NQO1) and hypoxia-inducible factor (HIF)-1 in those Cr(VI)-transformedcells leading to elevated level of vascular endothelial growth factor (VEGF). Inhibition of EGFR by its shRNAor kinase inhibitor AK1478 suppresses HIF-1 in Cr(VI)-transformed cells. Our findings indicate that EGFRfunctions as an initiator in angiogenesis and causes a chain of events through constitutive activation of Nrf2 inCr(VI)-transformed cells. The central hypothesis of this application is that in Cr(VI)-transformed cellsconstitutively activated EGFR phosphorylates p62 at S349 causing upregulations of Nrf2 and NQO1 which inturn activate HIF-1 and its target protein VEGF leading to angiogenesis and tumorigenesis. Aim 1 willdemonstrate that EGFR phosphorylates p62 at S349 causing increased binding affinity between p62 andKelch-like ECH-associated protein 1 (Keap1) a negative regulator of Nrf2 leading to reduced binding betweenKeap1 and Nrf2 and subsequently increased stabilization of Nrf2. Aim 2 will demonstrate that HIF-1 isupregulated by NQO1 due to its binding to HIF-1 in completion with prolyl hydroxylase domain protein 2(PHD2) and to cap-independent but internal ribose entry site (IRES)-independent translation. We will alsodemonstrate the elevated protein levels of p-EGFR p62 p-p62 Nrf2 NQO1 HIF-1 and VEGF in humanlung tumor tissues from Cr(VI)-exposed workers. Aim 3 will demonstrate that activation of EGFR/HIF-1/VEGFcauses angiogenesis and promotes tumorigenesis in vivo using animal models of intranasal exposure toCr(VI) Matrigel plug assay and orthotopic lung cancer.

project_terms:
Affinity;Animal Cancer Model;Animal Model;Animals;Binding;Biological Assay;Blood;Blood Vessels;Carcinogens;Cell physiology;Cells;Chronic;Development;Environmental Carcinogens;Epidermal Growth Factor Receptor;Epithelial;Event;Exhibits;Exposure to;Genetic Transcription;Goals;Human;Hypoxia Inducible Factor;Internal Ribosome Entry Site;International Agency for Research on Cancer;Investigation;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Metal exposure;Metals;NQO1 gene;Neoplasm Metastasis;Occupational;Occupational Exposure;Oncogenic;Oxidative Stress;Oxidoreductase;PECAM1 gene;Phosphorylation;Poison;Population;Post-Translational Protein Processing;Prevention;Procollagen-Proline Dioxygenase;Production;Proteins;Quinones;Receptor Signaling;Reporting;Ribose;Role;Signal Transduction;Site;Structure of parenchyma of lung;Tertiary Protein Structure;Testing;Tissues;Translations;Tumor Tissue;Up-Regulation;VEGFA gene;Vascular Endothelial Growth Factors;angiogenesis;animal tissue;cancer cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;exposed human population;in vivo;interstitial;kinase inhibitor;matrigel;non-smoking;nuclear factor-erythroid 2;receptor function;response;small hairpin RNA;transcription factor;tumor;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE The International Agency for Research on Cancer (IARC) classifies Cr(VI)-containing compounds as Group1 human carcinogens. The long term goal of this application is to understand the mechanism of Cr(VI)-carcinogenesis and its prevention. This application focuses on role of epidermal growth factor receptor (EGFR)signaling in angiogenesis and tumorigenesis of Cr(VI)-transformed cells.


application_id: 9689011
project_number: 5R01ES027881-03
project_title: Air Pollution Circadian Rhythm Disruption and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2019-04-04
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 027881
program_official: SCHUG, THADDEUS
project_start_date: 2017-05-01
project_end_date: 2022-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
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:
ARNTL gene;Aerosols;Affect;Air;Air Pollution;Animal Model;Aorta;Attenuated;Biochemical Process;Biological;Biological Availability;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Characteristics;Circadian Dysregulation;Circadian Rhythms;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Eating;Endothelium;Exposure to;Gene Expression;Genes;Goals;Health;Human;Individual;Industrialization;Injury;Insulin Resistance;Knockout Mice;Laboratories;Lead;Life Style;Light;Link;Lung;Mediating;Metabolism;Modeling;Modernization;Mus;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Oxidation-Reduction;Oxidative Stress;Particulate;Periodicity;Peripheral;Phase;Physiological Processes;Policies;Pollution;Post-Translational Protein Processing;Predisposition;Prevention strategy;Research;Sleep Deprivation;System;Testing;Toxic effect;Transcriptional Regulation;Urbanization;Work;air filter;ambient air pollution;atherogenesis;base;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;chemical property;circadian;diabetes risk;epidemiologic data;evidence based guidelines;mortality;mouse model;novel;overexpression;particle;physical property;pollutant;premature;prevent;response;sleep behavior


application_id: 9688922
project_number: 5R37AI052218-18
project_title: In Vitro Glycorandomization of Natural Products
administering_ic: NIAID
award_notice_date: 2019-04-25
opportunity_number: PA-11-260
application_type: 5
activity_code: R37
ic: AI
serial_number: 052218
program_official: DAVIS, MINDY I
project_start_date: 2002-06-03
project_end_date: 2022-05-31
study_section: NSS
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT OF THE RESEARCH PLAN The studies to be pursued under the proposed extension fall within three general areas: i) enzyme catalystengineering and modulation (theme 1); ii) selected platform applications (theme 2); and iii) a systematic studyof the impact of glycosylation on fundamental drug properties (theme 3). The key tenets of each are brieflydescribed below and parallel the consistently high level of significance and innovation reflected in past periodsof support. The overarching significance stems from the anticipated advancements of universal principles forenzyme catalyst engineering/modulation novel enabling strategies for synthesis and biosynthetic study uniqueprobes or leads of significance to diverse therapeutic areas and a potential new conceptual framework for thegeneral use of glycosylation in drug development. Anticipated drivers of innovation are both by design(particularly novel synthetic and assay strategies) and directed discovery (unprecedented glycosyltransferasemodulators and probes/leads with high potential to lead to new understanding in the fundamentals ofimmunomodulation and/or inflammation). Studies directed toward enzyme catalyst engineering and modulation (theme 1) will focus on comparing thedirected evolutionary paths among the structurally similar glycosyltransferases (GTs) OleD and OleI assessingthe transferability of beneficial mutations across OleD and OleI and identifying mutational hot spots within theatypical GTB-fold GT AmphD1. The comparative OleD/OleI studies will consist of: i) the evaluation of an OleILoki which contains the 5 key mutations of structurally conserved residues that led to OleD Loki; and ii) aparallel epPCR-directed evolution approach for increasing OleI proficiency/permissivity using the same screensand mutational strategy that led to the discovery of enhanced OleD progeny. Key outcomes of this comparativestudy will be a potential universal blueprint for improving the proficiency/promiscuity of most GTB-fold GTs andimproved GTs for select sugar-conjugation (D-Gal analogs) to support theme 3. The directed evolution ofAmphD1 (and parallel proposed structure elucidation and structure-based engineering) will also follow our OleDprecedent and offers both the potential to expand the universal GT engineering blueprint toward atypical GTsand to identify GT variants to dramatically simplify the targeted synthesis of the unique preclinical antifungal lead2-epi-amphotericin (theme 2). In addition we will pursue the mechanistic study of small molecule inhibitors andactivators identified via the ClNP-Glc-based HT screen - studies that hold high potential in the discovery of newparadigms for GT catalytic modulation that may extend to other enzyme families and/or have pharmacologicapplications. Finally while we remain enthusiastic about the uncharted frontier of enzyme modulation viacontrolled electrical fields such technically challenging experiments require the physical presence of both thematerials scientists and enzymologists and unfortunately our local collaborator (Prof. Hinds) recently relocatedto the University of Washington. Thus this has become a lower priority in the near term. Among the various selected platform applications (theme 2) we will direct the real-time NMR-based assaytoward key and novel late-stage biosynthetic transformations - specifically to understand the stepwiseaminopentose N-alkylation reactions en route to enediynes and indolocarbazoles and the key steps of enediyne-associated thiosugar biosynthesis. The main outcome of these studies will be the elucidation of what isanticipated to be (based on bioinformatics) novel enzyme-catalyzed chemistries. In addition we will continue theongoing studies discussed within the progress report (immunomodulatory studies with macrolide neoglycosidesanti-Mtb studies with spectinomycin neoglycosides and further advancing protein glycosylation studies) andinitiate new combined (neo)glycorandomization diversification efforts toward a prioritized list of additional targets.Specifically we seek to generate and evaluate (neo)glycorandomized libraries of a third or fourth generation ?-lactam antibiotic (primary objective to broaden antibacterial scope) rapamycin (primary objectives to assessmechanistic modulation and potency) and daptomycin (primary objectives to improve formulation potencyand/or antibacterial scope). For all targets selected we have access to the necessary fundamental evaluativeactivity assays within my lab or via the Center of Pharmaceutical Research and Innovation (under mydirectorship) and these new initiatives hold promise for the discovery of new potential anti-infective anticancerand/or immunomodulatory probes/leads and for advancing new tools for biopharmaceutical development. As highlighted in the progress report we have also initiated arguably one of the first broad systematic studiesof the impact of glycosylation on fundamental drug properties (theme 3) the strategic design of which will probeboth the impact of the sugar and corresponding drug leaving group on key drug property principles. Thecorresponding in vitro and in vivo drug properties of the ?-glucosides will be evaluated by Vertex. In parallelProf. Leggas (co-I) will evaluate the in vitro and in vivo drug properties of a SN-38 10-O-?-glycoside sugar variantseries from which the top 2-3 analogs will be selected for subsequent in vivo anticancer efficacy studies. Thesestudies are anticipated to reveal fundamental insights regarding the impact of the sugar drug and correspondingglycosidic bond as the basis of a potentially new conceptual framework for the general use of glycosylation as atransformative drug development tool.

project_terms:
Alkylation;Amphotericin;Anabolism;Anti-Bacterial Agents;Anti-Infective Agents;Antifungal Agents;Area;Bioinformatics;Biological Assay;Biological Products;Chemistry;Comparative Study;Daptomycin;Development;Directed Molecular Evolution;Engineering;Enzymes;Evaluation;Family;Formulation;Generations;Glucosides;Glycosides;Hot Spot;In Vitro;Inflammation;Lead;Libraries;Macrolides;Monobactams;Mutation;Mycobacterium tuberculosis;Natural Products;Outcome;Outcome Study;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Progress Reports;Property;Protein Glycosylation;Reaction;Research;Route;SN-38;Scientist;Series;Sirolimus;Spectinomycin;Structure;Therapeutic;Time;Universities;Variant;Washington;analog;anti-cancer;base;catalyst;comparative;design;drug development;efficacy study;experimental study;falls;frontier;glycosylation;glycosyltransferase;immunoregulation;improved;in vivo;innovation;insight;novel;pre-clinical;small molecule inhibitor;stem;sugar;thiosugar;tool;tool development


application_id: 9688628
project_number: 1R43CA228686-01A1
project_title: DIAGNOSTIC TEST FOR METASTATIC KIDNEY CANCER
administering_ic: NCI
award_notice_date: 2018-09-12
opportunity_number: PA-18-574
application_type: 1
activity_code: R43
ic: CA
serial_number: 228686
suffix: A1
program_official: LOU, XING-JIAN
project_start_date: 2018-09-14
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 DKUS-L (11)]
contact_pi_person_id: 15200618
contact_pi: CARRITHERS, STEPHEN
other_pis: COUGHLIN, RICHARD THOMAS
congressional_district: 04
department: Unavailable
primary_duns: 080083976
primary_uei: FR2EBJKP5G63
duns_number: 080083976
uei: FR2EBJKP5G63
fips: US
organization_id: 10040856
organization_name: LAGRANGE SCIENTIFIC, LLC
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
project_abstract:
ABSTRACT The goal of this Phase I SBIR is to address the absence of measureable and targeted metabolitebiomarkers in clear cell renal cell carcinoma (ccRCC) tissues that can predict disease metastasis. Anestimated 69990 Americans were diagnosed with kidney cancer in 2017 and approximately 14400 died as aresult of ccRCC primarily due to metastasis of the cancer. Ultimately we seek to identify those patients withmore aggressive renal cancers that might benefit from more aggressive treatment. Patients with indolentccRCC may choose less aggressive treatment while those with a greater risk of metastasis may elect adjuvanttherapy that may include drug treatments. There are no diagnostic tests that predict post-surgical disease progression on the market. Ourmethodology will utilize novel liquid chromatography (LC) and mass spectrometry (MS) methods developed byour collaborators along with several new methods we developed that will greatly increase quantitativeaccuracy and robustness. This will address a series of issues that have plagued the development of a reliablebiomarker panel for the diagnosis of renal cancer progression and metastasis. A major problem with metabolomic studies to date is that the heterogeneity of cancer tissues isfrequently overlooked. Thus an important part of our approach includes normalization calibration andquantitation of metabolites in both discovery and targeted modes. Specifically our method allows for theanalysis of metabolites in small biopsies and will permit histopathology to be performed on exactly the sametissue. Whereas normalization and quantitation are usually addressed after data has been acquired i.e. post-acquisition we add pre-acquisition normalization which will ensure that equal amounts of sample are injectedfor MS. Our use of chemical labeling and sample normalization will minimize the effects of ion suppressionsignal saturation column contamination aging and instrument performance drift. Essentially the day-to-dayand lab-to-lab variability which frequently affect MS will be minimized. In this proposal we will utilize the Eastern Virginia Medical School Biorepository PROBE cohort whichhouses over 300 renal tumors and associated clinical data including treatment vital status imaging data andlongitudinal follow-up after primary tumor resection. The database accompanying the Biorepository is regularlyupdated allowing us to identify those who progressed vs. those who are termed non-progressors. For thisPhase I proof-of-concept study tissues from 26 patients that developed metastasis will be analyzed andcompared to 174 patients that did not develop metastasis (n=200 patients). All tumor tissues  primary andmetastatic  will be paired with normal tumor-adjacent tissue from clear margins. In addition larger numbersof patients in the cohort will be analyzed using available histopathological and staging data as surrogates forclinical outcome. A side benefit to this study is the prospective addition to our ccRCC bank for Phase II studies.

project_terms:
Address;Adjuvant Therapy;Affect;Aging;Aldehydes;American;American Joint Committee on Cancer;Amines;Biological Markers;Biopsy;Blinded;Bromides;Calibration;Carboxylic Acids;Characteristics;Chemical Structure;Chemicals;Chlorides;Choking;Clear cell renal cell carcinoma;Clinical;Clinical Chemistry;Clinical Data;Clinical Trials;Complex;Complication;Computer software;Data;Databases;Development;Diagnosis;Diagnostic tests;Disease;Disease Progression;Enrollment;Ensure;Epidemiologist;Excision;FDA approved;Genomics;Goals;Health Care Research;Histology;Histopathology;Human;Image;Indolent;Intervention;Ions;Isotope Labeling;Ketones;Kidney Neoplasms;Label;Laboratories;Letters;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Metabolic;Methodology;Methods;Modeling;Molecular Weight;Neoplasm Metastasis;Normal tissue morphology;Oncologist;Operative Surgical Procedures;Outcome;Pathologist;Patients;Performance;Pharmacotherapy;Phase;Phenols;Physicians;Plague;Preparation;Primary Neoplasm;Process;Proteomics;Protocols documentation;Regulatory Pathway;Renal carcinoma;Research Personnel;Resected;Risk;Running;Sampling;Sampling Studies;Series;Side;Signal Transduction;Small Business Innovation Research Grant;Staging;Statistical Methods;Surgeon;Survival Rate;TNM;Testing;Tissue Extracts;Tissues;Tumor Tissue;Update;Virginia;Vital Status;base;biobank;biomarker panel;biomarker validation;blind;cancer heterogeneity;clinical application;cohort;follow-up;hazard;high risk;human disease;human tissue;instrument;ionization;liquid chromatography mass spectrometry;medical schools;metabolic profile;metabolome;metabolomics;novel;patient population;phase 2 study;predictive marker;predictive test;prognostic;prognostic assays;prospective;research and development;research clinical testing;sugar;testing services;tumor;tumor heterogeneity;tumor progression

public_health_relevance:
PROJECT NARRATIVEOur goal is to develop an FDA-approved prognostic test for metastatic clear cell renal cell carcinoma(ccRCC). The development of a specific panel of metabolic biomarkers will be associated with progressionfrom primary tumor to a disseminated metastatic disease state. Ultimately we will develop a laboratorytesting service for characteristics of ccRCC that are correlated with and predictive of progression tometastasis in this high-risk patient population. This will assist the physician/surgeon in facilitating interventionprior to metastasis. We envision this test being run by a specialized laboratory using our protocols atLAGRANGE SCIENTIFIC (or at a licensed laboratory). At an estimated $300 per test we envision a $21 million/yrmarket based on approximately 69900 samples per year from patients with potentially metastatic ccRCC.


