# projects

application_id: 9462917
project_number: 5P20GM113226-03
project_title: Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
administering_ic: NIGMS
award_notice_date: 2018-03-26
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6173
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
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: 2018-04-01
budget_end_date: 2019-03-31
project_abstract:
Liver injury of different etiologies leads to a wound healing process involving activation of hepatic stellate cells(HSCs). However an ongoing hepatocyte injury and inflammation results in an uncontrolled activation andproliferation of HSCs and development of hepatic fibrosis leading to cirrhosis and even hepatocellular cancer.Despite the advances made gaps remain in our understanding of the mechanisms involved in the process ofHSC transformation from quiescent to activated phenotype. Recently we discovered that thephosphodiesterase 4 (PDE4) subfamily of enzymes play a pathogenic role in the development of cholestaticliver injury and fibrosis. Notably PDE4s are not present in quiescent HSCs and are rapidly induced uponactivation in vitro. Further the PDE4 specific inhibitor rolipram effectively attenuates SMA collagenexpression and accompanying morphological changes in HSCs. PDE4 is the largest sub-family among cAMP-hydrolyzing PDEs which tightly regulate the levels of cellular cAMP. cAMP through its effector moleculesprotein kinase A (PKA) and Exchange Protein directly Activated by cAMP (EPAC) has been shown to down-regulate cytokine induced fibrogenic genes in non-hepatic cells. Hence we hypothesize that induction of PDE4expression and activity plays a causal role in HSC activation by decreasing cAMP-PKA/EPAC activities andpromoting fibrogenic signaling. We postulate that during HSC activation promoter associated epigeneticchanges and post-translational modifications play a significant role in the regulation of PDE4 expression andactivity. We also postulate that PDE4 inhibition will restore PKA/EPAC activities and attenuate TGF-Smadsignaling through: (i) inactivation of relevant MAPKs; and (ii) de-repressing PPAR leading to decreasedexpression of SMA and Col1A1. Importantly inhibition of PDE4 activity may be a significant therapeuticapproach for liver fibrosis. The specific aims of this proposal are to: 1) Determine the role of PDE4 in theregulation of fibrogenic signaling in HSCs; 2) Determine promoter-associated epigenetic modificationscontributing to the induction of PDE4 isoforms during HSC activation; and 3) Determine the post-translationalmodifications (PTMs) relevant for PDE4 isoform function during HSC activation. Importantly the results of thisCOBRE-funded project will provide proof-of-principle and mechanistic rationale for in vivo translational studies(R01) to examine PDE4 targeted strategies for prevention and treatment of hepatic fibrosis.

project_terms:
Address;Attenuated;Centers of Research Excellence;Cirrhosis;Collagen;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DNA Modification Process;Development;Enzymes;Epigenetic Process;Etiology;FDA approved;Family;Fibrosis;Funding;Genes;Genetic Transcription;Hepatic Stellate Cell;Hepatocyte;In Vitro;Inflammation;Injury;Knockout Mice;Liver Fibrosis;Mass Spectrum Analysis;Mediating;Modeling;Modification;Morphology;Myofibroblast;PDE4B;PPAR gamma;Pathogenicity;Phenotype;Phosphorylation;Play;Post-Translational Protein Processing;Prevention strategy;Primary carcinoma of the liver cells;Process;Promoter Regions;Protein Isoforms;Proteins;Proteomics;Rattus;Regulation;Role;Rolipram;Second Messenger Systems;Signal Transduction;Therapeutic;Toxicology;Transcriptional Activation;Transforming Growth Factor beta;Wound Healing;base;cell transformation;cytokine;experimental analysis;histone modification;in vivo;inhibitor/antagonist;liver injury;member;phosphodiesterase IV;promoter;translational study


application_id: 9462916
project_number: 5P20GM113226-03
project_title: Role of oxidized linoleic acid metabolites in the pathogenesis of alcoholic liver disease
administering_ic: NIGMS
award_notice_date: 2018-03-26
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6172
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
budget_end_date: 2019-03-31
project_abstract:
Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world andaffects millions of patients worldwide each year. Despite the progress made on ALD pathogenesis the specificmechanism(s) responsible for ALD development and progression remain poorly understood. Importantly thereis no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others havedemonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediatedliver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels ofcirculating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) inparallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in theoxidation of LA. These findings have led us to postulate that specific oxidized LA metabolites (OXLAMs) mayplay a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1(TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studiesdemonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms forstressor-induced pathogenesis and which upon activation trigger the release of highly pro-inflammatorycytokines interleukin-1 (IL-1) and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator ofinflammation and thus serves as a potential therapeutic target for treating hepatic inflammation in ALD. Basedon our own and other published findings our CENTRAL HYPOTHESIS is that OXLAMs play a significantrole in the development and progression of ALD. We hypothesize that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two mechanisms: 1) OXLAMs-mediated mitochondrialdysfunction and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation andIL-1 release. The proposed studies will lead to better understanding of molecular mechanisms contributing tothe pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to betterunderstand alcohol-diet interactions which may lead to identification of new therapeutic targets and potentialdietary interventions for treating ALD as well as help to explain why only some people who drink heavilydevelop clinically important ALD. A combination of in vitro in-vivo animal (knockouts and chimeric mousemodels) and human studies will be employed.

project_terms:
Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Centers of Research Excellence;Cessation of life;Chronic;Clinical;Data;Development;Diet;Dietary Intervention;Enzymes;Experimental Animal Model;FDA approved;Fatty Liver;Heavy Drinking;Hepatic;Hepatocyte;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Knock-out;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Mus;Oxides;Pathogenesis;Pathway interactions;Patients;Permeability;Pharmacology;Plasma;Play;Production;Publishing;Role;Signal Pathway;Signal Transduction;Testing;Toxicology;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;human study;in vitro testing;in vivo;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;mouse model;new therapeutic target;octadecadienoic acid;oxidation;peripheral blood;receptor;stressor;therapeutic target


application_id: 9462915
project_number: 5P20GM113226-03
project_title: ANIMAL MODEL AND BIOREPOSITORY CORE
administering_ic: NIGMS
award_notice_date: 2018-03-26
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6171
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: 2018-04-01
budget_end_date: 2019-03-31
project_abstract:
The primary function of Core D is to provide members of the Hepatobiology and Toxicology COBRE with theexpertise resources and facilities needed for animal husbandry necropsy and histological services for animalmodels of liver disease. The Core provides essential services by addressing the needs of COBRE-supportedjunior investigators COBRE members and other UofL investigators interested in liver disease research. Corepersonnel will ensure uniformity of husbandry and phenotyping so that the same set of characteristics ismeasured in each model. This uniformity ensures that the data generated within the COBRE are consistentand that results of one experiment will be directly comparable with the results of another. The Core will isolateprimary hepatic cells (parenchymal Kupffer stellate sinusoidal endothelial cells) for ex vivo and in vitrostudies. The Core will assist COBRE members in developing new mouse models of liver disease. The Corewill also facilitate cataloging and storage of animal and clinical samples in a biorepository that will providebiobanking infrastructure and support so that other researchers may share the tissue generated by COBRE-supported projects. The Core endeavors to contribute to the overall success and utility of the COBRE and toenhance the infrastructure and the technical and academic capabilities of the institution as a whole. In additionto its function as a service core Core D will also promote the education and training of the COBRE memberswith particular attention to the COBRE junior investigators. Core D will specifically communicate with COBREjunior investigators regarding their experimental requirements on a continual basis and appropriatelyparticipate in the planning execution and data analysis. To function as a vital integrative component of theCOBRE providing services not only for its members but also for the Institution as a whole Core D has thefollowing Specific Aims:1) To foster the development and success of current and future COBRE projects. 2) To educate andtrain investigators.3) To develop new protocols and techniques:4) To become an integral and self-sustaining component of the COBRE.

project_terms:
Address;Animal Husbandry;Animal Model;Animals;Attention;Autopsy;Basic Science;Biological Assay;Cataloging;Catalogs;Centers of Research Excellence;Characteristics;Clinical;Data;Data Analyses;Development;Endothelial Cells;Ensure;Equipment;Fee-for-Service Plans;Fostering;Future;Goals;Hepatic;Hepatocyte;Histologic;Human;Human Resources;In Vitro;Individual;Institution;Libraries;Liver;Liver diseases;Maintenance;Measurement;Measures;Methods;Mission;Modeling;Operative Surgical Procedures;Phenotype;Physiology;Procedures;Protocols documentation;Research;Research Activity;Research Infrastructure;Research Personnel;Resolution;Resources;Sampling;Services;Techniques;Tissue Banks;Tissues;Toxicology;Training;Training and Education;Translational Research;Translations;biobank;career;career development;design;experience;experimental study;flexibility;interest;investigator training;liver injury;meetings;member;mouse model;operation;success


application_id: 9462914
project_number: 5P20GM113226-03
project_title: ANALYTICAL CORE
administering_ic: NIGMS
award_notice_date: 2018-03-26
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6170
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: 2018-04-01
budget_end_date: 2019-03-31
project_abstract:
The University of Louisville Hepatobiology and Toxicology COBRE is a multidisciplinary group of investigatorsfocusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/drug interactions.The Bioanalytical Core is an integral part of the COBRE and will play a key role in the implementation andfuture development of COBRE-funded projects. The Core will provide the necessary expertise and state-of-the-art equipment for rigorous and comprehensive experimental evaluation of cell and tissue specimens toinvestigate the pathogenic mechanisms of liver disease. Besides providing requisite analytical services amajor goal of the Bioanalytical Core is to promote the education and training of the Center members withparticular attention to the COBRE junior investigators. The Bioanalytical Core will specifically communicatewith COBRE junior investigators regarding their experimental requirements on a continual basis andappropriately participate in the planning execution and data interpretation. The Bioanalytical Core will alsointeract with other COBRE Cores on a regular basis in order to avoid duplication of equipment orinstrumentation and to foster innovative protocol development and refinement exchange of ideas andintegrative analysis of data. The Core will provide technical and analytical expertise with centralized state-of-the-art equipment including Cellomics ArrayScan(R) VTI HCS Reader for automated microscope based highcontent screening and the Seahorse XF96 extracellular flux analyzer for cellular bioenergetics and metabolismstudies in real time. The Core facility is located in Clinical and Translational Research Building with 2500 sq.ftof operating space which is contiguous with the 20000 sq.ft laboratory space of the Hepatobiology andToxicology COBRE. Dr. Barve the Director of the Core has extensive experience in various analytical andexperimental approaches in the areas of liver injury and pathogenic mechanisms of liver disease. Before hismove to the University of Louisville he served for nearly a decade as the Director of the Molecular andCytokine Core Laboratory of the NIH-funded GCRC at the University of Kentucky and has considerableexperience in running a core laboratory. Also in this role he supported the career development of severaljunior faculty. To function as a vital integrative component of the Center providing services not only for itsmembers but also for the Institution as a whole the Bioanalytical Core has the following specific aims: 1) Tofoster the development and success of proposed COBRE projects and future pilots; 2) To play an active andsignificant role in the education and training of the investigators; 3) To assist and participate in thedevelopment of new experimental protocols and techniques; and 4) To become an integral and self-sustainingcomponent of the COBRE.

project_terms:
Address;Area;Attention;Award;Bioenergetics;Biological;Biological Assay;Cells;Centers of Research Excellence;Clinical Research;Communities;Continuing Education;Core Facility;Core Grant;Data Analyses;Detection;Development;Drug Interactions;Ensure;Environment;Equipment;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Felis catus;Fostering;Funding;Future;Genus Hippocampus;Glutathione;Goals;HIV;High Pressure Liquid Chromatography;In Vitro;Individual;Institution;Instruction;Journals;Kentucky;Laboratories;Liver;Liver diseases;Measurement;Measures;Metabolism;Methodology;Microscope;Mission;Molecular;Molecular Target;Pathogenicity;Performance;Phase;Play;Population;Proteins;Protocols documentation;Reader;Reagent;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Role;Running;S-Adenosylmethionine;Sampling;Services;Signal Pathway;Specimen;System;Techniques;Technology;Time;Tissues;Toxicology;Training and Education;Translational Research;United States National Institutes of Health;Universities;Whole Organism;base;career development;complex biological systems;cytokine;design;experience;experimental study;extracellular;innovation;instrumentation;interest;investigator training;liver injury;meetings;member;metabolic abnormality assessment;multidisciplinary;novel;programs;protocol development;research facility;screening;square foot;success;time use;toxicant

public_health_relevance:
The Bioanalytical Core is an integral part of the COBRE and will play a key role in the implementation andfuture development of COBRE-funded projects. The Core will provide the necessary expertise and state-of-the-art equipment for rigorous and comprehensive experimental evaluation of cell and tissue specimens toinvestigate the pathogenic mechanisms of liver disease.


application_id: 9462913
project_number: 5P20GM113226-03
project_title: OMICS CORE
administering_ic: NIGMS
award_notice_date: 2018-03-26
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6169
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: 2018-04-01
budget_end_date: 2019-03-31
project_abstract:
High-throughput 'omics analysis platforms are the technologies of choice for analyzing complex mixturesderived from tissues and biological matrices such as liver feces intestine blood and urine. To maximize ourcapability for deciphering the mechanism and therapy for liver injury nutrition and gut:liver interactions andliver:environment/toxin/drug interactions we propose an OMICS Core in this Hepatobiology and ToxicologyCOBRE proposal. Our OMICS Core is composed of three major components including Metabolomics CoreProteomics Core and Bioinformatics. The overarching goal of the OMICS Core is to support the proposedCOBRE research. This goal will be met through application of state of the art separations science and massspectrometry techniques to analyze research samples containing complex mixtures of metabolites proteinsand protein fragments. This goal is achieved through the following aims:Specific Aim 1: Application of liquid chromatography mass spectrometry (LC-MS) comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC/TOF-MS) and integrated laserablation inductively coupled plasma mass spectrometry (LA-ICP-MS) platforms for quantitative analysis ofmetabolites metal ions and metal-protein complex in biological samples.Specific Aim 2: Application of high-resolution multidimensional liquid chromatography mass spectrometry(MDLC-MS) and affinity enrichment methods for targeted protein quantification.

project_terms:
Ablation;Acetylation;Affinity;Alcohols;Arsenic;Binding;Bioinformatics;Biological;Blood;Cecum;Centers of Research Excellence;Chemicals;Complex Mixtures;Curcumin;Cysteine;DNA Binding Domain;Diet;Dimensions;Drug Interactions;Environment;Ethanol;Event;Feces;Gas Chromatography;Gel;Goals;Hepatic;Hepatic Stellate Cell;High Fat Diet;Immunoprecipitation;Inductively Coupled Plasma Mass Spectrometry;Inflammation;Injury;Intestines;Iodoacetamide;Iodoacetic Acid;Ions;Label;Lactobacillus casei rhamnosus;Large Intestine;Lasers;Linoleic Acids;Liquid Chromatography;Liver;Mass Spectrum Analysis;Measurement;Measures;Mediating;Metals;Methods;Methylation;Mus;Oxides;Pathology;Phenotype;Phosphopeptides;Phosphorylation;Plasma;Post-Translational Protein Processing;Production;Protein Fragment;Protein Isoforms;Proteins;Proteomics;Recombinant Proteins;Regulation;Research;Resolution;Role;Sampling;Science;Site;Small Intestines;Stable Isotope Labeling;Steatohepatitis;Techniques;Technology;Time;Tissue Sample;Tissues;Toxicology;Toxin;Tumor Promotion;Unsaturated Fatty Acids;Urine;Volatile Fatty Acids;Zinc;exosome;experimental study;feeding;liquid chromatography mass spectrometry;liver inflammation;liver injury;mass spectrometer;metabolomics;non-alcoholic fatty liver disease;novel;nutrition;oxidation;phosphodiesterase IV;protein complex;recombinant peptide;response;transcription factor;tumor growth;two-dimensional;zinc-binding protein


application_id: 9462910
project_number: 5P20GM113226-03
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2018-03-26
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: GOROSPE, RAFAEL
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: ZGM1-TWD-A(C1)
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 (UofL) Hepatobiology and Toxicology COBRE is a unique thematic research center. The UofL COBRE scientists comprise a multidisciplinary group senior mentors and junior investigators focusing on the mechanisms and therapy for liver injury nutrition and gut:liver interactions and liver:environment/toxin/dru interactions. The liver is the largest internal organ in the body and is possibly the most complexorgan in terms of metabolism. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) is the most common liver disease affecting about 1/3 of adults and over 10% of children in the US. NAFLD arises most commonly among overweight/obese individuals and is highly linked to the Metabolic Syndrome. Alcoholic Liver Disease (ALD) remains a common problem among those who drink. Environmental Toxicant Induced Liver Injury is an increasingly recognized problem and Louisville has been a leader in this area. Hepatitis B and C remain important causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Personalized Medicine is an increasingly important factor in medication efficacy. Drug-Induced Liver Injury (DILI) is the most common reason drugs are removed from the market and an important cause of liver failure. This COBRE brings together experienced senior mentors and promising junior investigators from across UofL in collaboration with scientists across the U.S./World to perform cross-cutting research on the unique topics of Hepatobiology and Toxicology. The Specific Aims of the Hepatobiology and Toxicology COBRE are to: 1. Develop a thematically-focused program in Hepatobiology and Toxicology that strengthens the overall research infrastructure at UofL. 2. Create a multidisciplinary program in research education mentoring and career development in Hepatobiology and Toxicology. 3. Provide the necessary research resources and translational science/basic technologies to support and sustain state-of-the-art research in Hepatobiology and Toxicology. 4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liver diseases/toxicant exposures and communicate our findings to the public.

project_terms:
Acute Liver Failure;Address;Adult;Affect;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;American;Area;Back;Basic Science;Blood Circulation;Carbohydrates;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communities;Complex;Core Facility;County;Data Analyses;Development;Diabetes Mellitus;Drug Interactions;Endotoxins;Environment;Enzymes;Evaluation;FDA approved;Fatty acid glycerol esters;Fostering;Goals;Government;Health;Hepatitis B;Hepatitis C;Hepatotoxicity;Home environment;Immune Tolerance;Individual;Industrialization;Industry;Kentucky;Link;Liver;Liver Failure;Liver diseases;Medical History;Mentors;Metabolic syndrome;Metabolism;Micronutrients;Molecular Target;Monitor;National Institute on Alcohol Abuse and Alcoholism;Neighborhoods;Obesity;Organ;Overweight;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Prevention;Primary carcinoma of the liver cells;Process;Production;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Scientist;Site;Specimen;Strategic Planning;Structure;Technology;Toxic Environmental Substances;Toxicant exposure;Toxicology;Toxin;Translational Research;United States National Institutes of Health;Universities;biobank;career development;education research;experience;liver injury;liver transplantation;medical complication;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;public health relevance;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE (provided by applicant): The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic research center. The UofL COBRE scientists comprise a multidisciplinary group senior mentors and junior investigators focusing on the mechanisms and therapy for liver injury nutrition and gut:liver interactions and liver:environment/toxin/drug interactions.


application_id: 9462412
project_number: 1R43GM123800-01A1
project_title: Novel fluorescent protein expression vector that simplifies the solubilization of membrane proteins
administering_ic: NIGMS
award_notice_date: 2017-09-18
opportunity_number: PA-16-302
application_type: 1
activity_code: R43
ic: GM
serial_number: 123800
suffix: A1
program_official: MARINO, PAMELA
project_start_date: 2017-09-20
project_end_date: 2019-03-19
study_section: Special Emphasis Panel[ZRG1 IMST-L (10)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
ABSTRACTSimple protein mutations can have serious consequences by causing diseases that affect people's lives. Proteintherapeutics are developed to target and replace those protein mutations and essentially to heal the disease.Distinctively membrane proteins make up over 60% of today's drug targets. However cumbersome time-consuming and often ineffectual purification methods have hampered membrane protein purification anddownstream experimentation. The long-term objective of this application is to develop a rapid and simplifiedmethod for enhanced expression and tailoring purification to each specific membrane protein; this wouldgreatly enhance commercial opportunities for this important therapeutic sector.The baculovirus expression vector system (BEVS) is commonly used for production of proteins for structure-function studies vaccines and therapeutics but membrane proteins are often poorly expressed and difficult topurify. ParaTechs (www.ParaTechs.com) currently markets insect cells and vectors that provide heightenedexpression of foreign genes due to delayed lysis and increased overall health of infected cells. This proposalseeks to expand our baculovirus product line through the development of this innovative tool by combining thevankyrin-enhanced baculovirus expression vector system with a novel fluorescent fusion tag that will aid theexpression and solubilization of membrane proteins. Aim one is to design baculovirus transfer vectors andviruses harboring both the vankyrin gene and membrane proteins fused to the novel fluorescent tag. Thesecond aim will evaluate the stability of the fluorescent tag in the detergents selected for the solubilizationscreen. Aim three of this application will compare the efficiency and efficacy of membrane protein expressionand purification using a new solubilization screen that is compatible with the recombinant baculovirusesproduced in the first aim.The here developed fluorescent selection technology will allow enhanced functional protein production rapididentification of detergents that enable successful solubilization and easy optimization of protein purificationconditions. This innovative technology will overcome two major barriers in the development of proteintherapeutics namely the expression of large quantities of pure properly processed membrane proteins and tosolubilize active proteins from membranes.

project_terms:
Affect;Antigens;Baculoviridae;Baculoviruses;Biological Assay;Cell Communication;Cells;Charge;Chimeric Proteins;Cloning;Column Chromatography;Complex;Cytolysis;Detergents;Development;Disease;Drug Targeting;Elements;Failure;Gene Proteins;Genes;Health;Incubated;Infection;Insecta;Life;Lipid Bilayers;Literature;Mammalian Cell;Membrane Proteins;Methods;Mutation;Nickel;Outcome;Phase;Process;Production;Property;Proteins;Reagent;Recombinants;Research;Sampling;Signal Transduction;Solubility;Structure;System;Technology;Testing;Therapeutic;Time;Transport Process;Ultraviolet Rays;Vaccines;Virus;Western Blotting;base;commercial application;cost effective;design;expression vector;healing;improved;innovation;innovative technologies;interest;laboratory equipment;novel;prevent;protein aggregate;protein expression;protein function;protein purification;protein structure function;screening;stability testing;synergism;technological innovation;therapeutic protein;tool;vector

public_health_relevance:
PROJECT NARRATIVEProtein therapeutics and vaccines are valuable tools that reduce or prevent illness enhance the quality of one'slife lengthen life and improves health overall. Unfortunately the difficulty of expressing and purifyingfunctional membrane proteins is a critical barrier to the progress in membrane protein research. This proposedresearch will create a technological innovation that will overcome those hurdles to further advance the utility ofprotein therapeutics.!


application_id: 9462392
project_number: 1R43AI136151-01
project_title: Exploiting activation-induced cell death as a means of inducing tolerance to kidney allografts
administering_ic: NIAID
award_notice_date: 2018-08-20
opportunity_number: PA-16-302
application_type: 1
activity_code: R43
ic: AI
serial_number: 136151
program_official: MINNICOZZI, MICHAEL
project_start_date: 2018-08-20
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZRG1 IMM-R (10)]
contact_pi_person_id: 8029708
contact_pi: YOLCU, ESMA S
other_pis: REDFIELD, ROBERT RAY
congressional_district: 03
department: Unavailable
primary_duns: 079603469
primary_uei: LNESEBSKBHK8
duns_number: 079603469
uei: LNESEBSKBHK8
fips: US
organization_id: 10037836
organization_name: FASCURE THERAPEUTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYKidney transplantation is the preferred treatment for patients with end-stage renal disease. However standardimmunosuppression to control rejection is the major limitation. Although standard immunosuppression hasgradually been improved for better efficacy and safety it still carries a great risk for adverse effects rangingfrom malignancies and infections to cardiovascular complications. As such there is an acute need fordeveloping novel immunomodulatory approaches that obviate the need for chronic immunosuppression ormitigate immunosuppression for improved safety. The goal of this phase I SBIR application is tosimultaneously target Fas and IL-2R as an innovative immunomodulatory approach to modulate pathogenic Teffector (Teff) and protective T regulatory (Treg) cells for induction of tolerance to rat kidney allografts in theabsence of any immunosuppression. FasCure Therapeutics is focused on the development of biologics with desired immunomodulatoryactivities for targeted indications. The Company has exclusive rights to a portfolio of proprietary novel immuneinhibitory ligands as components of a therapeutic platform for prevention and treatment of autoimmunediseases and foreign graft rejection. The Companys lead therapeutic platform involves the use of SA-FasLand IL-2D as novel forms of Fas and IL-2R agonists respectively to directly target pathogenic Teff cells forphysical elimination (apoptosis) and protective Treg cells for expansion. Teff cells are the main culprits ofallogeneic graft rejection. These cells upregulate Fas receptor on their surface following antigen activation andbecome sensitive to Fas/FasL-mediated apoptosis. IL-2 is critical for the generation and expansion ofCD4+CD25+FoxP3+ Treg cells. IL-2 is also involved in apoptosis of Teff cells by down-regulating anti-apoptoticgenes. As such the combination of SA-FasL and IL-2D has the potential to physically eliminate Teff andexpand Treg cells. An increased Treg/Teff ratio has significant potential to sustain renal allograft survival in theabsence of chronic immunosuppression. This notion is supported by strong preliminary data in allogeneicpancreatic islet and cardiac graft models in mice. The major goals of this phase I SBIR application is to: i)establish a lead SA-FasL+IL-2D treatment protocol that sustains permanent rat kidney allograftsurvival in the absence of any immunosuppression and ii) investigate the mechanistic basis ofsustained graft survival and the safety profile of the immunomodulatory protocol. If efficacy is shown inthe proposed rat model this protocol will be further developed as a novel product in a Phase II SBIRapplication for translation into nonhuman primates as a prelude to clinical trials.

project_terms:
Acute;Adverse effects;Agonist;Allogenic;Allograft Tolerance;Allografting;Antigens;Apoptosis;Apoptotic;Autoimmune Diseases;Binding;Biologic Development;CASP3 gene;CD95 Antigens;Cardiovascular system;Cell Death;Cells;Chronic;Clinical;Clinical Trials;Complex;Containment;Contracts;Data;Down-Regulation;End stage renal failure;Equilibrium;Eragrostis;FOXP3 gene;Failure;Formulation;Frequencies;Generations;Genes;Goals;Graft Rejection;Graft Survival;Heart;Heart Transplantation;Homologous Transplantation;Human;IL2 gene;IL2RA gene;Immune;Immune Targeting;Immune response;Immunosuppression;Infection;Interleukin-2;Islets of Langerhans;Kidney;Kidney Transplantation;Lead;Ligands;Maintenance;Malignant Neoplasms;Manufacturer Name;Mediating;Membrane;Modeling;Molecular;Mus;Organ;Outcome;Pathogenicity;Patients;Peripheral;Phase;Physiological;Play;Prevention;Protocols documentation;Rattus;Recombinant Proteins;Regulation;Regulatory T-Lymphocyte;Rights;Risk;Rodent;Role;Safety;Small Business Innovation Research Grant;Solid;Streptavidin;Surface;T-Lymphocyte;Therapeutic;Toxic effect;Translational Research;Translations;Transplantation;Transplantation Tolerance;Treatment Protocols;Tumor Necrosis Factor Ligand Superfamily Member 6;allograft rejection;cGMP production;cell type;clinical translation;delta protein;efficacy testing;first-in-human;immunoregulation;improved;innovation;islet;kidney allograft;nonhuman primate;novel;product development;scale up;success;technological innovation

public_health_relevance:
PROJECT NARRATIVEKidney transplantation is the preferred treatment for patients with end-stage renal disease. However standardimmunosuppression to control rejection is the major limitation as it carries a great risk for adverse effectsranging from malignancies infections and cardiovascular complications. As such there is an acute need fordeveloping novel immunomodulatory approaches that obviate the need for chronic immunosuppression ormitigate immunosuppression with improved safety. The goal of this phase I SBIR application is to use twonovel biologics as an innovative immunomodulatory approach to achieve permanent renal allograft survival theabsence of chronic immunosuppression as a prelude to clinical trials.


application_id: 9462201
project_number: 5R01HL120507-04
project_title: Lipid phosphate phosphatase 3 as a novel atherosclerosis suppressor
administering_ic: NHLBI
award_notice_date: 2018-03-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 120507
program_official: HASAN, AHMED A K
project_start_date: 2015-04-01
project_end_date: 2021-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: MORRIS, ANDREW J
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) is an essential bioactive phospholipid mediator that regulates a range of developmental and physiological processes which are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque increases during acute myocardial infarction triggers phenotypic responses in smooth muscle cells and disrupts endothelial integrity. We and others have demonstrated that LPA promotes both the development of intimal hyperplasia following injury and atherosclerosis in experimental models. Lipid phosphate phosphatase 3 (LPP3) encoded by the PPAP2B gene is an integral membrane enzyme that regulates the bioavailability of LPA. We have recently demonstrated that LPP3 is an intrinsic negative regulator of vascular inflammation suppresses smooth muscle cell proliferation and promotes endothelial barrier function likely by limiting LPA signaling. Analysis of data from a series of genome-wide association studies of coronary artery disease (CAD) identified a striking association between the PPAP2B locus and myocardial infarction. We provide evidence that CAD-risk associated PPAP2B variant disrupts an intronic enhancer that increases transcription of the gene and LPP3 expression in ox-LDL stimulated macrophages. These findings suggest the testable hypothesis that LPP3 functions as an atherosclerosis suppressor and that reduced PPAP2B gene expression aggravates cellular events underlying atherosclerosis and increases the likelihood of myocardial infarction. In this proposal we will define the role of LPP3 in the development of atherosclerosis provide insight into the molecular mechanism(s) involved and validate the predicted risk allele associated with CAD in humans. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPP3. Completion of these studies promises to provide valuable insight into the mechanism(s) by which extracellular bioactive lipid mediators influence the development of atherosclerosis and provide novel and innovative targets to predict prevent and treat CAD.

project_terms:
Acute myocardial infarction;Alleles;Arterial Fatty Streak;Atherosclerosis;Attenuated;Binding;Biological Availability;Blood Cells;Blood Vessels;CCAAT-Enhancer-Binding Proteins;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Proliferation;Cell Survival;Cell model;Cell surface;Cells;Clinical;Complement;Coronary Arteriosclerosis;Coronary artery;Cultured Cells;Data Analyses;Deposition;Development;Developmental Process;Diagnosis;Disease;Drosophila genus;Enhancers;Enzymes;Event;Experimental Models;Family;Gene Expression;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Genetic Variation;Goals;Homologous Gene;Human;Human Genetics;Hyperplasia;Inflammatory;Injury;Introns;Investigation;Knowledge;Lipids;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Membrane;Molecular;Mus;Myocardial Infarction;Myocardial Ischemia;Phenotype;Phospholipids;Phosphoric Monoester Hydrolases;Physiological Processes;Positioning Attribute;Predisposition;Publishing;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Risk;Risk Factors;Role;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Site-Directed Mutagenesis;Smooth Muscle Myocytes;Stable Isotope Labeling;Stimulus;Testing;Therapeutic;Tissues;United States;Up-Regulation;Variant;Work;base;cardiovascular disorder risk;cell motility;disorder risk;extracellular;genetic variant;genome wide association study;improved;innovation;inorganic phosphate;insight;lipid mediator;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;monocyte;mortality;mouse model;novel;novel therapeutic intervention;oxidized low density lipoprotein;prevent;public health relevance;response;risk variant;tool;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Ischemic heart disease is a leading cause of death in the United States. Genetic variation in the gene encoding lipid phosphate phosphatase 3 (LPP3) an enzyme that regulates the bioavailability of lysophospholipids was recently identified to predict the development of coronary artery disease and acute myocardial infarction. We propose that LPP3 functions as an atherosclerosis suppressor. Completion of our work will define mechanism(s) involved and may implicate bioactive lipid mediators in the development of ischemic heart disease which will ultimately provide novel and innovative targets to predict prevent and treat coronary artery disease.


application_id: 9462048
project_number: 5F32AR069985-03
project_title: Enhancing myoblast fusion in muscular dystrophy
administering_ic: NIAMS
award_notice_date: 2018-05-11
opportunity_number: PA-14-149
application_type: 5
activity_code: F32
ic: AR
serial_number: 069985
program_official: BOYCE, AMANDA T
project_start_date: 2016-04-01
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZRG1-F10B-B(20)L]
contact_pi_person_id: 11651573
contact_pi: HINDI, SAJEDAH M
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:
DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disorder. Augmenting the regeneration potential of endogenous muscle progenitor cells is one of the potential approaches to attenuate disease progression in DMD. Moreover introduction of exogenous muscle stem cells can be used as an approach to restore dystrophin levels in DMD patients. However transplantation of muscle stem cells into dystrophic muscles typically results in minimal engraftment which is attributed at least in part o the poor fusion of the introduced myogenic cells with injured myofibers. While the mechanisms of myoblast fusion remain less understood enhancing fusion of endogenous or introduced myogenic cells has enormous potential for the development of novel cellular therapies for DMD patients. Ongoing studies in my laboratory have identified myeloid differentiation primary response gene 88 (Myd88) as a major positive regulator of myoblast fusion. Our preliminary studies have shown that levels of Myd88 are increased during muscle regeneration and upon induction of differentiation in cultured myoblasts. Genetic deletion of Myd88 specifically inhibitsmyoblast fusion without affecting their proliferation and differentiation. While our preliminary studies clearly demonstrate that Myd88-mediated signaling promotes myoblast fusion it remains unknown whether augmenting the levels of Myd88 in myoblasts can stimulate myofiber regeneration and improve engraftment of introduced myoblasts in DMD. In this project we have proposed to investigate the effects of myoblast-specific ablation and overexpression of Myd88 on disease progression in a preclinical mouse model of DMD. Our hypothesis and specific aims are: AIM I: Investigate the effects of myoblast-specific deletion of Myd88 in myopathy of mdx mice. Hypothesis I: Myoblast-specific deletion of Myd88 will inhibit repair of injured myofibers and exaggerate myopathy in mdx mice. AIM II: Investigate the effects of myoblast-specific overexpression of Myd88 in the pathogenesis of mdx mice. Hypothesis IIa: Overexpression of Myd88 in exogenous myoblasts (before transplantation) will improve their engraftment in dystrophic muscle of mdx mice; and Hypothesis IIb: Myoblast-specific transgenic overexpression of Myd88 will enhance myofiber regeneration and mitigate myopathy in mdx mice. Successful completion of this work will provide basis for considering Myd88 as therapeutic target in preclinical trials for patients with DMD. Furthermore the project will provide me outstanding new training to achieve my goal of becoming a tenure-track faculty in an academic institution.

project_terms:
Ablation;Adult;Affect;Attenuated;Caliber;Cell Therapy;Cells;Cessation of life;Complementary DNA;Defect;Development;Disease Progression;Duchenne muscular dystrophy;Dystrophin;Engraftment;Faculty;Fibrosis;Fluorescence;Future;Gene Expression;Genes;Genetic;Genetic Diseases;Genomics;Goals;Impairment;In Vitro;Inbred mdx Mice;Individual;Injury;Institution;Interleukin-1;Knock-out;Knockout Mice;Laboratories;Lentivirus Vector;Life;Mediating;Messenger RNA;Mus;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myelogenous;Myoblasts;Myopathy;Natural regeneration;Pain;Pathogenesis;Pathway interactions;Patients;Phenotype;Physiological;Pre-Clinical Model;Process;Proteins;Proteomics;Reporting;Role;Signal Pathway;Signal Transduction;Signaling Protein;Skeletal Muscle;Small Interfering RNA;Stem cells;Toll-like receptors;Training;Transgenic Mice;Transgenic Organisms;Transplantation;WNT Signaling Pathway;Wild Type Mouse;Work;barium chloride;disability;gain of function;improved;injured;interleukin-18 receptor;knock-down;loss of function;molecular targeted therapies;mouse model;muscle regeneration;muscle transplantation;novel;overexpression;pre-clinical;preclinical trial;premature;promoter;public health relevance;reduced muscle strength;repaired;response;tenure track;therapeutic target;tibialis anterior muscle

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is the most prevalent form of muscular dystrophy which involves severe muscle-wasting fibrosis and premature death of afflicted individuals. We have identified Myd88 as a major regulator of myoblast fusion. We will investigate whether enhancing the levels of Myd88 in myoblasts can improve their fusion and improve regeneration of myofibers in preclinical models of DMD. Our proposed studies will provide strong basis whether Myd88 can be used as novel molecular target for treatment of DMD patients in future therapies.


application_id: 9461971
project_number: 8UG1OD024954-02
project_title: The Kentucky Pediatric Clinical Trials Rural/Urban Partnership
administering_ic: OD
award_notice_date: 2017-04-11
opportunity_number: RFA-OD-16-001
application_type: 8
activity_code: UG1
ic: OD
serial_number: 024954
program_official: BLAISDELL, CAROL J
project_start_date: 2016-09-23
project_end_date: 2020-08-31
study_section: ZHD1-DRG-S(55)
contact_pi_person_id: 2311234
contact_pi: SULLIVAN, JANICE E
other_pis: WATSON, SARA E
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/ABSTRACT As a predominantly rural state Kentucky leads the nation in many pediatric and adult chronic andenvironmentally-related diseases and ranks nationally in low educational achievement. These adverse factorscombine to make Kentuckians especially unhealthy residents with a high prevalence of obesity diabetessmoking alcohol use heart disease stroke lung cancer etc. Many of these diseases are environmentallyrelated to poor nutrition obesity smoking drug abuse and work-place exposures. Kentucky also leads thenation in the percentage of pediatric populations with special health care needs. Prior work has shown thatmost adult diseases begin in childhood and some begin during intrauterine exposure making childhood theideal time for intervention with the goal of improving health outcomes into adulthood. Improving healthcare outcomes and wellness in children is contingent on expanding high quality clinicalresearch to include more diverse populations. Pediatricians at the University of Louisville (UofL) with ourHealthcare Partners serve a highly diverse patient population that includes the rural and urban poor a uniqueAppalachian community refugees and numerous ethnic minorities. In order to better serve this population wepropose to build upon our current programs expand our bidirectional community engagement effortscollaborate with other institutions on pediatric clinical trials through the IDeA Pediatric Trials Network andcollaborate with ECHO and CHEAR sites to advance healthcare for children. The Kentucky-Pediatric IDeA Research Center (K-PIRC) as part of the IDeA States Pediatric Clinical TrialNetwork will make it possible for 1) underserved rural and urban infants children and adolescents toparticipate in clinical research; 2) junior investigators to be trained in clinical research and communityengagement improve the health of both children and adults in Kentucky through this research and developtheir academic career; and 3) create a regional network of partners to sustain this clinical research initiative.The four primary focus areas of research are 1) upper and lower airway disease; 2) obesity; 3) pre- peri- andpostnatal outcomes; and 4) neurodevelopmental outcomes. These primary focus areas have a highprevalence in Kentucky therefore K-PIRC will enable strengthening current collaborations and accelerate thedevelopment of new networks within the state through bidirectional community engagement and feedback tosupport pediatric clinical research. Ultimately through these efforts the health outcomes of Kentucky childrenand adults will improve and a sustainable pediatric clinical research workforce locally and nationally will beestablished.

public_health_relevance:
PROJECT NARRATIVEThe Kentucky-Pediatric IDeA Research Center (K-PIRC) as part of the IDeA States Pediatric Clinical TrialNetwork will make it possible for: 1) underserved rural and urban infants children and adolescents toparticipate in clinical research; 2) junior investigators to be trained in clinical research and communityengagement improve the health of both children and adults in Kentucky through this research and developtheir academic career; and 3) create a regional network of partners to sustain this clinical research initiative.The four primary focus areas are 1) upper and lower airway disease; 2) obesity; 3) pre- peri- and postnataloutcomes; and 4) neurodevelopmental. These primary focus areas are highly prevalent in Kentucky thereforethe efforts of the K-PIRC in collaboration with our community partners will improve the health outcomes ofKentucky children and adults.


application_id: 9461957
project_number: 5F30ES025099-04
project_title: Xenobiotic Receptors Modulate PCB-induced Steatohepatitis
administering_ic: NIEHS
award_notice_date: 2018-03-06
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: ES
serial_number: 025099
program_official: SCHUG, THADDEUS
project_start_date: 2015-04-15
project_end_date: 2019-04-14
study_section: Special Emphasis Panel[ZRG1-F06-S(20)L]
contact_pi_person_id: 12058438
contact_pi: CLAIR, HEATHER B
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): Non-alcoholic fatty liver disease (NAFLD) is intimately associated with obesity diabetes and the metabolic syndrome. Traditionally NAFLD has been associated with caloric excess on a susceptible genetic background however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of steatosis and steatohepatitis particularly inthe context of hypercaloric diet coexposure. Our proposed study uses exposure parameters informed by our recent analysis of serum samples from a previously-described cohort of individuals residing in Anniston AL who were exposed to high levels of PCB-containing waste. Although many of these individuals have serum levels of PCBs above that found in the general population of the US their exposures remain well below the levels implicated in acute liver injury. Nevertheless these individuals have significantly elevated biomarkers of liver injury as well as elevated inflammatory cytokines elevated prevalence of diabetes and increased BMI when compared to an unexposed population. A frustrating finding of previous toxicity studies has been the very different pathological response of mice and humans to such subacute chronic and environmentally relevant PCB exposures. Our preliminary data in a mouse model of subacute PCB exposure shows paradoxical elevations of liver injury biomarkers fatty change and inflammatory cytokines at lower exposure vs. higher exposure to a PCB mixture (20mg Aroclor 1260/kg body weight vs. 200mg/kg body weight Aroclor 1260). In two knockout mouse models that lack the constitutive androstane receptor (CAR) or the pregnane and xenobiotic receptor (PXR) our laboratory has found differential transcription of the gene targets of these receptors in response to Aroclor 1260 and high-fat diet exposure. These patterns of pathological and phenotypic responses are consistent with a transcription-factor based mechanism of PCB toxicity. The differences in disease endpoints may therefore be due to differences in ligand specificity and target gene cohort between the human and mouse forms of these receptors. We therefore propose to expand our investigation of receptor-based mechanisms of PCB toxicity with the use of a novel triple-transgenic mouse model expressing human forms of AhR PXR and CAR. We hypothesize that using both an acute-exposure primary hepatocyte culture and a whole animal chronic exposure model we will find that differences in the structure and function of these receptors will drive a differential transcriptioal response to PCBs and ultimately differences in PCB-associated disease endpoints.

project_terms:
AHR gene;Acute;Address;Adolescent;Adult;Affect;Affinity;Animals;Aryl Hydrocarbon Receptor;Biological Markers;Body Weight;Cessation of life;Chemicals;Chronic;Cirrhosis;Comorbidity;Complex;Computer Simulation;Data;Diabetes Mellitus;Diet;Disease;Dose;Energy Intake;Environmental Exposure;Environmental Risk Factor;Enzymes;Etiology;Exposure to;Fatty Change;Fatty Liver;Gene Expression;Gene Targeting;General Population;Genes;Genetic;Genetic Transcription;Hepatic;Hepatocyte;High Fat Diet;Human;Individual;Industrialization;Inflammation;Inflammatory;Insulin Resistance;Investigation;Knockout Mice;Laboratories;Ligands;Lipids;Liver;Liver diseases;Mediating;Metabolic Diseases;Metabolic syndrome;Metabolism;Microarray Analysis;Modeling;Molecular Weight;Mus;National Health and Nutrition Examination Survey;Nutritional;Obesity;Odds Ratio;Overweight;Participant;Pathologic;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Pollution;Polychlorinated Biphenyls;Population;Pregnanes;Prevalence;Primary carcinoma of the liver cells;Receptor Activation;Research;Role;Sampling;Serum;Specificity;Steatohepatitis;Structure;Testing;Toxic Environmental Substances;Toxic effect;Transcript;Transgenic Mice;Transplantation;Wild Type Mouse;Xenobiotics;acute liver injury;base;carbohydrate metabolism;cardiovascular risk factor;cohort;constitutive androstane receptor;cytokine;design;exposed human population;improved;liver injury;mRNA Expression;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;persistent organic pollutants;population based;public health relevance;receptor;receptor function;response;transcription factor;transcriptome;transcriptomics;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traditionally non-alcoholic fatty liver disease has been associated with high caloric intake however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of fatty liver and liver disease. This application studies the connection of pollution andliver disease.


application_id: 9461345
project_number: 3R00CA181500-04S1
project_title: The Role of Protein Tyrosine Phosphate PRL3 in Leukemia Development
administering_ic: NCI
award_notice_date: 2017-08-31
opportunity_number: PA-17-138
application_type: 3
activity_code: R00
ic: CA
serial_number: 181500
suffix: S1
program_official: JHAPPAN, CHAMELLI
project_start_date: 2017-08-01
project_end_date: 2018-07-31
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA 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 aggressive and unpredictable nature of relapsed T-cell acute lymphoblastic leukemia (T-ALL) represents a major clinical challenge in large part due to highly toxic and ineffective chemotherapies. Further advances in therapy will require a detailed understanding of the molecular underpinnings of T- ALL development and relapse. To this end I have completed a highly innovative screen in zebrafish to identify genes associated with T-ALL progression and have found that the protein tyrosine phosphotase PRL-3 was commonly amplified in single T-ALL cells as they developed increased ability to form relapse over time. In transgenic animals PRL-3 over-expression significantly enhanced primary T-ALL development and relapse formation. I have found that PRL-3 amplified in a subset of human T-ALL and is highly expressed by a majority of T-ALL patient samples. These cells are also sensitive to PRL-3 knock-down through the induction of apoptosis. These results imply that PRL-3 activity has an important role in T-ALL malignancy and that PRL-3 and its substrates may represent novel therapeutic targets for the treatment of T-ALL. The objectives of this proposal are to 1) define the contribution of PRL-3 to T- ALL progression and relapse and 2) identify the mechanism by which PRL-3 drives T-ALL malignancy. This objective will be achieved through two specific aims. During the K99 phase of this award I will complete Aim 1 where I will examine the effect of PRL-3 gain-of-function and loss-of-function in various stages of T-ALL development in zebrafish including invasion from the thymus intravasation proliferation and relapse and I will also test the effects of PRL-3 knock-down on human cells in a murine xenograft model. During this phase I will learn techniques to directly image cancer progression in live animals and to develop orthotopic leukemia xenografts in mice. With this knowledge in hand during the R00 phase I will complete Aim 2 where I will identify the target substrates of PRL-3 in T-ALL cells and test the contribution of these genes and pathways to T-ALL malignancy using in vivo and in vitro epistasis experiments. In total this work will lay the foundation for the development of small molecule PRL-3 and pathway inhibitors for potential therapeutic use in T-ALL. The mentored phase of this award will occur under the guidance of Dr. David Langenau an expert in zebrafish models of cancer and Dr. Thomas Look an internationally recognized leader in the field of leukemia research. Their proven track record of mentorship coupled with an intensive didactic component and the rigorous and nurturing academic environment offered by the research community of Massachusetts General Hospital and Harvard Medical School offer the best opportunity for my success as I transition to becoming an independent investigator.

project_terms:
Acute;Acute T Cell Leukemia;Adult;Adverse effects;Animals;Award;B-Cell Acute Leukemia;Behavior;Cancer Model;Cell Line;Cells;Chemotherapy-Oncologic Procedure;Child;Childhood;Chronic Myeloid Leukemia;Clinical;Clinical Treatment;Communities;Coupled;Data;Development;Drug Targeting;Environment;Foundations;General Hospitals;Genes;Genetic Epistasis;Goals;Hand;Human;In Vitro;Induction of Apoptosis;International;Knowledge;Learning;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Modeling;Molecular;Molecular Target;Multiple Myeloma;Mus;Nature;Oncogenes;Outcome;Pathway interactions;Patients;Phase;Phosphorylation;Play;Protein Tyrosine Phosphatase;Proteins;Relapse;Research;Research Personnel;Role;Sampling;Solid Neoplasm;Survival Rate;Techniques;Testing;Therapeutic;Therapeutic Uses;Thymus Gland;Time;Transgenic Animals;Tumor stage;Tyrosine;Work;Xenograft Model;Xenograft procedure;Zebrafish;base;cancer imaging;cancer type;chemotherapy;defined contribution;experimental study;gain of function;improved;in vivo;inhibitor/antagonist;innovation;inorganic phosphate;knock-down;leukemia;loss of function;medical schools;molecular targeted therapies;mortality;mouse model;new therapeutic target;novel;outcome forecast;overexpression;phosphoproteomics;pre-clinical trial;public health relevance;small molecule;small molecule inhibitor;success;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Relapse in the major cause of mortality in patients with T-cell acute lymphoblastic leukemia due to ineffective therapeutics. The protein tyrosine phosphotase PRL-3 is emerging as an important contributing oncogene in cancer progression. This proposal will define the mechanism by which PRL-3 drives T-ALL malignancy to identify novel molecular targets for the treatment of T-ALL.


application_id: 9461023
project_number: 5R44AT008312-03
project_title: Harvesting specific plant metabolites from hairy root cultures using magnetized nanoparticles
administering_ic: NCCIH
award_notice_date: 2018-03-23
opportunity_number: PA-16-302
application_type: 5
activity_code: R44
ic: AT
serial_number: 008312
program_official: HOPP, CRAIG
project_start_date: 2014-06-01
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1-BST-F(10)B]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Plant cell cultures are becoming a commercially valuable source of pharmaceuticals particularlythose that are too complex for economical chemical synthesis. For example Phyton Biotech in Germany hasachieved great commercial success by generating taxoids for Paclitaxel production in sterile plant cellbioreactors. However the efficiency of these systems is limited by the loss in viability of the slow-growing plantcells associated with conventional extraction procedures. The objective here is to develop a system thatallows plant cells to be harvested repeatedly for high value pharmaceutical products without losing viability.Phase I demonstrated that nanoparticles can be functionalized to enter plant cells and bind specific bioactiveflavonoid metabolites before being extruded and these metabolites recovered all without loss of plant cellviability. Phase II now aims to demonstrate that a similar but more selective approach can be used to harvesthigher value pharmaceuticals from plant cells (i.e. proof of application). The most valuable types of metabolitecurrently produced from plants include isoflavones alkaloids and monoclonal antibodies (the latter fromtransgenic plants). Phase II aims to show that each of these types of product can be harvested from plant cellsby their selective binding to nanoparticles on which specific oligopeptides have been conjugated. Each productexample is relevant to anti-cancer therapeutics. The first is the phytoestrogen liquiritigenin which is a selectiveagonist of the estrogen receptor (ER)beta that should reduce risk of breast cancer post-menopause. Thisflavanone will be harvested from overproducing mutant cultures of licorice root by selective binding to theERbeta ligand-binding oligopeptide conjugated to nanoparticles. The second example is to nanoharvest thechemotherapeutic vinca alkaloids (currently extracted from intact plant material by Eli Lilly) from overproducingmutant cultures of Catharanthus roseus. These alkaloids will be harvested by affinity to nanoparticles bearingoligopeptides representing their binding sites on human tubulin. These two examples are natural metabolitesbut the most commercially important application of this technology may be to harvest foreign polypeptides i.e.biologics such as antibodies from transgenic plant cells. Here the example will be the harvesting fromtransgenic tobacco cell cultures of a monoclonal antibody (mAbH10) directed against tumor cells. Selectivebinding will be achieved using nanoparticles in which an oligopeptide mimicking the antibody-binding site onthe antigen has been conjugated to the surface. In all of these examples the objective is to show thatnanoparticles can repeatedly remove the desired commercial product without loss of plant cell viability. Thiswill reduce down time and could also reduce response time for example the urgent requirement forantibodies or vaccines in an outbreak of disease. In addition separation of product by affinity to anoligopeptide binding site means that the harvested products will be simultaneously semi-purified. Phase IIshould demonstrate proof of application for the nanoparticle harvesting technology as applied to high valueanti-cancer pharmaceuticals. The applicants will then move toward commercialization in partnership withidentified pharmaceutical and biotechnology companies in the US and Europe (see Commercialization Plan).

project_terms:
Affect;Affinity;Agonist;Agreement;Alkaloids;Antibodies;Antibody Binding Sites;Antigens;Artificial nanoparticles;Binding;Binding Sites;Bioreactors;Biotechnology;Breast Cancer Risk Factor;Catharanthus roseus;Cell Culture Techniques;Cell Survival;Cells;Characteristics;Chemicals;Complex;Development;Disadvantaged;Disease Outbreaks;Engineering;Equilibrium;Estrogen Receptor beta;Europe;Excision;Exposure to;Flavanones;Flavonoids;Fluorescence;Germany;Harvest;Human;Immobilization;In Vitro;Individual;International;Isoflavones;Legal patent;Licensing;Licorice;Ligand Binding;Monoclonal Antibodies;Mutation;Nicotiana tabacum;Oligopeptides;Paclitaxel;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Phytoestrogens;Plant Roots;Plants;Postmenopause;Procedures;Production;Proteins;Quartz;Reaction Time;Source;Sterility;Surface;System;Taxoids;Technology;Testing;Therapeutic Effect;Time;Tissues;Tobacco;Transgenic Organisms;Transgenic Plants;Tubulin;Vaccines;Vinca Alkaloids;anti-cancer;anti-cancer therapeutic;antigen binding;base;cell injury;chemical synthesis;chemotherapy;commercialization;crystallinity;experimental study;indexing;kartocid;mutant;nanoparticle;neoplastic cell;polypeptide;protein aminoacid sequence;radioligand;solvent extraction;success

public_health_relevance:
Project narrativeDrugs can be produced in plant cell cultures as an alternative to extracting them from intact plants. This hassome advantages but a major disadvantage is that harvesting the drugs requires the destruction of the slowgrowing and expensive plant cell cultures. This phase II proposal is to further develop a continuous harvestingsystem in which nanoparticles can be used to extract drugs from plant cells without damaging the cells.


application_id: 9460586
project_number: 5R24OD021479-03
project_title: Developing Regeneration Resources for a Model Amphibian
administering_ic: OD
award_notice_date: 2018-03-31
opportunity_number: PAR-13-252
application_type: 5
activity_code: R24
ic: OD
serial_number: 021479
program_official: MIROCHNITCHENKO, OLEG
project_start_date: 2016-06-01
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: THORSON, JON SCOTT
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This Multi-PD/PI application seeks to develop resources that will better enable studies of a highly regenerative amphibian the Mexican axolotl (Ambystoma mexicanum). There is need to probe axolotl regeneration more deeply with the same powerful approaches that have proven so effective in genetic model organisms. Specific Aim 1 will accomplish the first chemical genetic screen of axolotl regeneration using an embryo tail regeneration assay. Using pre-feeding axolotl embryos that are efficiently reared in micro-titer plates up to 10000 soluble chemicals from commercial clinical-stage and novel natural products libraries will be tested for impact on tail regeneration. Preliminary data show that the chemical screen and tail regeneration assay are likely to identify new molecules that impact regeneration. Positive hits from this screen including previously identified inhibitors of Wnt Tgf and Fgf signaling will be reported to the community and investigated further under Specific Aim 2 using cellular and transcriptional approaches. In particular assays will be developed to assess chemical effects on formation of the wound epidermis which acts as an early signaling center in the recruitment of progenitor/stem cells. Also assays will be developed to assess cellular proliferation and de- differentiation two processes that are associated with endogenous regeneration. Genes found to be expressed differently between control and chemically treated embryos will be prioritized for knock out using the CRISPR/Cas9 method. For each gene target two gRNA pairs will be designed and injected into single cell axolotl embryos. Embryos will be reared to assess viability and then administered tail amputations to confirm CRISPR gene editing and test for regeneration competence. Embryos associated with CRISPRs that block or cause abnormal regeneration will be prioritized for founding stable lines. Specific Aim 3 will generate fluorescent reporter lines to assay signaling activity through major pathways known to function in regeneration and will also compare efficacies of two methods for developing gene-specific reporter lines using as tester loci genes already known to mark cell populations critical for regenerative responses (neural stem cells glia muscle satellite cells). The chemical and genetic hits and biological information arising from this model will be shared through a community website (Sal-Site). The proposed transgenics will be distributed by the Ambystoma Genetic Stock Center. Overall this project integrates expertise across chemical screening pharmacology histology transcription transgenesis and vertebrate biology to discover reagents and develop tools that are needed to enhance the axolotl for stem cell and regenerative biology.

project_terms:
Accelerometer;Amaze;Ambystoma;Ambystoma mexicanum;Amphibia;Amputation;Animal Model;Biological;Biological Assay;Biological Process;Biology;CRISPR/Cas technology;Candidate Disease Gene;Cell Lineage;Cell Proliferation;Cells;Chemical Models;Chemicals;Chimeric Proteins;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Competence;Couples;Data;Development;Embryo;Event;Expression Profiling;FDA approved;Future;Gene Expression;Gene Targeting;Gene Transfer Techniques;Genes;Genetic;Genetic Models;Genetic Screening;Genetic Transcription;Guide RNA;Histology;Hormone use;Insertional Mutagenesis;Investigation;Knock-out;Libraries;Mediating;Methods;Modeling;Molecular;Mosaicism;Muscle satellite cell;Mutagenesis;Mutation;Natural Products;Natural regeneration;Neuroglia;Organism;Pathway interactions;Pharmacology;Phenotype;Population;Process;Production;Reagent;Regenerative Medicine;Regenerative response;Reporter;Reporting;Research;Research Infrastructure;Resources;Salamander;Signal Pathway;Signal Transduction;Site;Somatic Cell;Stem Cell Research;Stem cells;Tail;Testing;Thyroid Hormones;Time;Tissues;Transforming Growth Factor beta;Transgenic Organisms;Tretinoin;Vertebrate Biology;blastema;chemical genetics;comparative efficacy;design;dosage;feeding;in vivo monitoring;inhibitor/antagonist;mutant;nerve stem cell;network models;notch protein;novel;progenitor;promoter;public health relevance;recruit;regenerative;screening;stem cell biology;tool;web site;wound;wound epidermis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application seeks to develop resources that will better enable the fundamental study and application of a highly regenerative amphibian the Mexican axolotl (Ambystoma mexicanum). Specifically this project integrates unique infrastructure and expertise to discover reagents and develop tools that are needed to enhance the axolotl for stem cell biology and regeneration.


application_id: 9460039
project_number: 4UH3DA041115-03
project_title: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2017-07-31
opportunity_number: RFA-DA-15-017
application_type: 4
activity_code: UH3
ic: DA
serial_number: 041115
program_official: KLINE, RICHARD
project_start_date: 2015-09-15
project_end_date: 2020-07-31
study_section: ZDA1-JXR-D(12)R
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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:
DESCRIPTION (provided by applicant): Cocaine abuse is a major public health problem that directly or indirectly affects most communities and families. There is still no FDA-approved medication specific for cocaine addiction or overdose. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via a route similar to the principal cocaine-metabolizing pathway-cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma-is recognized as the most efficient treatment strategy for cocaine overdose and addiction. Since the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-cocaine is low (kcat = 4.1 min and KM = 4.5 M) we have recently designed and discovered a set of BChE -1 mutants known as cocaine hydrolases (CocHs) with at least 1000-fold improved catalytic efficiency against (- )-cocaine compared to wild-type BChE. In vivo and clinical data for the first one of our discovered and patented CocHs demonstrate the promise of enzyme therapy for cocaine abuse. In addition to improved efficacy our recently designed discovered and patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine but also possess much longer biological half-lives Built on our success in rational design and discovery of the highly efficient CocHs and their long-acting forms (LAFs or CocH-LAFs) this investigation will focus on further optimization manufacturing process development formulation development and preclinical testing of the most promising CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine but also a long biological half-life; (2) to test feasibility of lage- scale expression of promising CocH-LAF entities; (3) to develop large-scale manufacturing processes for the most promising CocH-LAF selected in Aim 2; (4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in animal models with the CocH-LAF material produced in Aim 3. The most promising CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for a monthly dosing schedule for treatment of cocaine addiction in humans. This investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing Practices) protein manufacturing Investigational New Drug (IND)-enabling studies and subsequent clinical trials. Thus this investigation will move a promising therapeuticcandidate closer toward FDA approval for cocaine addiction treatment.

project_terms:
Affect;Albumins;Animal Model;Animals;Antibodies;Binding;Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cell Line;Clinical Data;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Communities;Computer Simulation;Data;Development;Dose;Drug Kinetics;Enzymes;Evaluation;FDA approved;Family;Formulation;Half-Life;Human;Hydrolase;Hydrolysis;Immunoglobulins;In Vitro;Injection of therapeutic agent;Investigation;Investigational Drugs;Legal patent;Medical;Metabolic;Metabolism;Monkeys;Monoclonal Antibodies;Neuraxis;Neurons;Pathway interactions;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology and Toxicology;Plasma;Preclinical Testing;Process;Production;Proteins;Public Health;Rattus;Route;Self Administration;Self-Administered;Serum Albumin;Technology;Testing;Toxic effect;Treatment Protocols;Vaccines;Work;base;cell bank;clinical development;cocaine overdose;design;drug of abuse;enzyme therapy;expression cloning;immunogenicity;improved;in vivo;innovation;manufacturing process;manufacturing process development;mutant;novel;novel therapeutics;public health relevance;small molecule;social;success;therapeutic candidate;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE The long-acting cocaine hydrolase developed in this project will be a promising candidate for therapeutic treatment of cocaine addiction.


application_id: 9459892
project_number: 5P42ES007380-21
project_title: Postnatal Complications of Perinatal Polychlorinated Biphenyl Exposure - Project
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
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
arra_indicator: N
budget_start_date: 2018-04-01
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;Aryl Hydrocarbon Receptor;Attenuated;Beta Cell;Biochemical;Body Composition;Breast;Child;Chlorinated Hydrocarbons;Data;Development;Diabetes Mellitus;Discipline of Nursing;Disease;Dose;Environment;Environmental Health;Environmental Impact;Environmental Pollutants;Environmental Pollution;Epidemic;Erythroid;Etiology;Exercise;Exposure to;Fatty acid glycerol esters;Female;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;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;liver inflammation;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: 9459863
project_number: 5U01DE025833-03
project_title: Oral Health Promotion (OHPROM) Strategy for Persons with Intellectual & Developmental Disabilities
administering_ic: NIDCR
award_notice_date: 2018-03-29
opportunity_number: PAR-15-059
application_type: 5
activity_code: U01
ic: DE
serial_number: 025833
program_official: RICE, ELISE
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: ZDE1-CF(05)
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: JOHNSON, KNOWLTON WILLIAM
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:
DESCRIPTION (provided by applicant): People with intellectual and/or developmental disabilities (IDD) living in group homes are more likely to have poor oral hygiene poor dietary practices increased decay periodontal disease and total tooth loss than the general population-a significant health disparity. To improve the oral health care of this population we are conducting a stratified cluster Phase 2 randomized controlled trial to test for the efficacy ofan oral health promotion (OHPROM) strategy on persons with IDD living in group homes. This intervention is based on behavioral and public health theory derived from the literature and includes features to enhance sustainability.  The sample of consented participants is projected to be about 23 home managers 258 caregivers and 258 persons with IDD who reside in 86 group homes. Assuming the attrition rate observed in a pilot study it is projected that the final participants will be 20 managers 240 caregivers and 240 persons with IDD residing in 80 group homes. The homes are managed by three nonprofit partnering organizations and three sites of ResCare the nation's largest provider of residential services to persons with IDD in or near the Metro Louisville area in Kentucky and Southern Indiana. Managers are responsible for the conduct of caregivers in a small cluster of group homes are generally former caregivers and are paid staff. Caregivers are responsible for ensuring daily personal hygiene and dietary guidance for persons with IDD and are paid staff of the partner organizations. The OHPROM strategy is comprised of (a) planned action that entails caregivers signing a behavioral contract and engaging in oral health action planning for persons with IDD (b) caregiver capacity- building that includes didactic and observational learning as well as oral health devices (c) environmental adaptations with reminder posters and change of oral hygiene location (physical environment) and administrative oral health support (social environment) and (d) reinforcement through caregiver coaching.  The primary study objective is to assess change in oral health status of persons with IDD living in group homes. A second objective is to assess change in proximal and intermediate outcomes (i.e. mechanisms of change) and the extent to which these outcomes moderate the intervention effects on the oral health of persons with IDD. As a third objective the study will assess implementation quality as delivered to home managers and caregivers and the association of intervention components with the mechanisms of change.  The study results are intended to affect the fields of dentistry and behavioral research by demonstrating whether a theory-based prevention strategy can improve the oral health of persons with IDD living in group homes and may also improve the oral health of other at-risk dependent populations. Ultimately the study may produce changes in service organizations oral health care policies and practices of the study organizations. Diffusion of the tested oral health strategy if proven efficacious is also important; thus creating infrastructure for diffuson is also a study priority.

project_terms:
Affect;Applications Grants;Area;Behavior;Behavioral;Behavioral Research;Caregivers;Caring;Classification;Cognitive;Communities;Consent;Contracts;Data;Dementia;Dental;Dental General Practice;Dental Hygiene;Dentistry;Dentists;Developmental Disabilities;Devices;Diagnosis;Diet;Dietary Practices;Diffusion;Disabled Persons;Elderly;Ensure;Evaluation;Exhibits;Expectancy;Future;General Anesthesia;General Population;Group Homes;Health;Health Care Costs;Health Policy;Health Promotion;Health Status;Health behavior;Healthcare;Home environment;Hygiene;Impaired cognition;Indiana;Individual;Intellectual functioning disability;Intervention;Journals;Kentucky;Learning;Link;Literature;Location;Longitudinal Studies;Medical Records;Modeling;Oral;Oral health;Organizational Policy;Outcome;Parents;Participant;Periodontal Diseases;Persons;Phase;Physical environment;Pilot Projects;Pneumonia;Population;Prevention strategy;Preventive;Procedures;Process;Provider;Psychological reinforcement;Public Health;Publishing;Randomized;Randomized Controlled Trials;Research;Research Infrastructure;Risk;Risk Factors;Sampling;Self Efficacy;Services;Severities;Site;Social Environment;Systemic disease;Target Populations;Testing;Tissues;Tooth Extraction;Tooth Loss;United States;base;behavioral health;community setting;design;developmentally disabled;dosage;effective intervention;efficacy study;efficacy testing;efficacy trial;environmental adaptation;health disparity;health literacy;health plan;health related quality of life;improved;intervention effect;member;post intervention;posters;programs;public health relevance;recruit;service organization;social;theories

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People with intellectual and/or developmental disabilities (IDD) living in group homes are more likely to have poor oral hygiene poor dietary practices increased decay periodontal disease and total tooth loss than the general population-a significant health disparity. In the short term the effects of a Phase II stratified cluster randomized controlled efficacy trial can provide evidence that argues for public health and organizational policies that include oral health promotion (OHPROM) strategies for persons with IDD. In the long term this study is expected to demonstrate that the OHPROM strategy targeting caregivers and persons with IDD may potentially be generalized to other organizations that provide services to persons with IDD. Assuming future studies also show that oral health outcomes are positively affected by this intervention the overall health care cost could be reduced because persons with IDD will have less need for expensive procedures resulting from lack of proper oral health behaviors.


application_id: 9459828
project_number: 5F30AI114194-04
project_title: Elucidating binding fusion and entry of HMPV in cell culture and host tissue
administering_ic: NIAID
award_notice_date: 2018-04-13
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: AI
serial_number: 114194
program_official: KIM, SONNIE
project_start_date: 2015-05-01
project_end_date: 2018-05-12
study_section: Special Emphasis Panel[ZRG1-F13-C(20)L]
contact_pi_person_id: 12024712
contact_pi: KLIMYTE, EDITA MARIA
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): Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen in the Paramyxoviridae family that infects nearly 100% of the world population. This enveloped virus causes severe viral respiratory disease in infants the elderly and immunocompromised patients worldwide. In fact HMPV is estimated to be the second most common cause of pediatric lower respiratory illness following the closely related respiratory syncytial virus. Furthermore the rate of hospitalization for respiratory disease caused by HMPV in adults over the age of 65 is near that of influenza. Despite its clinical significance there is no antiviral treatment or vaccine available at this time. Since its discovery several key factors have been identified to play a role in HMPV entry but much of the mechanisms of binding fusion and entry remain unsolved. It has been previously shown by our group that heparan sulfate is a required moiety for HMPV binding and infectivity; however it is not known if heparan sulfate proteoglycans (HSPGs) serve as a receptor or mediate other necessary cellular factors on the plasma membrane. Furthermore the route of entry has not been identified for HMPV. Thus to elucidate the role of HSPGs we will utilize a collection of currently available HMPV strains from laboratory strains and clinical isolates to determine the effects of heparan sulfate blocking molecules and knockdown studies on specific HSPGs; in order to identify the route of entry we will utilize viral particles with fluorescent labeled envelopes to track if membrane fusion is occurring at the plasma membrane or within intracellular compartments. Finally we propose to study HMPV entry in the context of traditional cell culture utilizing physiologically relevant cell lines derived from human lung tissue such as Beas-2B Calu-3 and A549 as well as novel human airway epithelial tissue to elucidate important details about its life cycle in this model and identify potential factors that may affectHMPV infection in vivo. We hypothesize heparan sulfate proteoglycans specifically the syndecan moieties serve as an attachment factor for HMPV which is required for internalization and membrane fusion occurs in intracellular compartments. We expect heparan sulfate is also critical for viral infectivity in human airway epithelium. We also anticipate tissus derived from patients with chronic respiratory disease will show an increased permissibility to HMPV infection.

project_terms:
A549;Address;Adult;Affect;Antigens;Antiviral Agents;Area;Asthma;Binding;Biological Models;Bronchiolitis;Caveolins;Cell Culture Techniques;Cell Line;Cell membrane;Cells;Chemicals;Child;Childhood;Chimeric Proteins;Chronic;Chronic Disease;Clathrin;Clinical;Collection;Complex;Dendrimers;Dependence;Development;Disease;Dynamin;Elderly;Endocytosis;Endosomes;Epithelial;Epithelium;Escherichia coli;Excision;Family;Glycoproteins;HIV;Heparan Sulfate Proteoglycan;Heparitin Sulfate;Hospitalization;Human;Human Metapneumovirus;Immunocompromised Host;Infant;Infection;Influenza;Intervention;Label;Laboratories;Life Cycle Stages;Lipids;Lung;Lung diseases;Mediating;Membrane Fusion;Modeling;Molecular;Mucous body substance;Paramyxovirus;Pathway interactions;Patients;Peptides;Physiological;Play;Pneumonia;Pneumovirinae;Population;Predisposition;Production;RNA Viruses;Respiratory Signs and Symptoms;Respiratory Tract Diseases;Respiratory syncytial virus;Role;Route;Site;Structure of parenchyma of lung;Surface;System;Time;Tissue Model;Tissues;Trypsin;Unspecified or Sulfate Ion Sulfates;Vaccines;Viral;Virus;Virus Replication;airway epithelium;airway hyperresponsiveness;cell type;cellular targeting;clinically significant;hospitalization rates;human disease;human old age (65+);in vivo;inhibitor/antagonist;knock-down;member;monolayer;mortality;novel;older patient;particle;pathogen;public health relevance;receptor;reconstitution;respiratory;syndecan;therapeutic vaccine;uptake;virus envelope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Human metapneumovirus is a prevalent cause of respiratory disease in children and adults all over the world. It is important to understand how the virus getsinto the cells of the lungs in order to develop treatments and vaccines for this virus.


application_id: 9459425
project_number: 5R01NS097781-02
project_title: Altered Motor Function & Force Feedback After Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2018-03-20
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 097781
program_official: JAKEMAN, LYN B
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-BDCN-N(91)S]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: NICHOLS, T. RICHARD
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Animals;Area;Behavior;Bilateral;Chest;Data;Data Collection;Databases;Decerebrate State;Decerebration procedure;Development;Distal;Dorsal;Extensor;Feedback;Felis catus;Gait;Goals;Golgi Targeting;Golgi Tendon Organs;Human;Immunohistochemistry;Injury;Joints;Laboratories;Lateral;Leg;Lesion;Limb structure;Link;Locomotion;Maps;Mediating;Methods;Modeling;Motor;Movement;Muscle;Normal Statistical Distribution;Pathway interactions;Pattern;Performance;Phase;Preparation;Procedures;Production;Publishing;Recovery;Reflex action;Rehabilitation therapy;Research;Silver;Spinal;Spinal Cord;Spinal cord injury;Stains;System;Testing;Time;Walking;Weight;Work;base;design;experimental study;gait examination;gait rehabilitation;injured;innovation;insight;kinematics;locomotor tasks;motor control;motor disorder;nervous system disorder;novel;programs;receptor;relating to nervous system;response;spinal tract;treadmill;white matter


application_id: 9459303
project_number: 5R01AI087849-07
project_title: Biosynthesis of nucleoside antibiotics targeting bacterial translocase I
administering_ic: NIAID
award_notice_date: 2018-03-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 087849
program_official: XU, ZUOYU
project_start_date: 2011-06-15
project_end_date: 2021-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
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:
New antibiotics are needed particularly those that can be considered as new chemical entitiesand have novel targets relative to the current clinical armament of antibiotics. Highly modifiednucleoside antibiotics that inhibit bacterial translocase I (TL1) involved in cell wall biosynthesis fitboth these descriptions and have excellent potential in part because they are (i) nanomolarinhibitors of TL1 (ii) inhibit a target that has been proven to be essential for the survival of mostif not all bacteria (iii) are effective antibiotics in both in vitro and in vivo models and (iv) have noapparent toxicity in mice. We have defined the biosynthetic mechanism leading to the coredisaccharyl-nucleoside structure of several promising nucleoside antibiotics including A-90289from Streptomyces sp. SANK 60405 muraminomicin from Streptosporangium sp andmuraymycin from Streptomyces sp. LL-AA896 using a combined in vivo and in vitro approach.The results have defined a multi-enzyme pathway highlighted by divergence from the primarybuilding block UMP and reconvergence to form the core nucleoside. This data was utilized to scanthe wealth of genomic information to identify a new lead antibiotic sphaerimicin which wasisolated and revealed to share the nucleoside core structure but have several unique featuresincluding a dihydroxylated piperidine ring of unknown origin. We will now accomplish the followingspecific aims: (i) to define the mechanism for the attachment of the 3-amino-3-carboxypropyl(3A3CP) moiety that generates the last shared intermediate in the biosynthesis of A-90289muraminomicin muraymycin and sphaerimicin which is hypothesized to occur via a new enzymestrategy catalyzed by a pyridoxal-5-phosphate-dependent protein and (ii) to delineate thebiosynthetic mechanism for divergence from the last shared intermediate to generate uniquenucleoside core scaffolds that are further decorated by fatty acids polyketides nonribosomalpeptides and/or saccharides. A biosynthetic mechanism for the diazepanone ring for A-90289and the highly unusual fused piperidine ring system in sphaerimicin will be defined.

project_terms:
AIDS/HIV problem;Aldehydes;Amides;Anabolism;Anti-Bacterial Agents;Antibiotics;Bacteria;Cell Wall;Cessation of life;Chemicals;Clinic;Clinical;Data;Decarboxylation;Development;Dioxygenases;Disease;Drug Resistance Multiple Bacterial;Drug resistance;Drug resistance in tuberculosis;Enzymes;Fatty Acids;Genetic Engineering;Genome;Genomics;Goals;Health;Hospitals;Human;In Vitro;Lead;Logic;Methodology;Mining;Modality;Molecular;Mus;Natural Product Drug;Nucleosides;Oxidoreductase;Pathway interactions;Peptides;Peptidoglycan;Pharmaceutical Preparations;Phosphotransferases;Process;Proteins;Public Health;Pyridoxal Phosphate;Research;S-Adenosylmethionine;Scanning;Side;Staphylococcus aureus infection;Streptomyces;Structure;System;Time;Toxic effect;Transaldolase;Transketolase;Tuberculosis;United States;Uridine;Uridine Monophosphate;World Health Organization;alpha ketoglutarate;analog;clinical application;community setting;drug discovery;enzyme pathway;expectation;improved;in vivo;in vivo Model;inhibitor/antagonist;member;methicillin resistant Staphylococcus aureus;multi-drug resistant pathogen;nanomolar;novel;nucleophilic substitution;pathogen;piperidine;prevent;scaffold;synthetic biology;tool;translocase

public_health_relevance:
Diseases caused by multidrug resistant bacteria are becoming a significant threat to humanhealth worldwide. The goal of this proposal is to study nucleoside antibiotics that represent anew structural class of antibiotics have a different mode of action than clinically usedantibacterial drugs are effective antibiotics in both in vitro and in vivo models and are ingeneral not toxic to mice.


application_id: 9459265
project_number: 272201000033I-1-27200005-1
administering_ic: NIAID
project_start_date: 2016-05-26
project_end_date: 2018-05-25
contact_pi_person_id: 14614836
contact_pi: JONATHON, WARAWA
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
funding_mechanism: R and D Contracts
project_title:
Task A91: Development of a Murine Model of Subcutaneous (SC) Melioidosis for Use in Vaccine Evaluation

project_abstract:
This contract provides for the development and standardization of small animal models for infectious diseases and may include testing of candidate products.

project_terms:
Animal Model;Burkholderia pseudomallei;Contracts;Development;Melioidosis;Standardization;Testing;Translational Research;animal model development;infectious disease model;mouse model;subcutaneous;vaccine evaluation


application_id: 9457672
project_number: 2R01EY012716-19
project_title: Circuit Assembly in the developing thalamus
administering_ic: NEI
award_notice_date: 2018-02-14
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2022-02-28
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
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_terms:
Acute;Address;Adult;Affect;Anatomy;Area;Attention;Attention Deficit Disorder;Autistic Disorder;Axon;Biological Models;Brain;Brain Stem;CRH gene;Cell Differentiation process;Cell Nucleus;Childhood;Childhood Neurological Disorder;Cognitive;Conscious;Deafferentation procedure;Decision Making;Development;Development Plans;Diffuse;Disease;Dorsal;Electrophysiology (science);Epilepsy;Failure;Feedback;Gap Junctions;Generations;Genetic;Glutamates;Goals;Imagery;In Vitro;Injections;Knowledge;Lateral Geniculate Body;Light;Link;Modality;Motor;Mus;Nature;Neocortex;Neurons;Pathway interactions;Pattern;Play;Preparation;Reporter;Retinal Ganglion Cells;Role;Schizophrenia;Sensory;Series;Signal Transduction;Sleep;Sleep Disorders;Slice;Source;Structure;Synapses;Testing;Thalamic Nuclei;Thalamic structure;Tomatoes;Trauma;Viral;Vision;Visual;Visual Cortex;Wakefulness;awake;basal forebrain;basal forebrain cholinergic neurons;cell type;cellular development;cholinergic;cognitive function;developmental disease;experimental study;in vivo;insight;loss of function;mouse model;mutant;neonatal brain;nerve supply;nervous system disorder;optogenetics;postnatal;postsynaptic;response;retinogeniculate;sensory input


application_id: 9456681
project_number: 5R01CA203257-03
project_title: Natural product-based modulators of 4E-BP1 phosphorylation
administering_ic: NCI
award_notice_date: 2018-03-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 203257
program_official: FU, YALI
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1-BCMB-D(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: SHE, QING-BAI
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:
DESCRIPTION (provided by applicant): Metastatic colorectal cancer (CRC) is difficult to treat and patients have few long term effective therapeutic options. The aggressiveness of this disease is in part driven by the aberrant expression of oncoproteins. At the molecular level cap-dependent translation of the precursor oncogenic mRNAs is frequently activated. Specifically this occurs via 4E-BP1 phosphorylation which when not phosphorylated functions as a mRNA translation repressor downstream from mTOR. We recently discovered that activated signaling via the PI3K/AKT and RAS/RAF/MEK/ERK pathways cooperate to promote CRC progression by convergent phosphorylation of 4E-BP1. Our work further demonstrated that 4E-BP1 phosphorylation-mediated oncogene translation functions as a critical node that integrates oncogenic signals of the AKT and ERK pathways for CRC tumorigenesis and metastasis. Moreover we found that CRC resistance to upstream kinase targeted therapy is associated with incomplete inhibition of 4E-BP1 phosphorylation. Notably genetic blockade of cap-dependent translation by a dominant active and non-phosphorylated 4E-BP1 mutant can effectively suppress tumor growth and metastasis in the mouse models of CRC. Our overarching hypothesis is that directly targeting 4E-BP1 phosphorylation- mediated oncogene translation represents a novel strategy for cancer drug development and therapy. Using a cap-dependent translation-based reporter assay we recently identified naturally occurring pyranonaphthoquinones that act as selective inhibitors of 4E-BP1 phosphorylation in a manner that is mechanistically distinct to existing mTOR inhibitors. The primary goals of the proposed studies are to determine the fundamental mechanism of pyranonaphthoquinone-based inhibition of 4E-BP1 phosphorylation and identify optimized analogs with suitable in vitro and in vivo potency and selectivity. Cumulatively the proposed studies offer high potential for the identification and development of structurally and functionally novel agents to target the translational control of CRC progression and metastasis with the potential to define new molecular probes and early stage leads for first-in-class targeted therapies to treat CRC.

project_terms:
Antineoplastic Agents;Binding;Biological Assay;CCI-779;Colorectal Cancer;Complex;Development;Disease;Disease Progression;Drug Kinetics;Drug resistance;EIF4EBP1 gene;FRAP1 gene;Generations;Genetic;Genetic Translation;Goals;In Vitro;Knowledge;MEKs;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Messenger RNA;Modeling;Molecular;Molecular Probes;Mutation;Naphthoquinones;Natural Products;Neoplasm Metastasis;Oncogenes;Oncogenic;Oncoproteins;PI3K/AKT;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacotherapy;Phosphorylation;Phosphotransferases;Production;Property;Protein Inhibition;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Ras/Raf;Reactive Oxygen Species;Reporter;Research;Resistance;Ribosomes;Signal Pathway;Signal Transduction;Testing;Therapeutic;Therapeutic Index;Toxic effect;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Work;Xenograft procedure;analog;base;cancer cell;cancer therapy;cell growth;clinical efficacy;colorectal cancer progression;colorectal cancer treatment;drug development;effective therapy;expectation;in vitro Assay;in vivo;inhibitor/antagonist;interest;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;mouse model;mutant;novel;novel strategies;novel therapeutic intervention;pre-clinical;prevent;public health relevance;targeted treatment;tumor;tumor growth;tumor xenograft;tumorigenesis;upstream kinase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal seeks to identify and optimize unique natural product-based modulators of 4E-BP1-regulated cap-dependent translation. The agents developed as part of this work offer potential as unique molecular probes to advance the understanding 4E-BP1 in tumorigenesis and metastasis and as early first-in-class preclinical leads to treat advanced colorectal cancers (CRCs) for which there currently are few if any effective therapies.


application_id: 9455813
project_number: 5R01NS093920-04
project_title: Microglia responses to CNS injury: targeting p38 MAPK signaling
administering_ic: NINDS
award_notice_date: 2018-04-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 093920
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
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:
DESCRIPTION (provided by applicant): Microglia are the resident tissue myeloid cell in the brain. Acute isolation and molecular profiling of adult microglia have clearly identified a microglia-specific gene expression profile not found in other macrophage populations or other cells in the CNS. As a molecular and functionally unique population of cells microglia exhibit a remarkable ability to survey the brain and rapidly undergo a spectrum of responses to insults or tissue damage. These coordinated responses normally result in protection against injury but can be dysfunctional and exacerbate or even cause neurological disease. An added layer of complexity occurs when monocytes are recruited to the brain following disease or injury. As a functionally distinct population newly recruited monocytes/macrophages make different contributions to disease progression compared to microglia. One of the top canonical pathways in microglia/macrophages is the p38 MAPK pathway a well-established signaling pathway important in stress responses. In the last funding period we documented the importance of the p38alpha isoform in microglia proinflammatory cytokine production and found that suppression of p38alpha can prevent the inflammatory response that causes subsequent neuronal/synaptic damage. In two mouse models of diffuse traumatic brain injury (TBI) we found that deletion of p38alpha in myeloid cells was associated with decreased microglia activation and a rescue of vestibulomotor deficits cognitive impairments and synaptic protein loss. Our data demonstrating the importance of p38alpha in regulating key functions of macrophages/microglia that are altered by a brain injury provides a strong precedent for further mechanistic and translational studies. We have now developed an exceptionally specific small molecule p38alpha inhibitor (termed MW150) that is CNS- penetrant has drug-like properties and no adverse effects at very high doses. MW150 is a novel reagent with high translational relevance for future therapeutic development. As a foundation for future development we now propose to address mechanistically how to target p38alpha to improve outcomes following a TBI. To this end we need to answer: 1) When can p38alpha be targeted; i.e. what is the optimal therapeutic window after TBI? 2) Where and how can p38alpha be targeted; i.e. does p38alpha in other inflammatory cell types besides microglia (infiltrating macrophages astrocytes endothelial cells)contribute to neuroinflammatory responses after TBI? Our studies will provide key mechanistic information about how injury-induced p38alpha-dependent inflammatory responses in multiple cell types synergize and cross-talk to drive neurologic impairments. We will test the hypothesis that suppression of p38alpha signaling in appropriate therapeutic windows and appropriate cell types after CNS injury can lead to selective beneficial outcomes. Our aims are: Aim 1. Establish the post-injury therapeutic window for efficacy of our small molecule p38a inhibitor. Aim 2. Define the contribution of p38a in resident microglia versus infiltrating macrophages to TBI-induced impairments. Aim 3. Determine how p38alpha in other CNS inflammatory cell types (astrocytes and endothelial cells) contributes to injury-induced responses.

project_terms:
AD pathology;Acute;Address;Adult;Adverse effects;Alzheimer's disease model;Astrocytes;Brain;Brain Injuries;Cells;Central Nervous System Diseases;Chronic;Clinical;Cognitive deficits;Craniocerebral Trauma;Data;Dementia;Development;Diffuse;Disease;Disease Progression;Dose;Drug Kinetics;Endothelial Cells;Exhibits;Foundations;Functional disorder;Funding;Future;Gene Expression Profile;Immune response;Impaired cognition;Impairment;Inflammatory;Inflammatory Response;Injury;Intervention;Knockout Mice;Lead;MAPK14 gene;Medical;Microglia;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mus;Myeloid Cells;Nervous System Physiology;Nervous System Trauma;Neuroglia;Neurologic;Neurons;Outcome;Paracrine Communication;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Population;Production;Property;Protein Isoforms;Proteins;Reagent;Reporting;Research;Risk;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Surveys;Synapses;Testing;Therapeutic;Therapeutic Intervention;Tissues;Traumatic Brain Injury;analog;biological adaptation to stress;cell type;central nervous system injury;clinical development;cytokine;defined contribution;effective therapy;improved outcome;inhibitor/antagonist;macrophage;mitogen-activated protein kinase p38;monocyte;mouse model;nervous system disorder;neuroinflammation;novel;prevent;public health relevance;recruit;response;small molecule;small molecule inhibitor;stressor;targeted treatment;therapeutic development;therapeutic target;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury represents a major unmet medical need for which there is no effective therapy to improve outcome and prevent the cognitive impairment long-term neurologic morbidity or increased risk of dementia and other medically intractable complications. Successful completion of these studies will define when where and how the important inflammatory kinase p38alpha can be targeted for beneficial outcomes. Our results will provide a foundation for the future clinical development of p38alpha inhibitors for head injury.


application_id: 9455618
project_number: 5R01CA186661-05
project_title: Small molecule targeting of MIF as a novel melanoma therapeutic
administering_ic: NCI
award_notice_date: 2018-03-29
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 186661
program_official: ALLEY, MICHAEL C
project_start_date: 2014-04-03
project_end_date: 2020-03-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
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):  Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are critically important determinants of solid tumor immunosuppression neovascularization and metastatic dissemination. Despite intensive efforts aimed at identifying TAM/MDSC regulatory effectors very few have been identified that can orchestrate this process and be effectively targeted.  Macrophage migration inhibitory factor (MIF) is one the oldest cytokine activities described and is a centrally important mediator of monocyte/macrophage immune responses. TAMs and MDSCs from melanoma bearing MIF-deficient mice exhibit a unique reversion in their "polarization" state resulting in a switch from n immunosuppressive angiogenic phenotype (MIF+/+ TAM/MDSC) into an immunostimulatory non-angiogenic phenotype (MIF-/- TAM/MDSC) which results in significant reductions in primary and metastatic melanoma disease progression. Intriguingly our previously discovered MIF small molecule antagonist - 4-iodo-6- phenylpyrimidine (4-IPP) - fully recapitulates MIF-deficiency both in vitro and in vivo and serves to attenuate TAM and MDSC alternative activation immunosuppression neoangiogenesis and melanoma disease progression [1601]. We very recently discovered that 4-IPP functionally inhibits MIF by dramatically reducing intracellular MIF protein levels in a proteasome-dependent manner. However relatively high 4-IPP IC50 values and a lack of information on its mechanism of action bioavailability and chronic toxicity dictate that much more study is needed to fully identify optimize and characterize lead MIF-degradation inducing compounds before moving forward with small molecule MIF targeting in a clinical setting. To fulfill the stated objectives of this application the following aims areproposed: Aim 1: Delineate the mechanisms of action of 4-IPP and MIF-dependent TAM/MDSC polarization Aim 2: Characterize TAM/MDSC modulatory in vivo bioavailability toxicity and anti-tumor activities of existing and newly identified MIF inhibitor scaffolds and Aim 3: Evaluatethe therapeutic potential of lead MIF small molecule antagonists as individual and combinatorial modalities against established melanoma.

project_terms:
5'-AMP-activated protein kinase;American;Antibody Therapy;Attenuated;Binding;Biological Availability;Cancer Center;Cancer Patient;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Chronic;Clinical;Clinical Trials;Cytotoxic T-Lymphocyte-Associated Protein 4;Denileukin Diftitox;Diagnosis;Disease Progression;Distal;Drug Targeting;Effector Cell;Exhibits;Expression Profiling;Future;Gene Expression;Goals;Growth;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppression;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;In Vitro;In complete remission;Individual;Innate Immune Response;Invaded;Lead;Lesion;Lifetime Risk;Ligands;Malignant Neoplasms;Mediator of activation protein;Melanoma Cell;Metastatic Melanoma;Migration Inhibitory Factor;Modality;Mus;Myeloid-derived suppressor cells;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Phenotype;Population;Process;Proteins;Quantitative Structure-Activity Relationship;Regulatory T-Lymphocyte;Resistance;Role;SLEB2 gene;Signal Pathway;Skin Cancer;Solid;Solid Neoplasm;Specificity;Stromal Cells;Survival Rate;Testing;Therapeutic;Toxic effect;Tumor-associated macrophages;United States;analog;angiogenesis;anti-cancer;base;cancer cell;clinical efficacy;combinatorial;cytokine;design;efficacy study;immunoregulation;improved;in vivo;inhibitor/antagonist;insight;lung metastatic;macrophage;melanoma;monocyte;mouse model;multicatalytic endopeptidase complex;neovascularization;novel;novel therapeutics;partial response;polarized cell;prevent;public health relevance;receptor;scaffold;small molecule;small molecule inhibitor;subcutaneous;therapeutic target;therapy resistant;tumor;tumor microenvironment;tumorigenic

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Malignant melanoma is the most deadly form of skin cancer due in large part to its aggressive ability to locally invade and distally metastasize. One in 50Americans has a lifetime risk of developing melanoma and nearly 69000 people in the United States were diagnosed with it last year. The five year survival rate for those diagnosed with stage IV metastatic melanoma remains unacceptably low at only 5 - 10%. Despite the advent of new immunotherapies designed to enhance the patient's immune response to attack melanocytic cancer cells no appreciable improvements have been observed in overall patient survival percentages. Our recent studies now demonstrate that small molecule targeting of macrophage migration inhibitory factor (MIF) induces substantial resistance to implantable subcutaneous and lung metastatic melanoma. Studies described in this proposal seek to fully delineate the mechanism(s) by which small molecule MIF antagonists induce intracellular degradation of MIF thereby reverting immunosuppressive pro-angiogenic TAM/MDSC cell populations into immunostimulatory non-angiogenic innate immune effector cells. These studies will rigorously characterize and refine the clinical efficacy of small molecule MIF targeting as both an individual and combinatorial therapeutic modality targeting malignant melanoma.


application_id: 9455117
project_number: 1R36DA043714-01A1
project_title: Alprazolam and Simulated Driving Performance: Next Day Effects
administering_ic: NIDA
award_notice_date: 2017-09-13
opportunity_number: PA-16-443
application_type: 1
activity_code: R36
ic: DA
serial_number: 043714
suffix: A1
program_official: KAUTZ, MARY A
project_start_date: 2017-09-15
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 F16-R (20)]
contact_pi_person_id: 12438105
contact_pi: COE, MARION AMANDA
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT There has been a significant rise in drugged driving and associated traffic accidents and fatalities inthe United States over the last decade. While illegal substances account for the majority of druggeddrivingcases there are a number of prescription medications that can also impair driving ability. Most concerning arethe prescription drugs which may impair driving ability after the presumed duration of therapeutic action. Thisphenomenon was highlighted when the FDA mandated relabeling of all hypnotic drugs containing zolpidemdue to the presence of potentially impairing blood concentrations of the drug even after 8 hours; an effect thathad sex-specific in its severity. This effect was exacerbated in females compared to males. Alprazolam sharesmany pharmacological properties with zolpidem and converging evidence suggests it may also causeprolonged psychomotor impairment beyond the proposed therapeutic duration of action. This project proposesa study enrolling an equal number of male and female healthy volunteers who will participate in six overnightsessions to evaluate if alprazolam has a negative impact on cognitive or psychomotor performance themorning after administration compared to positive and negative controls. Performance on a highlysophisticated driving simulator with high external validity will be tested before and the morning after drugadministration. This randomized double-blind study will test three therapeutic doses of alprazolam apotentially impairing dose of zolpidem and placebo in a mixed-factorial designwith each subject receiving alldrug conditions. To evaluate if sex influences next-day alprazolam effects sex will be analyzed as a between-subjects factor. The proposed experiment will use sensitive behavioral and analytic assessments to yieldquantitative and qualitative data on previously unexplored properties of alprazolam. In light of the prevalenceof drugged driving in the United States the simulated driving data obtained from this study will have significantpublic health and safety implications.

project_terms:
Accidents;Acute;Adult;Alcohols;Alprazolam;Anxiety;Anxiety Disorders;Area;Automobile Driving;Autopsy;Behavioral;Benzodiazepines;Binding Sites;Biological Assay;Blood;CYP3A4 gene;Clinical Research;Clinical Trials;Commuting;Control Groups;Dangerousness;Data;Data Analyses;Data Collection;Diazepam;Dose;Double-Blind Method;Drug Controls;Drug Evaluation;Drug Prescriptions;Enrollment;Evaluation;Female;Funding;Guidelines;Hour;Impairment;International;Intoxication;Investigation;Killings;Label;Light;Marketing;Measurement;Measures;Molecular;Monitor;Motor Vehicles;National Institute of Drug Abuse;Outcome Measure;Panic Disorder;Performance;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase I Clinical Trials;Physiological;Placebo Control;Placebos;Plasma;Policies;Positioning Attribute;Prevalence;Property;Psychomotor Impairments;Psychomotor Performance;Public Health;Randomized;Recommendation;Research;Research Design;Research Priority;Safety;Severities;Sex Characteristics;Sleep disturbances;Sleeplessness;Statutes and Laws;Testing;Therapeutic;Time;Traffic accidents;United States;United States Food and Drug Administration;United States National Institutes of Health;Woman;base;behavioral outcome;cognitive performance;design;drug clearance;drug driving;experimental study;gender difference;hangover;healthy volunteer;hypnotic;impaired driving performance;male;men;primary outcome;receptor;research clinical testing;response;secondary outcome;sedative;sex;standard measure;volunteer;zolpidem

public_health_relevance:
PROJECT NARRATIVE This study will provide important information about the potential for a commonly prescribed anti-anxietymedication to produce unexpected hangover effects that may negatively impact driving ability.


application_id: 9453734
project_number: 5R21NS098186-02
project_title: Changing serotonin receptor 2C splice variants to combat spasticity after spinal cord injury
administering_ic: NINDS
award_notice_date: 2018-04-26
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: NS
serial_number: 098186
program_official: JAKEMAN, LYN B
project_start_date: 2017-04-01
project_end_date: 2019-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
other_pis: RABCHEVSKY, ALEXANDER GEORGE
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummarySpinal cord injury (SCI) affects approximately 300000 Americans resulting in devastating neurologicaland physical limitations. SCI in the chronic phase is complicated by muscle spasms which are to alarge degree caused by hyperactivation of the serotonin receptor 2C (5HT2C) caudal to the injury.Through a combination of alternative splicing and editing the G-protein coupled receptor generates atleast 25 isoforms with different regulatory properties: one intracellular truncated receptor 5HT2C_tr onenon-edited full-length receptor 5HT2C_Fl_INI and 23 full length edited receptors 5HT2C_FL_ed. The ratio of these isoforms wherein the 5HT2C_FL shows constitutive activity plays a major partin the maladaptation after injury. SCI leads to a loss of editing activity of ADAR2 (adenosine deaminaseacting on RNA) which results in a downregulation of 5HT2C_FL_ed isoforms relative to the5HT2C_FL_INI. Extending our joint published work (Zhang et al. 2016 EMBO Mol. Med)1 weconcentrated on the novel 5HT2C_tr isoform that sequesters the 5HT2C_FL intracellularly. We foundan increase of the 5HT2C_tr isoform after SCI possibly as an adaptation to prevent the constitutivelyactive 5HT2C_FL_INI from hyperactivity. To intervene with the isoform ratios we developed a series of oligonucleotides that eitherincrease or decrease the 5HT2C_tr /5HT2C_FL_INI ratio as well as an antiserum that is specific for the5HT2C_tr protein. Using these tools we will test the hypothesis that SCI leads to an increase in bothconstitutively active 5HT2C_FL_INI and its downregulating 5HT2C_tr isoform. This change deregulatesspinal cord neuronal activity leading to spasms likely due to insufficient 5HT2C_tr isoform to stop the5HT2C_FL_INI activity. We will thus further test whether these spasms can be mitigated using ourdeveloped oligonucleotides that promote 5HT2C_tr. Using an established S2 spinal cord transection rat model we will map the spatial and temporalchanges in receptor isoforms and test the influence of splicing-changing oligonucleotides on thedevelopment of tail spasms. The oligonucleotides interfere with the serotonin system by changing thesurface localization of constitutive active 5HT2C_FL which is a novel approach compared to ligand-based drugs activating surface receptors. Using this innovative approach targeting the pre-mRNAthese studies are significant with great potential to treat spasticity which is a major co-morbidity of SCI.

project_terms:
Activities of Daily Living;Affect;Agreement;Alternative Splicing;American;Cells;Chronic Phase;Collaborations;Comorbidity;Contusions;Coupled;DRADA2b protein;Development;Down-Regulation;G-Protein-Coupled Receptors;GTP-Binding Proteins;Genes;Hyperactive behavior;Injury;Intervention;Intrathecal Injections;Joints;Laboratory Study;Lead;Length;Ligands;Maps;Membrane Proteins;Metabolism;Modeling;Molecular;Molecular Target;Motor Neurons;Neurologic;Neurons;Oligonucleotides;Persons;Pharmaceutical Preparations;Play;Property;Protein Isoforms;Proteins;Publishing;RNA;RNA Splicing;Rattus;Series;Serotonergic System;Serotonin Receptor 5-HT2C;Spasm;Spinal Cord;Spinal Cord transection injury;Spinal cord injury;Surface;System;Tail;Testing;United States;Variant;Work;adenosine deaminase;base;combat;innovation;mRNA Precursor;novel;novel strategies;prevent;receptor;spasticity;tool;uptake

public_health_relevance:
Spinal cord injury affects more than 300000 Americans leading to spasms that interferewith living activities as they occur repeatedly on a daily basis. We will determine themolecular basis for the spasms and test a synthetic RNA as a possible drug intervention.


application_id: 9453729
project_number: 5R01NS101105-02
project_title: Promoting and understanding recovery of breathing after chronic spinal cord injury
administering_ic: NINDS
award_notice_date: 2018-02-07
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 101105
program_official: JAKEMAN, LYN B
project_start_date: 2017-03-15
project_end_date: 2022-02-28
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8838438
contact_pi: ALILAIN, WARREN JOSEPH
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_terms:
Acute;Adverse effects;Americas;Anatomy;Animals;Applications Grants;Behavior;Breathing;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chondroitin ABC Lyase;Chondroitin Sulfate Proteoglycan;Chondroitinases;Chronic;Communities;Equilibrium;Excision;Extracellular Matrix;Health Care Costs;Healthcare;Hypersensitivity;Hypoxia;Injury;Intervention;Investigation;Knowledge;Lead;Learning;Length;Measures;Mechanical Ventilators;Mediating;Modeling;Motor;Motor Activity;Motor Neurons;Natural regeneration;Paralysed;Patients;Pattern;Periodicity;Play;Population;Positioning Attribute;Process;Production;Quality of life;Recovery;Recovery of Function;Regimen;Rehabilitation therapy;Research;Respiratory Diaphragm;Role;Saline;Serotonin;Spinal Cord;Spinal cord injury;Subgroup;Testing;Therapeutic Intervention;Time;Training;Translating;United States;Work;effective intervention;experimental study;functional outcomes;health management;improved;inhibitor/antagonist;injured;insight;motor recovery;motor rehabilitation;neurotransmission;novel therapeutics;optimal treatments;prevent;receptor;respiratory;response;response to injury;restoration;serotonin receptor;success


application_id: 9453650
project_number: 5R25CA203637-02
project_title: Training in Interprofessional Education for Palliative Care in Oncology
administering_ic: NCI
award_notice_date: 2018-02-19
opportunity_number: PAR-15-151
application_type: 5
activity_code: R25
ic: CA
serial_number: 203637
program_official: RADAEV, SERGEY
project_start_date: 2017-03-14
project_end_date: 2022-02-28
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
other_pis: HEAD, BARBARA A
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:
Accreditation;Address;Cancer Patient;Caring;Collaborations;Communication;Complex;Crowding;Development;Diagnosis;Discipline;Discipline of Nursing;Education;Educational Activities;Educational Curriculum;Educational workshop;Faculty;Future;Goals;Health Sciences;Institution;Knowledge;Lead;Learning Skill;Length;Logistics;Malignant Neoplasms;Medicine;Mentors;Modeling;Nature;Nurses;Outcome;Palliative Care;Patient Care;Patient-Centered Care;Patients;Physicians;Pre-Post Tests;Program Sustainability;Quality of life;Research Infrastructure;Resources;Role;Site;Social Work;Social Workers;Students;Teacher Professional Development;Time;Trainers Training;Training;Training Programs;Work;base;cancer care;cancer diagnosis;cancer education;cancer palliative treatment;design;experience;health care service utilization;improved;instrument;interest;method development;oncology;outcome forecast;palliative;patient oriented;pedagogy;practice setting;programs;science teacher;skills;student training;success;symposium;webinar


application_id: 9452924
project_number: 5R01CA188118-04
project_title: Determine the Functional Role Dub3 in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2018-03-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188118
program_official: AULT, GRACE S
project_start_date: 2015-04-01
project_end_date: 2020-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) presents with an aggressive clinical history development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC has an activated epithelial-mesenchymal transition (EMT) program which provides cells with the increased phenotypic and cellular plasticity required during embryonic development tissue remodeling wound healing and metastasis. Our long-term goal is to discover the molecular circuitry that governs the functional plasticity of BLBC cells in metastasis and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last nine years we have systematically studied the function of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our studies clearly indicate that Snail levels are regulated predominantly through protein ubiquitination. High levels of Snail due to protein stabilization contribute significantly to theincreased invasion therapeutic resistance CSC-like properties and tumor recurrence. However the mechanism by which Snail escapes ubiquitination and degradation remains unknown; uncovering this mechanism is crucially important for the development of novel approaches to treat BLBC. Recently we discovered that Dub3 is a bona fide deubiquitinase of Snail and contributes to Snail stabilization in breast cancer. Dub3 is evolutionarily conserved from Drosophila to humans. Dub3-knockout downregulated Snail and disrupted gastrulation (an event that requires EMT) in Drosophila. Elevated expression of Dub3 correlates unequivocally with Snail expression in BLBC samples and cell lines. Overexpression of Dub3 in luminal breast tumor MCF7 and T47D cell lines which contain no detectable endogenous Dub3 and Snail induces transformation to a basal-like phenotype; whereas Dub3-knockdown downregulates Snail and suppresses cell migration. Intriguingly Dub3 was an early response gene that appeared after exposure to inflammatory cytokines. We hypothesize that Dub3 is the long-sought "missing molecule" that regulates cellular plasticity by controlling the level of Snail durig EMT and metastasis. The objective of this proposal is to characterize the function and regulation of the Dub3-Snail axis and explore the clinical value of Dub3 as a prognostic biomarker and a druggable target for treating metastatic breast cancer. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to delineate th molecular mechanism by which Dub3 controls EMT; (2) to determine the function and regulation of Dub3 in breast cancer; and (3) to define the function and therapeutic efficacy of Dub3 in vivo. Our proposal is innovative and significant because it will not only uncover a new paradigm that significantly increases our understanding of the regulation of cellular plasticity during tumor progression and metastasis but also leads to the development of specific Dub3 inhibitors for treating metastatic breast cancer.

project_terms:
Address;Brain;Breast;Breast Cancer Cell;Breast cancer metastasis;Cell Line;Cells;Chromatin;Clinical;Coupled;Crystallization;Data;Deubiquitination;Development;Diagnosis;Disease;Distant Metastasis;Drosophila genus;E-Cadherin;ERG gene;Embryonic Development;Environment;Enzymes;Epithelial;Event;Exposure to;Genes;Goals;Growth;Human;Inflammatory;Intrinsic factor;Investigation;KDM1A gene;Knock-out;Knowledge;Libraries;Location;Lung;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mass Spectrum Analysis;Mesenchymal;Metabolic;Metastatic breast cancer;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncologist;Pathologist;Pharmaceutical Preparations;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Prognostic Marker;Property;Proteins;Public Health;Reagent;Recording of previous events;Recurrence;Regulation;Research;Role;Sampling;Signal Transduction;Site;Small Interfering RNA;Snails;Specimen;Stromal Neoplasm;Structural Biologist;Structure;T47D;Talents;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Cell Invasion;Tumor-associated macrophages;Ubiquitination;Validation;Wound Healing;Xenograft procedure;aerobic glycolysis;base;beta-Transducin Repeat-Containing Proteins;breast cancer progression;cancer stem cell;cancer therapy;cell growth regulation;cell motility;cytokine;diagnostic biomarker;druggable target;experimental study;functional plasticity;gastrulation;glycogen synthase kinase 3 beta;in vivo;inhibitor/antagonist;innovation;knock-down;loss of function;malignant breast neoplasm;multidisciplinary;neoplastic cell;new therapeutic target;novel strategies;outcome forecast;overexpression;prevent;prognostic;programs;promoter;public health relevance;recruit;screening;stem-like cell;success;targeted biomarker;targeted treatment;therapy resistant;tumor;tumor microenvironment;tumor progression;ubiquitin-protein ligase;virtual;young woman

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the molecular mechanism in controlling early-phase of tumor cell invasion dissemination and metastasis. When successfully completed these studies will offer new therapeutic target and diagnostic biomarker to prevent and treat metastatic basal- like breast cancer.


application_id: 9452874
project_number: 5R44DE023523-03
project_title: Mouth barrier rinse of sustained-release poly(curcumin) to treat oral mucositis
administering_ic: NIDCR
award_notice_date: 2017-07-27
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: DE
serial_number: 023523
program_official: CHEN, ZHONG
project_start_date: 2013-09-24
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-K(11)B]
contact_pi_person_id: 12547606
contact_pi: BHANDARI, ROHIT
other_pis: DZIUBLA, THOMAS DEAN;HOWERTON, BROCK ;JORDAN, CAROLYN
congressional_district: 06
department: Unavailable
primary_duns: 078529087
primary_uei: M9JMGN342NR5
duns_number: 078529087
uei: M9JMGN342NR5
fips: US
organization_id: 10032361
organization_name: BLUEGRASS ADVANCED MATERIALS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Oral mucositis (OM) is one of the most common side effects of most anti-cancer therapies affecting nearly 100% of head and neck cancer patients (5-6% of the 12.7 million new cancer cases worldwide annually). OM manifests by deep and extremely painful mouth ulcers that can force patients to halt life-saving anti-cancer treatments and experience increased emergency room visits and longer hospital stays. Lubricating and analgesic mouth rinses are the primary treatment options but provide only palliative care and have shown poor efficacy. Palifermin (recombinant keratinocyte growth factor) is the only approved drug for treating OM in patients with hematological malignancies but is not approved for solid tumors and carries the risk of neoplasia. Clearly an unmet need exists for effective and
safe drugs to treat this condition. Curcumin a multi-action antioxidant and anti-inflammatory compound derived from turmeric has been shown to reduce the incidence and severity of OM in preclinical studies and a recent human trial. Unfortunately the trial required an aggressive dosing regimen of 4 mouth rinses every 4 hours likely due to the known poor bioavailability of curcumin. Our innovation is a polymeric formulation that provides local and prolonged delivery of curcumin to buccal tissues which will increase its efficacy in treating OM. Bluegrass Advanced Materials' product to treat OM will be a drug-device combination composed of (1) a sachet containing a single dose of poly(curcumin) powder and (2) a wide-mouth bottle containing 5 ml of mucoadhesive solution. In Phase I we demonstrated that biodegradable microparticles of poly(curcumin) can provide a sustained release of curcumin for 24 hours under physiological conditions while retaining antioxidant activity. In a preclinical study we demonstrated that once-daily treatment with a poly(curcumin) oral rinse reduced the severity of OM in the Syrian hamster model. In Phase II we propose to: 1. Optimize efficacy of poly(curcumin) oral rinse to treat radiation-induced OM. 2. Scale up manufacturing to produce pilot preclinical batch. 3. Develop combination product packaging in sachets and bottles and perform stability testing. 4. Demonstrate safety of poly(curcumin) oral rinse in GLP preclinical studies. Successful completion of Phase II will accomplish the key tasks necessary to prepare for Phase I human clinical trials and enable us to approach the FDA to begin the approval process.

project_terms:
Adverse effects;Affect;Air;Analgesics;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biological Availability;Cancer Patient;Clinical Trials;Compliance behavior;Curcumin;Development;Devices;Disease;Dose;Drug Kinetics;Emergency department visit;Enteral Feeding;Film;Formulation;Frequencies;Hamsters;Health Care Costs;Hematologic Neoplasms;Hour;Human;Incidence;Infection;Inflammation;Interruption;Intravenous;Investigational New Drug Application;Laboratories;Length of Stay;Lidocaine;Life;Malignant Neoplasms;Mesocricetus auratus;Metabolism;Methods;Modeling;Mucositis;Narcotic Analgesics;Neoplasms;New Agents;Oral;Oral Ulcer;Oral cavity;Outcome;Oxidative Stress;Oxygen;Pain;Palliative Care;Particle Size;Patients;Pharmaceutical Preparations;Phase;Physiological;Plasticizers;Poa plant;Polymers;Powder dose form;Preparation;Process;Product Packaging;Quality of life;Radiation;Recombinants;Regimen;Risk;Safety;Savings;Severities;Site;Solid Neoplasm;Supportive care;Suspensions;Time;Tissues;Toxic effect;Tumeric;Viscosity;biomaterial compatibility;cancer therapy;chemotherapy;cytotoxicity;effective therapy;experience;head and neck cancer patient;improved;innovation;interest;irritation;keratinocyte growth factor;manufacturing scale-up;oral mucositis;palliative;pre-clinical;preclinical study;prevent;process repeatability;public health relevance;response;seal;stability testing;standard of care;systemic toxicity

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Oral mucositis (OM) is one of the most common side effects of most anti-cancer therapies affecting nearly 500000 new cancer patients every year in the US. OM which manifests as deep and extremely painful mouth ulcers forces patients to halt life-saving anti-cancer treatments and experience longer hospital stays. Bluegrass Advanced Materials' (BAM's) product to treat OM is a combination device composed of a sustained-release poly(curcumin) powder suspended in a viscous mucoadhesive solution which can be mixed quickly and rinsed in the mouth by patients. The sustained and localized release of curcumin into the mouth tissue will target the key underlying mechanisms of OM oxidative stress. Our product has the potential to greatly improve the quality of life of cancer patients.


application_id: 9452026
project_number: 5R01DA033862-06
project_title: Effect of structural interventions on substance use and HIV/HCV risk among rural PWUD
administering_ic: NIDA
award_notice_date: 2018-12-24
opportunity_number: PA-15-003
application_type: 5
activity_code: R01
ic: DA
serial_number: 033862
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2012-09-01
project_end_date: 2021-11-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Address;Affordable Care Act;Alcohol or Other Drugs use;Area;Behavior;Biological Models;Buprenorphine;Communicable Diseases;Communities;Complement;County;Data;Data Collection;Development;Disease Outbreaks;Disease Outcome;Drug abuse;Drug user;Effectiveness;Enrollment;Epidemic;Frequencies;Goals;HIV;HIV/HCV;Health;Health Promotion;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C Therapy;Hepatitis C Transmission;Hepatitis C virus;Heroin Abuse;Illicit Drugs;Indiana;Individual;Injecting drug user;Injections;Insurance Coverage;Intervention;Kentucky;Laws;Literature;Longitudinal trends;Measures;Medicaid;Modeling;Natural experiment;Nature;Needle Sharing;Outcome;Oxycodone;Participant;Personal Communication;Pharmacoepidemiology;Policies;Population;Population Density;Prevalence;Public Health;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Appalachia;Rural Population;Services;Shares syringes;Statistical Models;Sterility;Structure;Substance Use Disorder;Substance abuse problem;Syringes;Time;Treatment outcome;Uninsured;cohort;disease transmission;drug of abuse;follow-up;gabapentin;health disparity;improved;infancy;innovation;opioid abuse;opioid injection;prescription drug abuse;prescription opioid;programs;public health relevance;response;rural area;social;substance abuse treatment;suburb;success;therapy design;therapy development;uptake


application_id: 9451254
project_number: 5R21CA210202-02
project_title: Targeting melanoma hypoxia with lactic acid bacterium L. lactis
administering_ic: NCI
award_notice_date: 2018-02-15
opportunity_number: PAR-15-053
application_type: 5
activity_code: R21
ic: CA
serial_number: 210202
program_official: SCHWARTZ, ELENA IVAN
project_start_date: 2017-03-09
project_end_date: 2019-12-31
study_section: Special Emphasis Panel[ZRG1-OBT-A(55)R]
contact_pi_person_id: 10284580
contact_pi: GOMEZ-GUTIERREZ, JORGE G
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMelanoma is the most aggressive form of skin cancer and if disseminated through the dermis has a poorprognosis with a high mortality rate. Hypoxia is a component of the tumor microenvironment which reducesefficacy of both immuno- and chemo-therapies resulting in poor clinical outcome. Therefore we will exploit thehypoxic microenvironment as a target for gene therapy utilizing commensal facultative anaerobic bacteria. Theoverall goal of this proposal is to develop an effective and safe delivery system for cancer gene therapy bytargeting the hypoxic tumor microenvironment with food-grade lactic acid bacteria (LAB) Lactococcus lactis (L.lactis). The use of LAB as opposed to other bacteria represents a much more desirable strategy to delivertherapeutic genes than attenuated pathogenic strains as there is no risk of reversion or potential to instigatehost reactions in immunocompromised patients. Because identification of tumor-specific accumulation andbiodistribution of gene delivery vehicles in vivo is essential for translation of these agents to the clinic we willutilize a newly emerging technology multispectral optoacoustic tomography (MSOT). MSOT is a hybridmodality that detects sound waves generated by the absorption of electromagnetic energy thus enabling thecapability for 3D high-resolution at depth and in real time. Our preliminary data indicates that L. lactisexpresses high levels of -galactosidase (LacZ) and in combination with 5-bromo-4-chloro-3-indolyl--D-galactopyranoside (X-gal) produces a strong blue color to facilitate detection of L. lactis using MSOT. Giventhese findings we hypothesize that L. lactis will preferentially colonize the hypoxic areas of the tumormicroenvironment to deliver therapeutic genes in a safe tumor-specific and effective manner. We propose twoaims: (1) Evaluate the efficacy of L. lactis as a gene delivery vehicle in melanoma cells in vitro and (2)determine the biodistribution and tumor-specific accumulation of L. lactis in metastatic melanoma-bearingmice. The successful completion of this proposal will substantially influence the field of gene therapyspecifically utilization of facultative bacteria as delivery agents for tumor-specific targeting of melanoma.

project_terms:
Affect;Anaerobic Bacteria;Antibiotic Therapy;Area;Attenuated;BRAF gene;Bacteremia;Bacteria;Biodistribution;Blood;Cells;Characteristics;Clinic;Clinical;Clostridium;Color;Communicable Diseases;Consumption;Data;Dermis;Detection;Dose;Dyes;Electromagnetic Energy;Emerging Technologies;Food;Galactose;Galactosidase;Gastrointestinal Diseases;Gene Delivery;Gene Mutation;Gene Targeting;Gene Transfer;Genes;Goals;Home environment;Hybrids;Hypersensitivity;Hypoxia;Image;Immunocompromised Host;Implant;In Vitro;Indocyanine Green;Invaded;LacZ Genes;Lactococcus lactis;Ligands;Light;Listeria;Liver;Malignant Neoplasms;Melanoma Cell;Metastatic Melanoma;Methods;Mind;Modality;Molecular Probes;Mus;Oncogenes;Optics;Organ;Organism;Outcome;Oxygen;PD-1 inhibitors;Pathogenicity;Patients;Penetration;Pharmacotherapy;Photons;Production;Progression-Free Survivals;Proliferating;Reaction;Relapse;Reporter Genes;Resolution;Risk;Salmonella;Sentinel Lymph Node;Signal Transduction;Skin Cancer;Stains;Surface;System;Therapeutic;Time;Tissue Stains;Tissues;Toxicity due to chemotherapy;Translations;Ultrasonics;Virulent;Zinc;absorption;anti-cancer;attenuation;base;beta-Galactosidase;bioluminescence imaging;clinical application;design;experimental study;fluorescence imaging;fluorophore;gene therapy;genetic manipulation;imaging system;improved;in vivo;inhibitor/antagonist;lactic acid bacteria;melanoma;mortality;optoacoustic tomography;outcome forecast;photoacoustic imaging;promoter;routine Bacterial stain;sound;subcutaneous;targeted treatment;therapeutic gene;treatment response;tumor;tumor hypoxia;tumor microenvironment;tumor specificity;tumor-specific gene delivery;uptake

public_health_relevance:
Project NarrativeSome bacteria selectively grow in areas of low oxygen. We will evaluate the ability of L. lactis as a genedelivery vehicle to target areas of low oxygen within melanoma tumors implanted in the liver. Thebiodistribution and tumor accumulation of L. lactis will be evaluated using multispectral optoacoustictomography. The efficacy of L. lactis as a gene delivery vehicle into melanoma cells will also be evaluated.


application_id: 9449466
project_number: 5R01NS065842-11
administering_ic: NINDS
award_notice_date: 2018-02-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 065842
program_official: KOENIG, JAMES I
project_start_date: 2010-04-01
project_end_date: 2020-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
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
budget_start_date: 2018-04-01
project_title:
Alpha5Beta1 Integrin inhibition as a Profound Blood-Brain Barrier Stabilizing Neuroprotective Stroke Therapy

project_abstract:
DESCRIPTION (provided by applicant): Although stroke is the fourth leading cause of death in the U.S. the current treatment strategy of thrombolysis for the majority of strokes due to a blood clot (ischemic) has mixed results. Thus there is an urgent need for new and better stroke therapies. We have previously demonstrated that the domain V protein fragment of the brain extracellular matrix component perlecan is both neuroprotective and neuroreparative after ischemic stroke by interaction with the brain endothelial cell receptor 51 integrin. Intriguingy preliminary results now suggest that mice with an endothelial selective deletion of 51 integrinare profoundly resistant to experimental ischemic stroke; they show little to no signs of brain injury. Furthermore inhibition of the 51 integrin with ATN-161 or its more potent isoform Ac-PhScN-NH2 conveys nearly identical resistance to stroke injury in wild type mice. This may occur via stabilization of the blood-brain barrier through increased function of the brain endothelial cell tight junction protein claudin-5 which in turn minimizes vasogenic edema inflammation and injury. Therefore we hypothesize that endothelial cell 51 integrin could be a particularly effective therapeutic target for stroke. In this application we propose the followig specific aims: 1. Determine the effect of endothelial cell selective 51 integrin deletion on experimental ischemic stroke 2. Determine the potential of the 51 integrin as a therapeutic target in experimental ischemic stroke and 3. Determine in mechanistic detail the role of 51 integrin in modulating blood-brain barrier integrity and subsequent resistance to ischemic stroke. We will use several novel genetically modified mice (5 integrin endothelial cell specific knockdown mice claudin5 eGFP tagged mice) and newly characterized 51 integrin inhibitors in experimental stroke models and in vitro endothelial cell barrier assays. We expect to demonstrate that suppression or inhibition of 51 integrin in endothelial cells affords significnt blood-brain barrier-mediated resistance to experimental ischemic stroke supporting our long-term goal of developing 51 integrin as a novel human stroke therapeutic target.

project_terms:
Anatomy;Antineoplastic Agents;Apoptosis;Biochemical;Biological Assay;Blood - brain barrier anatomy;Blood coagulation;Blood flow;Brain;Brain Injuries;Cause of Death;Clinical;Dose;Endothelial Cells;Extracellular Matrix;Genetic;Glucose;Goals;Histology;Human;Immunohistochemistry;In Vitro;Infarction;Inflammation;Injury;Integrin Inhibition;Integrin alpha5;Integrin alpha5beta1;Integrins;Ischemia;Ischemic Brain Injury;Ischemic Stroke;Knock-out;Knockout Mice;Label;Link;Magnetic Resonance Imaging;Mediating;Methods;Middle Cerebral Artery Occlusion;Morbidity - disease rate;Motor;Mus;Oxygen;Peptides;Permeability;Protein Fragment;Protein Isoforms;Proteins;Proteoglycan;Receptor Cell;Receptor Inhibition;Recovery of Function;Resistance;Role;Signal Transduction;Stroke;Testing;Therapeutic;Tight Junctions;Time;Treatment Efficacy;Wild Type Mouse;analog;brain endothelial cell;cancer clinical trial;cell injury;cell type;cerebrovascular;deprivation;experience;in vivo;inhibitor/antagonist;innovation;knock-down;mouse model;novel;novel therapeutic intervention;perlecan;post stroke;prevent;public health relevance;receptor;repaired;response to brain injury;stroke model;stroke therapy;therapeutic target;thrombolysis;treatment strategy;vasogenic edema

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although stroke is the fourth leading cause of death in the U.S. current treatment options are limited in their application and efficacy. Towards that end we have identified a novel component of the brain's injury response derived from the brain's extracellular matrix which appears to protect cells from injury and help the brain to repair itself We further showed that this component termed perlecan domain V exerted its beneficial effects through interaction with the 51 integrin receptor on brain vascular (endothelial) cells Preliminary results now suggest that inhibition of this receptor profoundly protects the brain fromstroke injury and may do so by preventing breakdown of the blood-brain barrier. Therefore we propose to determine the therapeutic efficacy and mechanism(s) of action of targeting the 51 integrin in experimental ischemic stroke with the long term goal of developing better stroke therapies.


application_id: 9448681
project_number: 1R01EY027805-01A1
administering_ic: NEI
award_notice_date: 2018-01-19
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: EY
serial_number: 027805
suffix: A1
program_official: LIBERMAN, ELLEN S
project_start_date: 2018-02-01
project_end_date: 2023-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 14475772
contact_pi: FAMULSKI, JAKUB K
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Animal Model;Anterior;Behavior;Biological Assay;Biological Models;Biology;Blindness;Candidate Disease Gene;Cataloging;Catalogs;Cells;Cellular biology;Ciliary Muscle;Classification;Color;Comprehension;Confocal Microscopy;Congenital Disorders;Cornea;Corneal Endothelium;Coupled;Defect;Development;Developmental Process;Disease;Disease model;Embryo;Etiology;Event;Evolution;Eye Development;Family;Flow Cytometry;Future;Gene Combinations;Gene Expression Profiling;Genes;Genetic;Genetic Counseling;Genome engineering;Genomics;Glaucoma;Goals;Health;Human;Image;In Situ Hybridization;Individual;Inherited;Iris;Knowledge;Lesion;Light;Location;Maps;Mediating;Mesenchyme;Microscopy;Molecular;Mus;Neural Crest Cell;Optics;Patients;Pattern;Phenotype;Population;Predisposition;Regulation;Reporter;Research;Retina;Sampling;Sclera;Structure;Testing;Time;Tissues;To specify;Transgenic Organisms;Vision;Visual impairment;Visual system structure;Zebrafish;clinical practice;exome sequencing;gain of function;imaging approach;in vivo;in vivo imaging;induced pluripotent stem cell;lens;migration;next generation;novel;optogenetics;orbit muscle;screening;stem cell therapy;time use;transcription factor;transcriptome;transcriptome sequencing


application_id: 9448296
project_number: 1R01NS092552-01A1
project_title: Contribution of adult neurogenesis to epileptogenesis and recovery after TBI
administering_ic: NINDS
award_notice_date: 2018-05-18
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 092552
suffix: A1
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
project_terms:
Address;Adult;Affect;Antiepileptogenic;Behavior;Behavioral;Biological Neural Networks;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;Recovery;Recovery of Function;Regulation;Reporting;Risk;Rodent Model;Role;Seizures;Sirolimus;Site;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;neurogenesis;newborn neuron;optogenetics;prevent;therapeutic target;therapy design;therapy development


application_id: 9448188
project_number: 1R01AG055449-01A1
project_title: Contributions of Alzheimer's Pathology and Cerebrovascular Factors to Cognitive Aging
administering_ic: NIA
award_notice_date: 2017-09-13
opportunity_number: PAR-15-357
application_type: 1
activity_code: R01
ic: AG
serial_number: 055449
suffix: A1
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)]
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
project_terms:
Affect;Aging;Alzheimer's Disease;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;Plasticizers;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


application_id: 9447975
project_number: 1R01DK113625-01A1
project_title: Contributions of hepatic and intestinal pathways to cholesterol excretion
administering_ic: NIDDK
award_notice_date: 2017-09-13
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DK
serial_number: 113625
suffix: A1
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2017-09-13
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1 EMNR-P (02)]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Antisense Oligonucleotides;Atherosclerosis;Bile Acids;Bile fluid;Biliary;Cells;Cholesterol;Cholesterol Ester Transfer Proteins;Cholesterol Homeostasis;Data;Development;Distal;Event;Excision;Excretory function;GPBAR1 gene;Gallbladder;Genetic Complementation Test;Hepatic;Hepatobiliary;High Density Lipoprotein Cholesterol;Homeostasis;Intestines;Investigation;LDL Cholesterol Lipoproteins;Lipids;Lipoproteins;Liver;Measures;Metabolic Diseases;Metabolism;Methods;Micelles;Modeling;Mouse Strains;Mus;Operative Surgical Procedures;Organ;Output;Parabiosis;Pathway interactions;Peripheral;Pharmacology;Plasma;Play;Prevention;Process;Publishing;Regulation;Rodent;Role;Signal Transduction;Small Intestines;Sterols;Time;adeno-associated viral vector;liver metabolism;low density lipoprotein inhibitor;man;novel;receptor;response;reverse cholesterol transport;synergism;uptake


application_id: 9447565
project_number: 2RF1AG039621-06
project_title: Restoring Blood-Brain Function to Improve Cognition in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2017-12-22
opportunity_number: PA-16-160
application_type: 2
activity_code: RF1
ic: AG
serial_number: 039621
program_official: NEWMAN, ELIZABETH
project_start_date: 2011-09-01
project_end_date: 2023-08-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
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:
Increasing evidence indicates that blood-brain barrier dysfunction contributes to cognitive decline in Alzheimer'sdisease (AD). Two key elements of barrier dysfunction include 1) reduced levels of the blood-brain barrier trans-porter P-glycoprotein (P-gp) that clears A from the brain and 2) barrier leakage both of which have been linkedto A brain accumulation and cognitive impairment. While increasing evidence shows A involvement in barrierdysfunction the underlying mechanisms remain to be fully defined. Moreover therapeutic strategies to restorebarrier function are currently not available. Thus there is an unmet critical need to define the mechanism(s) thatlead/s to barrier dysfunction and to develop effective intervention strategies to help restore barrier function inAD. Absent effective strategies achievement of therapeutic advances in AD will likely remain challenging. Thelong-term goal of the investigator is to identify molecular pathways involved in regulating blood-brain barrierfunction that when disrupted contribute to brain disease and that can be exploited for developing new thera-peutic strategies. The overall objective in this application is to establish a novel combination therapy for AD bytargeting the underlying causes of barrier dysfunction in a mouse AD model to restore barrier function and slowthe rate of cognitive decline. Based on preliminary data the central hypothesis of this project is that restoringblood-brain barrier function will lead to lower brain A levels and slow the rate of cognitive decline in humanizedPXR/APP mice. The rationale for this research is that providing proof-of-concept that restoring barrier functionwill reduce cognitive decline in experimental animals would establish a framework for future clinical trials in ADpatients. This hypothesis will be tested by pursuing three specific aims: 1) Identify the signaling pathwayresponsible for A-mediated P-gp reduction at the blood-brain barrier. 2) Determine the underlying mechanism(s)responsible for A-mediated barrier leakage and 3) Develop a combination therapy to restore barrier function ina mouse AD model. Under Aim 1 the mechanism of A-mediated reduction of P-gp protein expression andactivity levels will be assessed in isolated healthy human brain capillaries. Under Aim 2 key signaling steps thattrigger barrier leakage will be determined in brain capillaries from healthy individuals and from AD patients. UnderAim 3 the therapeutic benefit of a combination therapy involving PXR activation and scavenging reactive oxygenspecies to restore barrier function lower A brain burden and slow the rate of cognitive decline will be assessedin a humanized PXR/APP mouse model. The proposed research is innovative because it represents a substan-tive departure from the status quo by shifting the focus to a disease-modifying combination therapy aimed at twonew molecular targets to restore barrier function and improve clinical symptoms. The proposed research issignificant because it holds the promise of a novel therapeutic approach to restore barrier function that has hightranslational potential for clinical use to advance treatment of AD patients. Ultimately such knowledge likely willbe applicable to other conditions with underlying barrier dysfunction.

project_terms:
Achievement;Aging-Related Process;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Animals;Area;Attenuated;Autopsy;Blood;Blood - brain barrier anatomy;Brain;Brain Diseases;Clinical;Clinical Trials;Cognition;Combined Modality Therapy;Data;Development;Diagnosis;Disease;Elements;Extravasation;Functional disorder;Future;Goals;Human;Impaired cognition;Individual;Intervention;Knowledge;Lead;Link;Matrix Metalloproteinases;Mediating;Mission;Molecular;Molecular Target;Mouse Protein;Mus;NADPH Oxidase;Neurodegenerative Disorders;Nuclear Receptors;Outcome;P-Glycoprotein;Pathologic;Pathway interactions;Patients;Public Health;Reactive Oxygen Species;Receptor Activation;Regulation;Research;Research Personnel;Sampling;Signal Pathway;Signal Transduction;Symptoms;System;Testing;Therapeutic;Tight Junctions;Ubiquitin;United States National Institutes of Health;Work;base;cerebral capillary;effective intervention;expectation;human disease;improved;innovation;mouse model;multicatalytic endopeptidase complex;new therapeutic target;novel;novel strategies;novel therapeutic intervention;overexpression;pre-clinical;pregnane X receptor;protein expression;receptor;restoration;treatment strategy

public_health_relevance:
The proposed research is relevant to public health because it is expected to advance understanding of blood-brain barrier function in neurodegenerative diseases and potentially establish a novel disease-modifyingtreatment strategy for Alzheimer's disease. Thus the proposed research is relevant to the mission of theNIH/NIA which is to develop fundamental knowledge that will help reduce the burden of human illness includingdiseases and conditions related to the aging process.


application_id: 9446116
project_number: 2R01DA016718-11
project_title: Licit and Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2018-09-19
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: DA
serial_number: 016718
program_official: ANDERSON, ANN
project_start_date: 2004-07-10
project_end_date: 2023-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Absence of pain sensation;Alcohols;Alprazolam;Autopsy;Benzodiazepines;Carbon Dioxide;Cessation of life;Characteristics;Clinical;Cognitive;Comparative Study;Crossover Design;Data;Decision Making;Dose;Double-Blind Method;Drug Controls;Drug Interactions;Drug Kinetics;Drug usage;Enrollment;Ensure;Epidemic;Fentanyl;Guidelines;Health;Heroin;Hospitals;Human;Individual;Inpatients;Intervention;Knowledge;Label;Laboratories;Laboratory Study;Measures;Medical;Metabolic Pathway;Morbidity - disease rate;Nature;Opioid;Opioid agonist;Outcome;Overdose;Oxycodone;Pain Disorder;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Physicians;Physiological;Placebos;Polypharmacy;Procedures;Property;Provider;Psychomotor Performance;Randomized;Recording of previous events;Reporting;Research;Research Personnel;Respiratory physiology;Risk;Safety;Sedation procedure;Supervision;Surgeon;Surveys;Testing;Time;Toxicology;United States;Work;benzodiazepine abuse;cognitive performance;design;experience;experimental study;gabapentin;illicit drug use;illicit opioid;indexing;mortality;opioid abuse;opioid misuse;opioid mortality;opioid overdose;opioid use disorder;overdose death;pain model;pain relief;prescription opioid;recreational drug use;sedative;statistics;targeted agent;volunteer


application_id: 9445408
project_number: 5R01CA205400-03
project_title: Distinct Redox Mechanism in Normal and Cancer Cells as a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2018-02-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 205400
program_official: PRASANNA, PAT G
project_start_date: 2016-04-01
project_end_date: 2021-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
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): Prostate cancer is the second leading cause of male cancer deaths in the U.S. but it is the most frequently diagnosed cancer in men. Although current therapeutic radiation strategies are successful in treating the initial cancer there are fw effective therapeutic options for patients with aggressive prostate cancer. Addition of cytotoxic or hormone therapy offers some benefit but each is associated with unwanted side effects to normal tissues. The goal of this research project is to develop an anticancer regimen that improves the efficacy of radiation therapy by sensitizing tumor tissue to radiation while simultaneously protecting normal tissue against the side effects of radiation therapy. It addresses the critical gap in scientific knowledge of how the intrinsic differences in the redox conditions of normal and tumor cells trigger differential adaptive responses to prooxidants and demonstrates the outcome of the proposed approach in a preclinical setting with the expectation that changes in clinical practice could result. We propose that the differences in redox homeostasis in normal and cancer cells create a therapeutic window for pushing cancer cells towards oxidative stress overload and death while stimulating adaptive responses in normal cells to enhance survival. Our preliminary data show that dimethylaminoparthenolide (DMAPT) a lactone water soluble prodrug of parthenolide selectively sensitizes prostate cancer cells to ionizing radiation (IR) but protects normal prostate epithelial cells against IR-induced injury. W screened a library of 760 FDA-approved compounds for drugs that can radiosensitize tumor cells but radioprotect normal cells and identified betamethasone (BET) a steroid as a lead compound with these properties. Interestingly both DMAPT and BET exhibit opposing effects in normal vs cancer cells on RelB a member of the NF-B alternative pathway. These results are very important as they allow us to focus on testing a concept and pathway rather than on a specific agent.  This proposed study involves proof-of-concept studies in experimental animal models coupled with in-depth mechanistic molecular and cellular studies using DMAPT and BET. Aim 1 will test the concept that aberrant redox conditions of cancer cells enables a redox-based approach that enhances radiation therapy efficacy by sensitizing cancer cells to radiation treatment while protecting normal cells from the side effects of radiation therapy of prostate cancer. Aim 2 will test the hypothesis that RelB mediates the effect of DMAPT and BET in protecting normal cells but sensitizing prostate cancer cells to IR.  The results of this study wil facilitate the translation of novel radiation sensitizers for clinical use and will fill in critica gaps in scientific knowledge of how the differences in redox conditions of normal and tumor cells trigger differential responses to pro-oxidants. Translation of this paradigm-shifting concept will have a major impact on the efficacy and morbidity of radiation therapy.

project_terms:
Acute;Address;Adverse effects;Affinity Chromatography;Amino Acids;Apoptosis;Autophagocytosis;Autopsy;Betamethasone;Biochemical;Biological Markers;Cancer Survivor;Cell Culture Techniques;Cell Line;Cells;Cessation of life;Clinical;Clinical Treatment;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Coupled;Couples;Cultured Cells;Cytotoxic Chemotherapy;Data;Development;Disulfides;Dose;Electron Spin Resonance Spectroscopy;Epithelial Cells;Exhibits;Experimental Animal Model;FDA approved;Family;Gene Targeting;Gene-Modified;Genetic Transcription;Goals;Histology;Homeostasis;In Vitro;Inflammatory;Injury;Ionizing radiation;Knowledge;Lactones;Lead;Libraries;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Messenger RNA;Methods;Modeling;Molecular;Molecular Biology;Morbidity - disease rate;Mus;Necrosis;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Primary Neoplasm;Prodrugs;Property;Prostate;Prostate Cancer therapy;Prostate carcinoma;Proteins;Proteomics;Quality of life;Radiation;Radiation Tolerance;Radiation exposure;Radiation therapy;Radiation-Sensitizing Agents;Radiodermatitis;Reactive Oxygen Species;Recurrence;Regimen;Research Project Grants;Role;Sesquiterpenes;Small Interfering RNA;Stable Isotope Labeling;Steroids;Sulfhydryl Compounds;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;Tumor Tissue;United States;Water;Work;anti-cancer;base;cancer cell;cancer diagnosis;clinical practice;cytotoxic;expectation;gene product;hormone refractory prostate cancer;hormone therapy;improved;in vivo;in vivo evaluation;in vivo imaging;luminescence;male;member;men;morphometry;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;parthenolide;personalized therapeutic;pre-clinical;prostate cancer cell;public health relevance;radiation resistance;radiation response;radiation-induced injury;radiosensitizing;response;treatment response;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This application will test a paradigm-shift concept for the development of novel therapeutic strategies that aim to increase radiation therapy efficacy while protecting normal tissue injury against the side effects of radiation therapy. We will test this concept by employing a lactone: dimethylaminoparthenolide which is in early stage clinical trials; and a steroid betametazone which is FDA approved for inflammatory related conditions. Results from these studies will lead to very concrete information potentially offering a specific course of action to improve radiation therapy efficacy and quality of life for cancer survivors.


application_id: 9444672
project_number: 3T32NS077889-05S1
project_title: Neurobiology of CNS Injury and Repair
project_terms: Neurobiology;central nervous system injury;injury and repair
administering_ic: NINDS
award_notice_date: 2017-04-07
opportunity_number: PA-11-184
application_type: 3
activity_code: T32
ic: NS
serial_number: 077889
suffix: S1
program_official: KORN, STEPHEN J
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: ZNS1-SRB-P(63)
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: GEDDES, JAMES W.
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
project_abstract:
DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT This is a new T32 application requesting funding for a Neurobiology of CNS Injury and Repair Training Program for 4 predoctoral fellows/year. The training of the predoctoral fellows will be carried out by training faculty in the University of Kentucky Spinal Cord & Brain Injury Research Center (SCoBIRC). The overall goal of the proposed program is to provide broad-based training in modern research concepts regarding the acute subacute and chronic pathophysiology of SCI and TBI and the identification of potential disease-modifying molecular targets that can drive the discovery of pharmacological and gene therapeutic strategies by which the devastating effects of these injuries can be ameliorated. These strategies will include both "neuroprotective" and "neurorestorative" approaches. Although it is anticipated that most of the trainees will pursue careers in laboratory-based therapeutic discovery research they will also receive training in clinical aspects of the targeted neurological disorders and the practical issues involved in the design and conduct of neurological clinical trials. To accomplish this the predoctoral fellows wil also spend one day/week for a semester shadowing neurological neurosurgical and/or neurorehabilitation clinical faculty and attending weekly grand rounds to gain an understanding of the clinical nature of TBI and SCI that their research is focused upon. This will enhance their future ability as independent investigators to not only make therapeutic discoveries in experimental injury models but also provide them with knowledge concerning how to design their basic research in a manner that will more readily enable the translation of promising therapeutic approaches into clinical studies and therapeutic trials.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This project will involve the development of a new training program to prepare 4 predoctoral fellows/year for neurological research careers directed at the discovery and translation of novel neuroprotective and neurorestorative therapies for the treatment of traumatic spinal cord and brain injuries. The training will be directed by basic science and clinical faculty of the University of Kentucky Spina Cord & Brain Injury Research Center.


application_id: 9444516
project_number: 5R01CA215095-02
project_title: Roles of RORalpha in breast cancer development and progression
administering_ic: NCI
award_notice_date: 2018-06-14
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 215095
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 10533977
contact_pi: XU, REN
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_terms:
Agonist;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Cell Polarity;Cellular Metabolic Process;Chronic;Coculture Techniques;Complex;Development;Down-Regulation;Epithelial Cells;Expression Profiling;Gene Expression;Gene Expression Profiling;Generations;Glutathione Disulfide;Goals;Human;Hydrogen Peroxide;Immunocompetent;Infiltration;Inflammation;Knockout Mice;Knowledge;Lead;Link;Malignant Neoplasms;Mammary gland;Measurement;Mediating;Metabolic;Metformin;Mitochondria;Modeling;Molecular;Mus;NADP;Nature;Neoplasm Metastasis;Nuclear Orphan Receptor;Oxidation-Reduction;Pathway interactions;Positioning Attribute;Production;Reactive Oxygen Species;Research;Role;Scheme;Source;Structure;Superoxides;System;TP53 gene;Testing;Tissue Microarray;Tissues;Tumor Suppressor Proteins;base;breast cancer progression;cancer cell;cancer prevention;cancer therapy;cytokine;druggable target;healing;improved;inhibitor/antagonist;insight;knock-down;loss of function;macrophage;malignant breast neoplasm;metabolomics;monocyte;multidisciplinary;novel;novel strategies;stable isotope;transcriptome;tumor;tumor microenvironment;tumor progression


application_id: 9444402
project_number: 5R01AA024405-04
project_title: SAM Deficiency Mediated Epigenetic Mechanisms in Alcohol induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2018-02-27
application_type: 5
activity_code: R01
ic: AA
serial_number: 024405
program_official: WANG, JOE
project_start_date: 2015-03-10
project_end_date: 2020-02-29
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
project_abstract:
CD4+ T cell depletion is a major component of the multiple detrimental effects of chronic alcoholconsumption on the immune system. Chronic alcohol abuse leads to abnormal S-adenosylmethionine (SAM)metabolism and decreased hepatic SAM levels. Our earlier work in CD4+ T cells has demonstrated thatethanol significantly decreases lymphocytic methionine adenosyltransferase (MAT II) expression and activitywith resultant SAM deficiency and also increases activation-induced Fas-mediated apoptotic death. Notablyexogenous SAM supplementation restored intracellular SAM and prevented apoptotic signaling and death inethanol treated CD4+ T cells. These data not only showed a causal role for SAM deficiency in ethanolmediated apoptotic death but also provided the proof-of-concept for SAM therapy in preventing alcoholinduced CD4+ T cell depletion and immune suppression. SAM functions as the critical methyl donor duringepigenetic regulation leading to enzymatic modification of histones and DNA cytosine residues. Our recentwork on ethanol treated primary human CD4+ T cells in vitro as well as CD4+ T cells obtained from alcoholicpatients has provided convincing preliminary data showing that ethanol exposure can cause transcriptionallypermissive modifications in histones associated with the FasL promoter. These histone modificationsenhance transcriptional activation of the FasL promoter resulting in increased mRNA expression apoptoticsignaling and cell death. The overall objective of this proposal is to systematically examine genome wide aswell as gene specific (promoter associated) histone and DNA modifications involved in alcohol-mediatedapoptotic signaling and death in CD4+ T cells. We expect that the results of our study will provide criticalmolecular insights in the alcohol-induced immunotoxicity of CD4+ T cells. We predict that results from thisresearch will also provide important insights into immune dysfunction/CD4+ T cell loss in alcohol consumingHIV-infected patients. The specific aims of this translational proposal investigating the epigeneticmechanisms involved in aberrant apoptotic signaling and cell death of CD4+ T lymphocytes in alcoholicpatients are: Aim 1: Examine the effects of alcohol on cellular SAM levels global histone and DNAmodifications and apoptotic cell death in CD4+ T cells. Aim 2: Determine the gene specific (promoterassociated) histone and DNA modifications occurring in response to alcohol-mediated SAM deficiency thatimpact the expression of apoptotic genes relevant to CD4+ T cell survival.RELEVANCE (See instructions):Alcohol abuse continues to be a significant burden on the US healthcare system. The studies proposed herewill examine epigenetic modifications involved in alcohol-induced depletion of CD4+ T lymphocytes usingboth a genome-wide approach as well as a hypothesis-based candidate gene approach. The data obtainedfrom these studies will yield mechanistic insights underlying alcohol induced immune suppression and howalcohol may further depress immune function in HIV-infected patients.

project_terms:
Alcohol abuse;Alcohol consumption;Alcohols;Apoptotic;CD4 Positive T Lymphocytes;Candidate Disease Gene;Cell Death;Cell Survival;Cessation of life;Chronic;Clinical;Cytosine;DNA;DNA Modification Process;Data;Depressed mood;Epigenetic Process;Ethanol;Gene Expression;Genes;Genetic Transcription;HIV;Healthcare Systems;Hepatic;Histones;Human;Immune System Diseases;Immune system;Immunosuppression;In Vitro;Instruction;Lymphocyte;Mass Spectrum Analysis;Mediating;Metabolism;Modification;Molecular;Patients;Proteomics;Research;Role;S-Adenosylmethionine;Signal Transduction;Supplementation;T-Cell Depletion;Transcriptional Activation;Work;alcohol abuser;alcohol effect;alcohol exposure;alcohol prevention;alcohol response;base;chronic alcohol ingestion;epigenetic regulation;genome-wide;histone modification;immune function;immunotoxicity;insight;mRNA Expression;methionine adenosyltransferase;prevent;problem drinker;promoter


application_id: 9444209
project_number: 1R01CA214638-01A1
project_title: A redox-mediated mechanism of UVB-induced metabolic switch in skin carcinogenesis
administering_ic: NCI
award_notice_date: 2017-12-19
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 214638
suffix: A1
program_official: JOHNSON, RONALD L
project_start_date: 2017-12-18
project_end_date: 2022-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Affinity;Anions;Antioxidants;Autophagocytosis;Basal cell carcinoma;Bioenergetics;Chemistry;Chemoprevention;Co-Immunoprecipitations;Consumption;Coupled;Data;Development;Diagnosis;Energy Metabolism;Epithelial Cells;Event;Exposure to;Genetic Enhancer Element;Genetic Transcription;Glucose;Glycolysis;Goals;Histologic;Human;Intervention;Kinetics;Knowledge;Lifetime Risk;Luciferases;Malignant Epithelial Cell;Malignant Neoplasms;Manganese;Mediating;Mediator of activation protein;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Molecular Biology;Molecular Chaperones;Molecular Genetics;Nitrates;Normal tissue morphology;Ontology;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Peroxonitrite;Prevention;Production;Proteins;Proteomics;Reporter Genes;Research;Risk;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Squamous cell carcinoma;Superoxide Dismutase;Superoxides;Testing;Tissues;Transgenic Mice;UV induced;UVB carcinogenesis;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;United States;Validation;Warburg Effect;base;cancer prevention;carcinogenesis;design;genetic approach;insight;knock-down;member;metabolomics;mimetics;nitration;novel;prevent;promoter;prototype;response;skin cancer prevention;stable isotope;transcriptome;tumor;ultraviolet


application_id: 9443612
project_number: 5R01CA217255-02
project_title: Studies to understand and exploit 10-membered enediyne biosynthesis
administering_ic: NCI
award_notice_date: 2018-02-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 217255
program_official: FU, YALI
project_start_date: 2017-03-01
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1-BCMB-U(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL;VAN LANEN, STEVEN GARY
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_terms:
Achievement;Alkylation;Amines;Anabolism;Anthraquinones;Anti-Infective Agents;Antibodies;Antitumor Natural Products;Architecture;Biochemical;Biogenesis;Bioinformatics;Biotin;Chemicals;Chemistry;Clinical;Collaborations;Complement;Complex;Crystallization;Cyclization;Development;Dynemicin;Enzymatic Biochemistry;Enzymes;Family member;Foundations;Genetic;Hybrids;Hydroxylation;Iodination reaction;Ligands;Mixed Function Oxygenases;Modality;Modification;Molecular;Monoclonal Antibodies;Natural Products;Nucleotides;Polyenes;Proteins;Reaction;Reagent;Route;Series;Structural Protein;Structure;Sulfur;Trisaccharides;analog;anti-cancer;base;cancer therapy;catalyst;chemical genetics;clinical development;design;enzyme pathway;glycosylation;glycosyltransferase;innovation;insight;non-Native;novel;novel strategies;oxidation;polyketide synthase;prototype;structural biology;structural genomics;sugar;targeted agent;thiosugar;tool;tumor


application_id: 9442859
project_number: 5R01NS062306-08
project_title: PPAR inhibition of spinal pain transmission
administering_ic: NINDS
award_notice_date: 2018-01-08
opportunity_number: PA-16-188
application_type: 5
activity_code: R01
ic: NS
serial_number: 062306
program_official: OSHINSKY, MICHAEL L
project_start_date: 2008-12-18
project_end_date: 2018-03-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
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:
Diabetes affects 9% of the United States population and approximately one-third of these patients experiencechronic neuropathic pain commonly referred to as painful diabetic neuropathy (PDN). PDN is difficult tomanage as analgesic treatments are only effective in a small subset of PDN patients. The development ofanalgesics for pain associated with diabetes in particular type 2 diabetes is stalled by our incompleteunderstanding of the underlying mechanisms of PDN. An important new clue comes from the recent findingthat methylglyoxal (MG) a highly reactive dicarbonyl product of glycolysis that accumulates withhyperglycemia is particularly high in patients with PDN. MG causes non-enzymatic glycation of proteins. Theresulting protein adducts or advanced glycation end products (MG-AGEs) are toxic and contribute to diabeticcomplications including PDN. Our central hypothesis is that elevated MG in type 2 diabetes causes pain andthat this can be alleviated with new classes of drugs targeting MG itself TRPA1 AC1 Epac and PPAR. Totest the hypothesis that MG drives neuropathic pain (PDN) in type 2 diabetes Specific Aim 1 will firstdetermine whether elevations in MG and its metabolizing enzyme Glyoxalase-1 occur in pain processingtissues in the hereditary Leprdb/db (db/db) mouse and Zucker Diabetic Fatty (ZDF) rat models of type 2diabetes. We then ask whether a promising new class of MG-scavenging peptides will alleviate affective painand spinal pain transmission. Our preliminary data indicate that genetic deletion or pharmacological inhibitionof TRPA1 a glycation target of MG blocks MG-induced pain. Indeed TRPA1 is a leading target for thedevelopment of new analgesics for chronic pain but has not been tested in models of type 2 PDN. To fill thisgap Specific Aim 2 will test the hypothesis that TRPA1 antagonists reduce affective pain and spinal paintransmission in db/db mice and ZDF rats. Consequent to TRPA1 channel opening (e.g. by MG) the resultingCa2+ influx into the cell leads to the activation of Ca2+-sensitive proteins which includes adenylyl cyclase I(AC1). Our data indicate that selective inhibition of AC1 with NB001 blocks type 2 PDN. AC1 generates theintracellular second messenger cAMP which targets not only protein kinase A but also exchange proteindirectly activated by cAMP (Epac). Specific Aim 3 will use novel Epac1 and Epac2 small molecule inhibitors todetermine which of these targets drive PDN. Among the 33 original research articles reviews and a bookpublished during the previous funding cycle (22 with the PI as first or senior author) our Progress includes thediscovery that pioglitazone a peroxisome proliferator-activated receptor gamma (PPAR) agonist that is FDA-approved to treat diabetes acts at dorsal horn neurons to inhibit the chronic pain associated with cutaneousinflammation and traumatic nerve injury. Our new data indicate additional efficacy in PDN and MG-inducedpain with surprisingly robust analgesic effects in females. Specific Aim 4 proposes to study PPARmechanism of action in db/db and ZDF with a new focus on sex differences in spinal nociceptive transmission.

project_terms:
Adenylate Cyclase;Advanced Glycosylation End Products;Affect;Affective;Agonist;Analgesics;Behavioral;Biological Assay;Blood;Books;Cations;Cells;Chemosensitization;Complications of Diabetes Mellitus;Conflict (Psychology);Cutaneous;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cytotoxin;Data;Development;Diabetes Mellitus;Diabetic Neuralgia;Diamond;Drug Targeting;Enzymes;Extracellular Signal Regulated Kinases;FDA approved;Female;Funding;Genetic;Glucose;Glycolysis;Hyperalgesia;Hyperglycemia;Inflammation;Inherited;Intrathecal Injections;Lactoylglutathione Lyase;Measures;Mechanics;Mediating;Metabolic;Modeling;Molecular;Motivation;Natural History;Nerve;Neurons;Nociception;Non-Insulin-Dependent Diabetes Mellitus;PPAR alpha;PPAR gamma;Pain;Patients;Peptides;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Pioglitazone;Plasma;Population;Posterior Horn Cells;Progress Reports;Proteins;Publishing;Pyruvaldehyde;Rattus;Research;Second Messenger Systems;Sex Characteristics;Signal Transduction;Spinal;Spinal Cord;Spine pain;Stimulus;Streptozocin;Structure of beta Cell of islet;TRPA1 Channel;Testing;Traumatic Nerve Injury;United States;adduct;adenylyl cyclase 1;chronic neuropathic pain;chronic pain;db/db mouse;diabetic;dorsal horn;experience;glycation;inhibitor/antagonist;innovation;male;mouse model;new therapeutic target;novel;novel drug class;overexpression;pain behavior;pain processing;pain reduction;pain relief;painful neuropathy;preclinical study;public health relevance;receptor;small molecule;small molecule inhibitor;tissue processing;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTDiabetes affects almost 9% of the United States population and approximately one-third of thesepatients experience chronic pain termed painful diabetic neuropathy (PDN). Commercial analgesicdrugs do not work well in patients with advanced PDN yielding pain relief in less than 50% of patientsand of those the pain relief is less than 50%. This project explores a new mechanism of PDN that isdriven by the toxic by-product of high glucose  methylglyoxal (MG)  and evaluates four promisingnew drug targets (MG itself TRPA1 AC1 and PPAR) towards a new pharmacotherapy for thisdebilitating condition.


application_id: 9441982
project_number: 1R15GM126446-01
project_title: Detecting and characterizing circular RNAs using high-throughput sequencing data
administering_ic: NIGMS
award_notice_date: 2017-09-13
opportunity_number: PA-16-200
application_type: 1
activity_code: R15
ic: GM
serial_number: 126446
program_official: NGUYEN, HAN
project_start_date: 2017-09-15
project_end_date: 2021-08-31
study_section: Genomics, Computational Biology and Technology Study Section[GCAT]
contact_pi_person_id: 14867184
contact_pi: PARK, JUW WON
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The purpose of this research is to improve our understanding of a recently discovered circular form ofRNA (circular RNA or circRNA) using high-throughput sequencing data to identify and characterizethese structures over a variety of contexts. Over the past two decades studies have discovered a specialform of alternative splicing (AS) that produces a circular form of RNA. This stands in contrast to normalAS which produces a linear form of RNA. Although these circRNAs have garnered considerableattention in the scientific community for their biogenesis and functions the focus of current studies hasbeen on the tissue-specific circRNAs that exist only in one tissue but not in other tissues or on thedisease-specific circRNAs that exist in certain disease conditions such as cancer but not under normalconditions. This approach was conducted in the relative absence of methods that analyze a group ofcommon circRNAs that exist in both conditions but are more abundant in one condition relative toanother (differentially expressed). Studies of common differentially expressed circRNAs between twoconditions would serve as a significant first step in filling this void. One of the major applications ofRNA sequencing (RNA-seq) a powerful technology for analysis of eukaryotic transcriptomes is todetect novel (or unannotated) mRNA transcripts. Since circRNAs are novel transcripts RNA-seqprovides a perfect platform for genome-wide detection of circRNAs. Our own preliminary result fromneurally-derived RNA-seq data (somata and neuropil layers of CA1 hippocampal region) has shown thatover 50 circRNAs were more abundantly expressed either in the somata or in the neuropil layer. Guidedby these data the current proposal will (Aim 1) develop a novel computational method for identifyingcharacterizing and quantifying differentially expressed circRNAs between any two biologicalconditions using RNA-seq data and (Aim 2) develop a new web server for aggregating catalogingand visualizing circRNAs derived from publicly available RNA-seq datasets. This proposal willaccomplish the objectives of the R15 AREA grant in: (i) supporting meritorious research; (ii)strengthening the research environment of non-research intensive institutions; and (iii) engagingundergraduate/graduate students in bioinformatics research. The proposed work would act as afoundation for the applicant to establish a program of research aimed at facilitating circRNA studiesusing high-throughput sequencing data. In turn this would provide researchers with critical informationregarding circRNAs in existing high-throughput sequencing datasets. Finally the proposed research willbe used as a vehicle to engage undergraduates in multi-disciplinary bioinformatics research and betterenable students from Kentucky a traditionally underrepresented state in bioinformatics to successfullyparticipate in advanced biomedical research.

project_terms:
Alternative Splicing;Area;Attention;Binding;Binding Sites;Biogenesis;Bioinformatics;Biological;Biomedical Research;Cataloging;Catalogs;Characteristics;Collection;Communities;Computing Methodologies;Data;Data Set;Databases;Deposition;Detection;Development;Disease;Drops;Environment;Exons;Faculty;Foundations;Future;Gene Expression;Genomics;Goals;Grant;High-Throughput Nucleotide Sequencing;Hippocampus (Brain);Human;Institution;Internet;Kentucky;Length;Malignant Neoplasms;Messenger RNA;Methods;MicroRNAs;Neurons;Neuropil;Play;Publishing;RNA;RNA Sequences;RNA-Binding Proteins;Regulation;Research;Research Personnel;Resources;Role;Sampling;Scientist;Structure;Students;Technology;Tissues;Transcript;Universities;Untranslated RNA;Virus Diseases;Work;Zika Virus;circular RNA;college;computerized tools;cost;cost effective;differential expression;experience;genome-wide;graduate student;improved;multidisciplinary;neuroblastoma cell;neuronal cell body;next generation sequencing;novel;online resource;programs;relating to nervous system;tool;transcriptome;transcriptome sequencing;undergraduate student;user-friendly;web portal

public_health_relevance:
Over the past two decades studies have discovered a special form of mechanism that produces a circularform of RNA (circRNA). The purpose of this research is to identify and characterize circRNAs usingnext generation sequencing technology. This research will provide researchers with critical informationregarding the circRNAs in the existing sequencing datasets in addition to enhancing research experiencesin multi-disciplinary bioinformatics research among college undergraduates in University of Louisville.


application_id: 9441821
project_number: 5P20GM121327-02
project_title: Project 4: The Role of Fatty Acid Synthase in Colorectal Cancer
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7099
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). My long-termgoal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis byunderstanding how changes in de novo fatty acid synthesis contribute to metastatic disease. Fatty acidsynthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated and activated in CRCand its activity is associated with poor prognosis higher risk of disease recurrence and death. I have identifiedFASN as a potential target for advanced stages of disease and showed that upregulation of this enzyme is akey mechanism supporting metastasis in CRC. However the underlying mechanisms of regulation ofmetastasis by FASN are not understood. The current application proposes a comprehensive research plan tostudy novel mechanisms of regulation of growth survival and metastasis by FASN in CRC. Our preliminarystudies show that overexpression of FASN is associated with an increase in cellular respiration including -oxidation inhibition of autophagy and accumulation of lipid droplets. Therefore in Aim 1 we will elucidate therole of FASN in reprogramming of metabolic pathways and lipid storage in order to maintain energyhomeostasis and promote survival of cancer cells. Furthermore our preliminary data suggest that the primaryproduct of de novo fatty acid synthesis palmitate is selectively used for sphingolipid synthesis andoverexpression of FASN increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipidknown to enhance migration and invasion of cancer cells. Therefore in Aim 2 we will test the hypothesis thatFASN promotes metastasis via activation of sphingosine kinases and an increase in S1P signaling. Finally inAim 3 we will test the effect of FASN inhibitor on proliferation in CRC patient-derived xenografts (PDXs) as amonotherapy and in combination with an autophagy inhibitor and identify potential biomarkers associated withCRC responsiveness to FASN inhibition. I will utilize biological samples from patients human primary cells and PDX models which are the mostadvanced models for pre-clinical target and drug evaluations. These models will be used in conjunction withstate-of-the-art approaches including Stable Isotope-Resolved Metabolomics (SIRM) to evaluate the effect ofFASN overexpression on cancer metabolism. The differential expression of FASN in normal versus cancercells makes de novo lipogenesis a desirable target for therapeutic intervention. I anticipate that the proposedwork will identify a subset of CRC patients who would benefit from targeted FASN inhibition and furtheradvance our understanding of the role of FASN in CRC that would potentially lead to the development of noveltherapeutic strategies to treat this disease.

project_terms:
Autophagocytosis;Biological;Biological Sciences;Cancer Cell Growth;Cancer Center;Cause of Death;Cell Proliferation;Cell Respiration;Cell Survival;Cells;Cessation of life;Characteristics;Colorectal Cancer;Data;Development;Disease;Disease-Free Survival;Drug Evaluation;Energy Supply;Enzymes;Evaluation;Fatty Acids;Fatty-acid synthase;Goals;Growth;Homeostasis;Human;Incidence;Kentucky;Lead;Link;Lipids;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic to;Modeling;Molecular;Neoplasm Metastasis;Oncogenic;Outcome;Palmitates;Patients;Play;Post-Translational Protein Processing;Pre-Clinical Model;Process;Production;Proteins;Publishing;Recurrence;Regulation;Research;Resected;Role;Sampling;Signal Transduction;Solid Neoplasm;Sphingolipids;Sphingosine;Stress;Testing;Therapeutic;Therapeutic Intervention;Tumor Angiogenesis;Universities;Up-Regulation;Work;Xenograft Model;Xenograft procedure;antitumor effect;base;cancer cell;cancer survival;colon cancer cell line;colon cancer patients;colorectal cancer metastasis;colorectal cancer treatment;differential expression;disorder risk;high risk;in vivo;inhibition of autophagy;inhibitor/antagonist;knock-down;lipid biosynthesis;metabolomics;migration;molecular marker;novel;novel therapeutics;outcome forecast;overexpression;oxidation;potential biomarker;prevent;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;tumor;tumor growth;tumor metabolism


application_id: 9441820
project_number: 5P20GM121327-02
project_title: Project 3: Role of RORa in Breast Cancer Metastasis
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7098
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_abstract:
PROJECT SUMMARYTumors have been described as wounds that do not heal. Similarities between tumors and wounds includetraits such as loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissuepolarity induced activation of the NF-B pathway and macrophage infiltration. However little is known of howdisruption of epithelial cell polarity induces the NF-kB pathway and macrophage infiltration. We have identifiedthe RAR-related orphan nuclear receptor  (ROR) as a potent tumor suppressor by analyzing global geneexpression profiles in polarized and non-polarized mammary epithelial cells. Our recent findings show thatROR inhibits NF-B activation and macrophage infiltration in the syngeneic mouse mammary tumor model.These results suggest that ROR is a potent suppressor of macrophage infiltration in mammary epithelial cells.We found that knockdown of ROR significantly induced ROS production in mammary epithelial cells. Reactiveoxygen species (ROS) is a driver of cancer progression and a critical regulator of the NF-B pathway. Basedon these novel findings the central hypothesis of our proposal is that downregulation of ROR in non-polarizedbreast cancer cells induces ROS-dependent NF-B activation thereby enhancing macrophage infiltration anddifferentiation in cancer tissue. We will integrate high-throughput metabolic analysis and global geneexpression profiling to delineate mechanisms by which ROR inhibits ROS production. The long-term goal ofthis proposal is to define the impact of the ROR/NF-B axis in mediating mammary epithelial cell-macrophagecrosstalk and regulating breast cancer progression. We have proposed following specific aims to test thehypothesis: The first aim is to elucidate the molecular mechanisms by which ROR inhibits the NF-B pathwayin polarized acinus; the second aim is to determine how reduced ROR expression in non-polarized breastcancer cells induces macrophage infiltration and differentiation; and the third aim is to define the impact ofROR in suppressing breast cancer formation and metastasis. This proposed study involves in-depthmechanistic molecular biochemical and cellular studies using state-of-the art metabolomics imagingtechniques and model systems. The results will establish a novel link between disruption of tissue polarity andmacrophage infiltration/differentiation a critical gap in scientific knowledge in this important research area.Expected study outcomes will also provide new insights in function and regulation of the NF-B pathway duringbreast cancer development and progression that will facilitate the development of mechanistic based target forcancer therapy.

project_terms:
Acinus organ component;Antibodies;Area;Arginine;Biochemical;Biological Assay;Biological Models;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Epithelial Cells;Breast cancer metastasis;Cancer Center;Cell Polarity;Centers of Research Excellence;Chronic;Coculture Techniques;Coupled;Development;Disease;Down-Regulation;Epithelial Cells;Event;Expression Profiling;Gene Expression Profiling;Goals;Human;Imaging Techniques;Infiltration;Inflammation;Kentucky;Knockout Mice;Knowledge;Link;Malignant Neoplasms;Mammary gland;Mass Spectrum Analysis;Mediating;Metabolic;Methylation;Molecular;Mus;NF-kappa B;Neoplasm Metastasis;Nuclear Orphan Receptor;Outcome Study;Oxidative Phosphorylation;Pathway interactions;Production;Protein-Arginine N-Methyltransferase;Reactive Oxygen Species;Regulation;Research;Role;Structure;TP53 gene;Testing;Tissue Microarray;Tissues;Transgenic Mice;Transplantation;Tumor Suppressor Proteins;Universities;base;breast cancer progression;cancer prevention;cancer subtypes;cytokine;experimental study;extracellular;in vivo;insight;knock-down;macrophage;malignant breast neoplasm;metabolomics;novel;stable isotope;targeted cancer therapy;trait;transcriptome;tumor;tumor metabolism;tumor progression


application_id: 9441819
project_number: 5P20GM121327-02
project_title: Project 2: Functional Role of the Serine Biosynthesis Pathway in Basal-like Breast Cancer
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7097
contact_pi_person_id: 11716117
contact_pi: WU, YADI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_abstract:
PROJECT SUMMARYBasal-like breast cancer (BLBC) is one of the most aggressive forms of human cancer because it lackseffective targeted therapies and presents with development of recurrence distant metastasis shorter survivaland usually occurs in young women. BLBC has the activated epithelial-mesenchymal transition (EMT)program which provides cancer cells with the phenotypic and cellular plasticity required for invasion cancerstem cell (CSC)-like features and drug resistance. In the last several years we have systematically studiedthe role of Snail and Twist two key EMT-inducers in BLBC. We discovered that Snail functions to repressgenes that prevent EMT (such as E-cadherin) whereas Twist by interacting with BRD4 serves as atranscription activator to induce genes that enhance EMT (such as Wnt5A). We also discovered that EMT iscoupled with a metabolic reprogramming which provides a metabolic growth advantage for BLBC cells. Ourmetabolic analyses clearly indicate that BLBC cells also have increased activity for the pathway driving denovo serine synthesis which is a significant branch derived from glycolysis. The serine biosynthetic pathway isintimately coupled to one-carbon metabolism which intertwines with the folate and methionine cycles tointegrate nutritional inputs from glucose amino acids and vitamins for the biosynthesis of nucleotides lipidsand proteins as well as the methylation of chromatin. Our laboratory has discovered that phosphoserineaminotransferase 1 (PSAT1) expression a key enzyme in serine biosynthesis is markedly increased in celllines and clinical BLBC samples. In addition we found that expression of Twist correlated with the level ofPSAT1 in BLBC and that Twist significantly induced PSAT1 expression. Knockdown of PSAT1 expression notonly reduced glucose uptake and lactate production but also inhibited cell proliferation migration and invasionin BLBC. We hypothesize that Twist is the key molecule controlling the expression of PSAT1 which isresponsible for the elevated activity of the serine biosynthetic pathway seen in BLBC. Guided by strongpreliminary data we will test this hypothesis by pursuing three specific aims: (1) to elucidate the regulatorymechanism of PSAT1 by Twist in BLBC; (2) to delineate the function of the serine/PSAT1 pathway in BLBC;and (3) to determine the function of the serine/PSAT1 pathway in vivo. Our proposal is innovative andsignificant because it incorporates a merged investigation of two essential cancer markers in BLBC metabolicreprogramming and EMT and because it leads to the development of an effective precision cancer therapyapproach in treating BLBC by combining metabolic drugs with epigenetic inhibitors.

project_terms:
Amino Acids;Anabolism;Antioxidants;Automobile Driving;Brain;Breast Cancer Cell;Breast Cancer cell line;Bromodomain;Cancer Cell Growth;Cancer Center;Carbon;Cell Line;Cell Proliferation;Centers of Research Excellence;Chromatin;Clinical;Coupled;Data;Development;Disease;Distant Metastasis;Drug resistance;E-Cadherin;Enzymes;Epigenetic Process;Epithelial;Folic Acid;Folic Acid Antagonists;Fructose;Genes;Glucose;Glycolysis;Goals;Grant;Growth;Human;Intrinsic factor;Investigation;Kentucky;Laboratories;Lipids;Lung;Maintenance;Malignant Neoplasms;Mediating;Mesenchymal;Metabolic;Metabolic Pathway;Metabolism;Methionine;Methylation;Molecular;Mus;Neoplasm Metastasis;Nucleic Acids;Nucleotide Biosynthesis;Nutritional;Pathway interactions;Patients;Pemetrexed;Pharmaceutical Preparations;Phenotype;Phosphoserine aminotransferase;Production;Proteins;Recurrence;Repression;Role;Sampling;Serine;Signal Transduction;Snails;Specificity;Specimen;Testing;Transcription Coactivator;Universities;Warburg Effect;Xenograft Model;aerobic glycolysis;base;cancer biomarkers;cancer cell;cancer stem cell;cancer therapy;druggable target;glucose uptake;in vivo;inhibitor/antagonist;innovation;knock-down;malignant breast neoplasm;migration;neoplastic cell;novel therapeutic intervention;outcome forecast;overexpression;prevent;programs;stem-like cell;targeted treatment;tumor;tumor metabolism;tumor microenvironment;vitamin biosynthesis;young woman


application_id: 9441818
project_number: 5P20GM121327-02
project_title: Project 1: The Role of Vitamin D in Protecting Against Cachexia in Cancer Patients
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7096
contact_pi_person_id: 10544123
contact_pi: THOMAS, DAVID TRAVIS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_abstract:
PROJECTSUMMARYVitamin D repletion is linked to improved muscle mitochondrial function lipid deposition and preservation;however while vitamin D insufficiency is common in cancer the mechanistic effects of vitamin D on musclemetabolic health in cancer patients have not been studied. This is important to address because cancercachexiaischaracterizedbymarkedmusclewastinganabolicresistanceectopicfatinfiltrationmitochondrialdysfunctionandcontributestodecreasedsurvival.Withnovelstrategiestoaddressthisknowledgegapwewilluse a combination of advanced metabolic analytical approaches with complementary model systems in cellculture and human subjects to understand the biochemical and physiological mechanisms underlying cancercachexia in relation to the role of Vitamin D in conjunction with resistance exercise (RE). By combininganalysesofmusclesizeandlocaltissuehemodynamicsinvivometabolomicsanalysesofmuscletissueandisolated mitochondria and changes in anabolic cell signaling lipid metabolism and oxidative capacity ofprimary muscle cells in vitro we will identify mechanisms underlying muscle response to vitamin D repletion.Our previous findings together with data that exercise improves muscle vitamin D storage and retrievalsuggest that vitamin D repletion synergizes with RE to improve muscle metabolic function and proteinsynthesis. Our overall objective is to examine mitochondrial function and anabolic resistance as potentialtargets of action of vitamin D on muscle metabolism size and strength in preventing the progression ofcachexia. The aims of this study are to: 1) non-invasively quantify lipid redistribution local muscle tissuemetabolismandmusclemassandstrengthofcancerpatientsbeforeandafter12weeksofvitaminDrepletionwithexerciseandproteinsupplementation(VitD)comparedtoexerciseandproteinsupplementationonly(Ctl);2) determine differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemiusfrom VitD compared to Ctl; and 3) identify mechanisms whereby vitamin D and exercise regulate muscleanabolicsignalingandmitochondrialactivityinprimaryhumanmyotubecultures.Ourcentralhypothesisisthatvitamin D promotes muscle lipid availability for -oxidation in response to exercise thereby preventinglipotoxicityinthemuscleandpotentiallyimprovinganabolicsensitivityinmuscleduringcancercachexia.Theimpact of this project the first nutrition and exercise study designed as an inexpensive intervention is tounderstand the effect of vitamin D on the metabolic and anabolic dynamics which underpin dysfunction incachecticmuscle.IfvitaminDpromoteslipidpartitioningmusclemetabolicfunctionand/oranabolicsensitivitytheseadaptationswillultimatelyimprovecancertherapybycombatingcancercachexia.Furtherdiffuseopticalspectroscopy techniques have the potential to identify the minimum effective intervention dose for optimizingmetabolichealthleadingtomorepracticalandindividualizedlifestyleprescriptionstoreducehealthcarecosts.

project_terms:
Address;Amino Acids;Biochemical;Biological Models;Biopsy;Cachexia;Calcitriol;Cancer Center;Cancer Patient;Caprylates;Cell Culture Techniques;Consumption;Coupled;Data;Defect;Deposition;Dietary Intervention;Dietary Proteins;Diffuse;Dose;Elderly;Energy Metabolism;Enrollment;Exercise;Fatty acid glycerol esters;Fiber;Functional disorder;Gastrocnemius Muscle;Glucose;Glutamine;Health;Health Care Costs;Human;Hybrids;In Vitro;Infiltration;Intervention;Kentucky;Knowledge;Lead;Life Style;Link;Lipids;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Measures;Mentorship;Metabolic;Metabolism;Mitochondria;Modeling;Muscle;Muscle Cells;Muscle Fibers;Muscle Mitochondria;Muscular Atrophy;Optics;Outcome;Oxygen;Patients;Periodicity;Physical activity;Physiological;Population;Protein Biosynthesis;Proteins;Research Design;Resistance;Retrieval;Role;Signal Transduction;Spectrum Analysis;Stem cells;Stretching;Supplementation;System;Techniques;Testing;Tissues;Translating;Universities;Vitamin D;cancer cachexia;cancer therapy;combat;effective intervention;functional improvement;hemodynamics;human subject;improved;in vivo;lipid metabolism;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;muscle form;muscle metabolism;muscle strength;novel strategies;nutrition;oxidation;preservation;prevent;resistance exercise;response;spectroscopic imaging;stable isotope;standard of care;tumor metabolism


application_id: 9441817
project_number: 5P20GM121327-02
project_title: Core C: Imaging Core
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7095
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_terms:
Achievement;Address;Aging;Area;Bioinformatics;Biological Sciences;Biomedical Research;Biometry;Cancer Center;Cell physiology;Cellular Structures;Centers of Research Excellence;Clinical;Color;Complex;Computer software;Consult;Consultations;Development;Disease Progression;Distant;Equipment;Evaluation;Extramural Activities;Faculty;Floor;Fluorescence;Focal Adhesions;Goals;Health Services Accessibility;Image;Image Analysis;Imaging Device;Imaging Techniques;Individual;Kentucky;Laboratories;Laboratory Research;Lasers;Link;Malignant Neoplasms;Metabolic;Metabolism;Methodology;Methods;Microscope;Mission;Monitor;NCI Center for Cancer Research;Neoplasm Metastasis;Organ;Pathology;Pilot Projects;Positioning Attribute;Preparation;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Sampling;Scanning;Scientist;Services;Slide;System;Time;Tissues;Training;Transfection;Universities;analytical tool;anticancer research;cancer therapy;career development;cost;cost effective;design;digital;experimental study;imaging capabilities;imaging modality;imaging system;in vivo imaging system;instrument;instrumentation;live cell imaging;metabolomics;microscopic imaging;multidisciplinary;novel;skills;success;tumor;tumor initiation;tumor metabolism;tumor microenvironment;tumorigenesis


application_id: 9441816
project_number: 5P20GM121327-02
project_title: Core B: Metabolism Core
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7094
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_terms:
Address;Algorithms;Biochemical;Biochemistry;Bioinformatics Shared Resource;Biological;Biomass;Biometry;Cancer Biology;Cancer Center;Cell Culture Techniques;Centers of Research Excellence;Chromatography;Classification;Collaborations;Complement;Consult;Culture Media;Data;Data Analyses;Databases;Development;Disease;Experimental Designs;Fourier Transform;Goals;Hour;Human Resources;In Situ;Informatics;Infusion procedures;Isotope Labeling;Isotopes;Kentucky;Label;Liquid Chromatography;Logistic Regressions;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Methods;Mole the mammal;Nuclear Magnetic Resonance;Pathway Analysis;Pathway interactions;Preparation;Procedures;Process;Protons;Research Personnel;Resolution;Retrieval;Sampling;Schedule;Services;Spectrum Analysis;Standardization;Statistical Data Interpretation;System;Techniques;Technology;Time;Tissue Harvesting;Tissues;Tracer;Universities;Update;analytical method;animal imaging;base;cell growth;data acquisition;data reduction;experimental study;forest;in vivo;medical specialties;metabolic abnormality assessment;metabolic profile;metabolomics;stable isotope;tumor metabolism;ultra high resolution;wiki


application_id: 9441815
project_number: 5P20GM121327-02
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7093
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
budget_end_date: 2018-12-31
project_terms:
Accountability;Address;Administrator;Advanced Malignant Neoplasm;Advisory Committees;Area;Arts;Biochemistry;Bioinformatics;Biomedical Research;Biometry;Cancer Center;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Clinical Sciences;Communication;Communication Programs;Coupled;Data Science;Development;Effectiveness;Ensure;Evaluation;Faculty;Fostering;Funding;Goals;Health;Health Sciences;Institutes;Kentucky;Knowledge;Lead;Leadership;Malignant Neoplasms;Mediator of activation protein;Medicine;Mentors;Mentorship;Metabolic;Metabolism;Molecular Medicine;Monitor;Obesity;Oncogenic;Oral;Pilot Projects;Play;Process;Productivity;Program Evaluation;Public Health;Research;Research Infrastructure;Research Personnel;Research Training;Resource Sharing;Resources;Role;Science;Scientist;Seasons;Senior Scientist;Services;System;Systemic disease;Translational Research;United States National Institutes of Health;Universities;Vision;anticancer research;base;biomedical informatics;cancer therapy;career development;college;design;flexibility;imaging capabilities;improved;meetings;metabolomics;multidisciplinary;next generation;novel;programs;skills;stable isotope;success;synergism;therapeutic target;tool;tumor metabolism


application_id: 9441813
project_number: 5P20GM121327-02
project_title: University of Kentucky Center for Cancer and Metabolism
administering_ic: NIGMS
award_notice_date: 2017-12-29
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: CALDWELL, SHEILA
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ZHOU, BINHUA P
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;Apoptosis;Area;Attention;Basic Science;Biochemistry;Bioinformatics;Biology;Biometry;Cancer Center;Cancer Death Rates;Cancer Patient;Cell Cycle;Cell Proliferation;Cell Survival;Centers of Research Excellence;Clinical;Collaborations;Core Facility;Coupled;Data;Data Science;Development;Discipline;Early Diagnosis;Environment;Event;Faculty;Fostering;Foundations;Funding;Future Generations;Goals;Grant;Growth;Image;Incidence;Interdisciplinary Study;Intervention;Investigation;Kentucky;Lead;Link;Location;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolic Diseases;Metabolism;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Pilot Projects;Proliferating;Quality of life;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Scientist;Seeds;Signal Transduction;System;Therapeutic;Training;Translations;United States National Institutes of Health;Universities;anticancer research;base;cancer cell;cancer imaging;cancer initiation;cancer therapy;career;cohesion;defined contribution;design;early detection biomarkers;imaging capabilities;improved;innovation;insight;interdisciplinary approach;metabolomics;mortality;multidisciplinary;novel;novel therapeutics;prevent;programs;recruit;skills;success;synergism;therapeutic target;therapy outcome;tool;trait;tumor metabolism;tumor microenvironment;tumor progression;tumorigenesis


application_id: 9441562
project_number: 1R15AG055906-01A1
administering_ic: NIA
award_notice_date: 2018-07-25
opportunity_number: PA-15-016
application_type: 1
activity_code: R15
ic: AG
serial_number: 055906
suffix: A1
program_official: KING, JONATHAN W
project_start_date: 2018-08-01
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1 RPHB-R (80)]
contact_pi_person_id: 8919163
contact_pi: SHAKE, MATTHEW C.
other_pis: CRANDALL, JASON
congressional_district: 02
department: PSYCHOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Bingocize: A Novel Mobile Application to Help Maintain or Improve Older Adults' Health Function and Cognition

project_abstract:
Project Summary/AbstractHealth-promoting interventions designed to improve physical and mental fitness can help reduce health carecosts and maintain or even improve quality of life for older adults. However getting older adults to adhere tohealth-promoting exercise interventions remains difficult because such programs are often perceived as beingtime-consuming painful or unenjoyable. The present proposals objective is to demonstrate the efficacy of anovel technological exercise intervention program for older adults through a clinical trial. In doing so we hopeto show the program is a health-promoting intervention that can maximize older adults independence andquality of life. Preliminary findings have established our approach is feasible; consider that most aging serviceshost bingo games which is a highly acceptable and familiar game to older adults. In our initial research bingoexercise and health education (Bingocize) were combined. In that study adherence rate over 97% andparticipants significantly improved muscular strength flexibility balance and cardiorespiratory fitness in asample of older adults (as compared to wait-listed controls). Subsequently we have developed a noveltechnological mobile app (e.g. for tablets and phones) that provides a novel opportunity for healthprofessionals to engage older adults in a fun activity that can be modified based on participants needs. One-hundred and sixty older adults will participate in a pre/post-intervention design with random assignment toeither the experimental or one of three comparison/control groups; each group will play the game in a socialsetting with other older adults. Participants in the experimental (multimodal) group will use the app to engage intwice-weekly Bingocize sessions for twelve weeks (i.e. Bingo+Exercise+Health Education); control(unimodal) groups will also use the app for twelve weeks but for either health education-only exercise-only orbingo-only. Using this design the effectiveness of the app will be tested to see whether it can lead toimprovements in functional performance knowledge of health topics and aspects of fluid cognitive abilities. Inaddition the design will allow for comparisons between multimodal and unimodal (e.g. health education-onlyor exercise-only) interventions the latter of which is much more commonly used in attempts to improve olderadult health. We hypothesize that our multimodal intervention using a mobile application will lead to positivephysical and mental benefits in historically underserved aging populations the vast majority of whom areexperiencing age-related cognitive decline and a variety of chronic physical ailments. The specific aims of thisproject are to: (1) identify the benefits of a multimodal social app-based health promotion program forcognitive function (2) identify the benefits for functional performance health knowledge and instrumentalactivities of daily living (IADLs) and (3) compare/contrast our multimodal intervention to unimodalinterventions which are more common in the literature.

project_terms:
Adherence;Adult;Aerobic Exercise;Age-associated memory impairment;Aging;Assisted Living Facilities;Attenuated;Cellular Phone;Chronic;Clinical Trials;Cognition;Cognitive;Communities;Control Groups;Custom;Dementia;Diet Habits;Effectiveness;Elderly;Engineering;Equilibrium;Exercise;Exercise intervention;Experimental Designs;Foundations;Gerontology;Goals;Grant;Health;Health Care Costs;Health Professional;Health Promotion;Health education;Impaired cognition;Independent Living;Intervention;Intervention Studies;Kentucky;Knowledge;Lead;Liquid substance;Literature;Measures;Muscle;Nature;Pain;Participant;Patients;Performance;Pharmaceutical Preparations;Physical Fitness;Play;Population;Problem Solving;Psyche structure;Quality of life;Rehabilitation therapy;Research;Resources;Retirement;Risk;Risk Reduction;Sampling;Science;Services;Social Interaction;Socialization;Tablets;Technology;Testing;Time;Use Effectiveness;Waiting Lists;Work;age group;base;cardiorespiratory fitness;cognitive ability;cognitive function;cognitive performance;community setting;comparison group;design;executive function;exercise program;experience;fall risk;fitness;flexibility;health knowledge;improved;instrumental activity of daily living;intervention program;mobile application;multi-component intervention;multimodality;novel;post intervention;programs;social;technological innovation;therapy design;tool

public_health_relevance:
Project NarrativeExercise interventions designed to improve physical and mental fitness have the potential to help reducehealth care costs and maintain or even improve quality of life for older adults. Many facilities serving olderadults are searching for creative ways to engage older adults in health enhancing and rehabilitative activities.The purpose of our proposal is to test the effectiveness of using a new mobile application (Bingocize) toimprove functional performance knowledge of health topics dietary habits and aspects of fluid cognitiveabilities.


application_id: 9441053
project_number: 5P40OD019794-04
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2018-02-08
opportunity_number: PAR-14-005
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1-BBBP-Y(45)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application seeks support to continue operations of the Ambystoma Genetic Stock Center (AGSC) at the University of Kentucky. The AGSC maintains a historically significant collection of Mexican axolotls (Ambystoma mexicanum) an endangered species that provides living materials in support of biomedical research nationally and internationally. Most notably axolotls are studied because they are unique among vertebrates in being able to regenerate numerous tissues and body parts. These include the spinal cord limbs jaw retina brain heart and tail all of which can be regenerated at any poit during embryonic larval and adult life. Also axolotls are used by researchers that work in many additional areas including neurobiology ecotoxicology development physiology cell biology genetics genomics and evolution. Over the next 5 years the AGSC will implement a new resource management plan to better ensure long-term sustainability of axolotl stocks and move each year towards greater self- sufficiency. This will be accomplished by providing high quality stocks that the community has come to depend upon increasing production and distribution of axolotls and offering new products and services. In particular the AGSC will offer a microinjection service to assist investigators in the creation of transgenic axolotls. The AGSC will continue to serve as an informatics hub where investigators obtain information about the collection technical procedures potential collaborators and research findings. Overall the project will ensure distribution and long-term sustainability of axolotl resources to NIH-funded investigators.

project_terms:
Adolescent;Adult;Advisory Committees;Ambystoma;Ambystoma mexicanum;Applied Research;Area;Behavior;Biological;Biomedical Research;Body part;Brain;Breeding;Cells;Cellular biology;Collection;Communities;Community Services;Computers;Custom;Data;Development;Embryo;Embryonic Development;Ensure;Equipment;Evolution;Funding;Genes;Genetic;Genome;Genomics;Health;Heart;Hour;Human;IACUC;Informatics;Injections;Institution;International;Jaw;Kentucky;Knock-in;Life;Limb structure;Methods;Microinjections;Mission;Modeling;Monitor;Natural regeneration;Neurobiology;Organ Model;Organism;Physiology;Population;Preparation;Procedures;Production;Protocols documentation;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Retina;Services;Site;Site-Directed Mutagenesis;Speed;Spinal Cord;System;Tail;Time;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Visit;Work;animal resource;base;experience;gene function;innovation;knowledge base;learning strategy;meetings;operation;organ regeneration;public health relevance;tissue repair;transcription activator-like effector nucleases;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Living stock resources are needed for the Mexican axolotl so that biomedical investigators can translate biological information to humans. The Mexican axolotl is a primary vertebrate model for organ regeneration tissue repair and post--- embryonic development.


application_id: 9440979
project_number: 5R44AI112048-03
administering_ic: NIAID
award_notice_date: 2018-02-07
opportunity_number: PA-15-269
application_type: 5
activity_code: R44
ic: AI
serial_number: 112048
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2014-12-15
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1-IDM-X(10)B]
contact_pi_person_id: 11545088
contact_pi: MAINS, JAMES WILLIAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
project_title:
Phase II: Feasibility assessment of a novel tool for mosquito vector control: Auto-Dissemination Augmented by Males (ADAM)

project_abstract:
Project summary/abstract Mosquito control remains the primary tool for combating many mosquito-vectored diseases such asDengue Chikungunya Zika and West Nile because no approved vaccine therapeutant or prophylaxis iscurrently available for use. Key deficiencies of existing vector control methods include resistance to existinginsecticides and the inability to find and treat cryptic breeding sites which provide refuge to immaturemosquitoes and allow for the rapid recovery of mosquito populations following conventional control efforts. Theself-delivering method known as `auto-dissemination' addresses this deficiency by using mosquitoes as thevehicle to deliver a potent mosquito growth regulator to cryptic breeding sites. The Phase 1 results haveincluded pilot laboratory and field work as a proof-of-principle against both Aedes aegypti and Aedesalbopictus. The epidemiology of Zika has led to an urgent need for preemptive vector control approaches.Specifically a majority of Zika virus infections in humans are not detected quickly. Delayed detection canundermine a public health protection plan that is based on reactive approaches i.e. a strategy of initiatingintensive vector control only after the detection of an epidemic because by the time of detection a largeproportion of the human population can be infected already. The approach being developed in the proposedwork is ideal as a preemptive approach because (1) it requires small amounts of chemical i.e. lessenvironmental impact and (2) the artificially-reared mosquito carriers can be delivered at any time e.g. beforean indigenous vector population reaches dangerous levels. The Auto-Dissemination Augmented by Males (ADAM) is based on mass-producing male mosquitoeswhich do not bite or transmit pathogens. The ADAM method can utilize wild type mosquitoes Wolbachia-infected mosquitoes or Genetically Modified mosquitoes. Integration with existing mosquito mass rearingprograms can speed the uptake of the ADAM technology. Adult ADAM males are treated with an Insect GrowthRegulator (IGR) and then released to deliver lethal doses of the IGR to oviposition sites. Phase I workincluded: 1) laboratory development 2) regulatory work e.g. approval of a Research Authorization from theCalifornia Department of Pesticide Regulation 3) field trials in KY against Ae. albopictus and 4) field trials incollaboration with the Consolidated Mosquito Abatement District (CMAD) to test the ADAM approach againstAe. aegypti. The laboratory results show that Ae. albopictus Ae. aegypti and Culex pipiens males can: 1)tolerate the IGR with negligible cost to the male carriers 2) directly deliver larvicide to breeding sites and 3)cross-contaminate females with IGR doses that are subsequently lethal to larvae. Field trials with both Ae.aegypti and Ae. albopictus show the ADAM method to cause significant larval mortality and significantreductions in the adult population when compared to the non-treated sites. Phase 1 work also included animprovement of methods for the mass manufacturing of adult male mosquitoes. In the proposed Phase II work we will conduct work to replicate and expand field trials against Ae.aegypti and Ae. albopictus from proof-of-principle trials to a scale that is adequate for operational use bymosquito abatement districts. By performing field trials with multiple abatement districts from different statesour proposed Phase II work will satisfy an EPA requirement for commercial registration i.e. that efficacy andsafety be demonstrated in multiple ecological contexts. In addition to the EPA the data will be submitted to theWorld Health Organization (WHO) Vector Control Advisory Group (VCAG) which serves as an advisory bodyon new forms of vector control. WHO approval is anticipated to increase international uptake of the ADAMtechnology. Additional Phase II work will extend Phase I work with Cx. pipiens an important vector of WestNile Virus. Specifically one or more field trials will provide efficacy data for use against this additionalimportant mosquito species which is another focus of abatement districts' vector control efforts.

project_terms:
Abate;Address;Adult;Aedes;Affect;Animals;Attention;Authorization documentation;Behavior;Blood;Breeding;California;Chemicals;Chikungunya virus;Collaborations;Culex (Genus);Culex pipiens;Culicidae;Dangerousness;Data;Dengue;Dengue Virus;Detection;Disease;Disease Vectors;Dose;Environmental Impact;Epidemic;Epidemiology;Face;Female;Florida;Flowers;Goals;Growth;Health protection;Human;Indigenous;Insecticide Resistance;Insecticides;International;Juvenile Hormones;Laboratories;Larva;Lead;Measurement;Measures;Methods;Minor;Monitor;Mosquito Control;Mosquito-borne infectious disease;Native-Born;Outcome;Oviposition;Partner in relationship;Pesticides;Phase;Plant Leaves;Population;Practice Management;Production;Prophylactic treatment;Public Health;Recommendation;Recovery;Regulation;Research;Resistance;Risk;Safety;Site;Speed;Techniques;Technology;Testing;Time;Trees;Vaccines;Visit;Water;West Nile virus;Wolbachia;Work;World Health Organization;ZIKV infection;Zika Virus;base;chikungunya;combat;commercialization;cost;drinking water;experimental study;feeding;laboratory development;male;meetings;milliliter;mortality;novel;pathogen;programs;sterile insect technique;success;tool;uptake;vector;vector control;vector mosquito;wasting

public_health_relevance:
NarrativeVector control remains the only means to combat many mosquito borne diseases including those caused byZika West Nile Dengue Chikungunya viruses and other pathogens. There is a need to develop additionaltools that target immature mosquito populations that remain hidden or protected within cryptic breeding sitesand that are inaccessible to conventional control techniques. The proposed work will further develop a novel`self delivering' approach that is based on the release of adult male mosquitoes as vehicles to deliver apowerful and safe Insect Growth Regulator.


application_id: 9439649
project_number: 5F32DE026939-02
project_title: Phosphotyrosine Signaling of Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2018-01-26
opportunity_number: PA-16-307
application_type: 5
activity_code: F32
ic: DE
serial_number: 026939
program_official: FRIEDEN, LESLIE A
project_start_date: 2017-03-01
project_end_date: 2018-09-14
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11206459
contact_pi: MILLER, DANIEL PATRICK
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPolymicrobial communities that exhibit synergistic pathogenicity cause periodontal disease one of the mostcommon infections of humans. As a model system for the study of polymicrobial synergy we are investigatingthe interactions of Porphyromonas gingivalis and Streptococcus gordonii. Heterotypic communities develop asphysiologically compatible organisms modulate their own and their partner's physiology resulting in enhancedfitness and virulence. S. gordonii is an early colonizer of the dental plaque biofilm and provides attachment andsupport for the more pathogenic keystone pathogen P. gingivalis. Contact-dependent and soluble metabolitesignaling regulates development of the dual species community. Initial development and ultimately constraintof community development depends upon a tyrosine phosphorylation-signaling cascade. The activities of thekinase and phosphatase Ptk1 and Ltp1 respectively signal upstream of the transcriptional regulator CdhR tocontrol gene expression of community effectors such as Mfa1 and LuxS. The objectives of this study are to: i)characterize the structure and function of the Ptk1 kinase activation domain that regulates kinase activity; ii)assess the complex balance of (de)phosphorylation by Ptk1 and Ltp1 that both regulates activity of eachprotein while controlling activity of downstream phosphorylation-dependent mediators; and iii) determine thesignaling network between tyrosine phosphorylation and CdhR that results in regulation of gene expression.The completion of this study will not only elucidate the mechanism of activation of Ptk1 but also provide criticalnew insights into the functional activation of BY-kinases. Additionally we will provide novel information aboutthe dynamic regulation of tyrosine phosphorylation between a BY-kinase and its cognate phosphatase. Finallywe will develop a detailed understanding of the tyrosine phosphorylation cascade that regulates communityformation and synergistic pathogenicity between P. gingivalis and S. gordonii. Our overall long-term goal is totranslate these novel molecular mechanisms into the development of future therapeutic approaches targetingpolymicrobial pathogenic communities. Additionally as BY-kinases are structurally distinct from eukaryoticprotein tyrosine kinases detailed molecular analysis of BY-kinase activation and regulation may provide criticalinsights for the identification of novel approaches targeting key bacterial signal transduction systems.

project_terms:
Affect;Antibiotic Resistance;Bacteria;Bacterial Infections;Binding;Biochemical;Biological Models;C-terminal;Cell physiology;Chronic;Communication;Communities;Community Developments;Complex;DNA Binding;Dental Plaque;Development;Disease;Disease model;Equilibrium;Eukaryota;Exhibits;Future;Gene Expression;Gene Expression Regulation;Genetic Transcription;Goals;Human;In Vitro;Infection;Inflammatory Response;Measurement;Measures;Mediator of activation protein;Microbial Biofilms;Molecular;Molecular Analysis;Mutate;Organism;Outcome;Pathogenicity;Pathway interactions;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Phosphotyrosine;Physiological;Physiology;Play;Population;Porphyromonas gingivalis;Production;Protein Dephosphorylation;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;Recombinants;Regulation;Role;Series;Signal Transduction;Streptococcus gordonii;Structure;Therapeutic;Tissues;Tooth structure;Translating;Tyrosine;Tyrosine Phosphorylation;Virulence;bone;dysbiosis;fitness;genetic regulatory protein;in vivo;insight;mouse model;mutant;novel;novel strategies;pathogen;phosphoproteomics;polymicrobial disease;prevent;protein function;response;stoichiometry;synergism

public_health_relevance:
Project NarrativePeriodontal diseases are one of the most common infections of humans and are caused by multiple bacterialspecies working synergistically to enhance pathogenicity. This study aims to understand the Porphyromonasgingivalis-signaling network that senses responds to and ultimately enhances virulence in response toStreptococcus gordonii. Understanding inter-bacterial communication and signaling is critical to development ofpotential therapeutics or approaches to prevent polymicrobial diseases.


application_id: 9438565
project_number: 5R01HL131925-03
project_title: Role of IKK in obesity and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2018-02-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131925
program_official: KIRBY, RUTH
project_start_date: 2016-04-01
project_end_date: 2020-02-29
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
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):  Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKK/NF-B signaling. However the role of IKK in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKK deficiency (driven by a SM22Cre-IKK- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity metabolic disorders and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKK positively regulates adipogenesis indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKK is essential for adipogenesis and atherogenesis and that high-fat diet-induced IKK activation promotes adipocyte differentiation and adipose inflammation leading to increased obesity insulin resistance and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKK in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKK to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKK by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKK in adipogenesis and atherogenesis and will reveal a critical link between overnutrition inflammation and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKK inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.

project_terms:
Ablation;Adipocytes;Adipose tissue;Antisense Oligonucleotides;Atherosclerosis;Blood Vessels;Cells;Chronic;Consumption;Country;Development;Diabetes Mellitus;Diet;Disease;Epidemic;Goals;High Fat Diet;Human;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Insulin Resistance;Link;Metabolic Diseases;Molecular;Mus;Myelogenous;Natural Immunity;Obesity;Overnutrition;Pathway interactions;Pharmacology;Phosphotransferases;Regulation;Reporting;Resistance;Role;Signal Transduction;Smooth Muscle Myocytes;System;Testing;Therapeutic;adipocyte differentiation;atherogenesis;cardiometabolism;gain of function;in vivo;inhibitor/antagonist;innovation;interest;lipid biosynthesis;loss of function;macrophage;mouse model;novel;novel strategies;obesity development;population health;precursor cell;progenitor;public health relevance;response;therapeutic target;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Obesity is a rapidly growing epidemic representing a serious threat to the health of the population in almost every country around the world. There is an urgent need to understand the mechanisms underlying the diet- induced obesity and associated cardiometabolic disease. The proposed study will investigate a novel mechanism that links overnutrition to obesity and metabolic disorders.


application_id: 9438446
project_number: 5R01HL091357-08
project_title: Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat
administering_ic: NHLBI
award_notice_date: 2018-02-16
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 091357
program_official: JAQUISH, CASHELL E
project_start_date: 2008-09-05
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-PSE-Q(90)S]
contact_pi_person_id: 1876483
contact_pi: ARNETT, DONNA K
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dyslipidemias remain a critical determinant of cardiovascular disease risk. Effective dietary and therapeutic interventions to reduce dyslipidemia including elevated triglycerides (TGs) and high non-HDL-cholesterol exist yet there is much variation in lipid and lipoprotein level's response to these interventions. Genetics partially explain this variation. We hypothesize that by using improved lipid phenotyping techniques we will be able further characterize this interindividual variation of lipids in respone to diet and drug. Recent advances in mass spectrometry-based techniques allow metabolomic characterization in large populations. Detailed and precise measurement of lipid molecular species a field known as "lipidomics" now offers an unprecedented picture of lipid metabolism. The Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study provides an ideal context in which to pursue this work. GOLDN is the largest family study conducted to date that has sought to identify genetic factors that explain response to two short-term interventions one to raise lipids (i.e. ingestion of a high-fat meal the "post-prandial lipemia" (PPL) intervention and one to lower lipids (i.e. treatment with fenofibrate (FFB)). The goal of the "Genomewide Association Study (GWAS) of Lipid Response to Fenofibrate and Dietary Fat" (Arnett PI R01-HL091357) was to identify the common genetic variants that explain response to the interventions. In addition to this GOLDN is also conducting a genome- wide epigenomics study and exome sequencing through the NIH Pharmacogenomics Research Network (PGRN). The proposed work will leverage this wealth of genomic data in the context of state-of-the-art lipidomic phenotypes specifically phospholipids neutral lipids and sterols to identify rare andcommon variants and epigenetic marks that determine response to GOLDN's diet and drug interventions. Specifically we aim to: (1) Quantify pre- and post-FFB treatment/PPL response of 350 metabolites. GOLDN recruited and examined 1048 Caucasians from 186 families. Participants were given an 83% fat meal and three weeks of FFB treatment 250 mg/d. Blood was drawn at fasting and 6-hr post ingestion and again after 3 wk of FFB treatment. Plasma from each of these time points will be analyzed with for 350 lipidomic species. PPL response (estimated as the 6-hr TG response adjusted for baseline) and fenofibrate response (estimated by the ratio of post/pre TG values) of the new lipidomic phenotypes will be calculated. Responsive and heritable metabolites will be moved forward to Aim 2. (2) Test the association of these small molecules with (a) common (GWAS) and rare (WES) variants (b) methylation at CpG sites (EWAS). (3) Replicate PPL findings in 500 subjects selected from extremes of the PPL response in the HAPI Heart Study. (4) Use induced pluripotent stem cell- derived hepatocytes to functionally validate fenofibrate response variants identified in Aim 2. If successful GOLDN will identify novel lipidomic biomarkers to predict efficacy and adverse responses to a high-fat meal and fenofibrate treatment leading to more personalized approaches to diet and pharmacologic treatment.

project_terms:
Age;Biological Assay;Biological Markers;Biological Models;Blood;Body Surface Area;Calcium-Activated Potassium Channel;Calories;Caucasians;Chemicals;Cholesterol;Data;Diet;Dietary Fats;Dietary Intervention;Disease;Drug Prescriptions;Drug Targeting;Dyslipidemias;Eating;Epigenetic Process;Family;Family Study;Fasting;Fatty Acids;Fatty acid glycerol esters;Fenofibrate;Fibrates;Funding;Genes;Genetic;Genome;Genomics;Goals;Heart;Hepatic;Hepatocyte;Heritability;Human;Hypertension;Hypertriglyceridemia;Ingestion;Institutes;Intervention;Link;Lipids;Lipoproteins;Mass Spectrum Analysis;Measurement;Measures;Metabolism;Methodology;Methylation;Modeling;Molecular;Myocardial Infarction;Nuclear;PPAR alpha;Participant;Pharmaceutical Preparations;Pharmacogenomics;Pharmacological Treatment;Phase;Phenotype;Phospholipids;Plasma;Population;Process;Protocols documentation;Reporting;Research;Sample Size;Sampling;Signal Transduction;Sister;Site;Standardization;Steroids;Sterols;Stroke;Techniques;Testing;Therapeutic Intervention;Time;Triglycerides;United States National Institutes of Health;Universities;Validation;Variant;Washington;Work;base;blood lipid;cardiovascular disorder risk;density;epigenome-wide association studies;epigenomics;exome sequencing;gene environment interaction;genetic pedigree;genetic variant;genome wide association study;genome-wide;genomic data;improved;induced pluripotent stem cell;inter-individual variation;lipid I;lipid metabolism;member;metabolic profile;metabolomics;novel;personalized approach;prevent;programs;public health relevance;rare variant;recruit;response;sex;small molecule;tandem mass spectrometry;trait

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People differ in the ways their bodies process dietary fats and in the ways they respond to drugs meant to lower elevated blood lipids (such as cholesterol and triglycerides factors that can increase the risk of cardiovascular disease). By studying the building blocks of lipids and the chemicals that lipids are broken down into this project seeks todetermine which genetic factors influence people's blood lipid concentrations after eating a high-fat meal or after taking a lipid- lowering drug. Ultimately this research may help doctors more accurately assess people's risk of cardiovascular disease and more effectively prescribe drugs to prevent disease.


application_id: 9437819
project_number: 5UM1HL113530-07
project_title: University of Louisville Regional Clinical Center for the CCTRN
administering_ic: NHLBI
award_notice_date: 2018-03-01
opportunity_number: RFA-HL-12-026
application_type: 5
activity_code: UM1
ic: HL
serial_number: 113530
program_official: EBERT, RAY F
project_start_date: 2012-03-22
project_end_date: 2021-02-28
study_section: ZHL1-CSR-O(F2)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The University of Louisville/Jewish Hospital has a remarkably vibrant basic and clinical research program in cardiovascular medicine particularly in the area of stem cells and patients with heart failure (HF) left ventricular assist devices (LVADs) and ischemic cardiomyopathy. A highly cohesive and collegial team of investigators from the Divisions of Cardiovascular Medicine and Thoracic and Cardiovascular Surgery has worked productively for many years in several multicenter trials with outstanding performance. This existing clinical infrastructure coupled with the strong preclinical research work conducted on cell-based therapies for several years provides a superb platform for participation in the CCTRN as a Regional Clinical Center. The ability of our Center to carry out Phase l/ll studies of stem cells is exemplified by our success i performing the first in-human study of c-kit+ cardiac stem cells in patients with HF (SCIPIO). The same investigators and the infrastructure that made SCIPIO possible will be leveraged for the CCTRN studies. Here we propose SENECA (StEm cell treatmeNt for End stage CArdiac failure) in which we will test the feasibility and safety (Aim 1) and efficacy (Aim 2) of intracoronary delivery of CD34+ cells or very small embryonic-like cells (VSELs) to patients with end-stage ischemic cardiomyopathy (ICM) following implantation of an LVAD. Our hypothesis is that cell therapy will promote repair and regeneration of the injured myocardium resulting in improved cardiac function functional capacity and overall quality of life and recovery of myocardial function to a degree that permits consideration of LVAD explantation. In Aim 3 we will identify patient characteristics and in vitro parameters of stem cell function that are associated with effectiveness (or lack thereof) of CD34+ cells and VSELs in improving LV function in vivo. SENECA will be the first study of VSELs in humans and the first controlled trial to test the effects of CD34+ cells in end-stage ischemic HF. Therefore the results will be entirely novel and may provide a new option for patients who currently have a dismal prognosis. Thus the potential impact of SENECA is considerable. No cell therapy study has ever been reported before in patients with LVADs and ICM although these are the very patients who need it the most. Therefore SENECA will address a major therapeutic gap in the management of cardiac patients. This trial has the potential to provide a novel clinical breakthrough in the treatment of end-stage ischemic heart disease.

project_terms:
Activities of Daily Living;Address;Affect;Area;Basic Science;CD34 gene;Cardiac;Cardiac Surgery procedures;Cardiovascular Surgical Procedures;Cardiovascular system;Cell Therapy;Cell physiology;Cells;Cellular biology;Characteristics;Clinical;Clinical Research;Collaborations;Coupled;Effectiveness;Embryo;Enrollment;Environment;Event;Faculty;Goals;Heart failure;Hospitals;Human;Human Resources;Implant;In Vitro;Institution;Letters;Life;Medicine;Motivation;Multicenter Trials;Myocardial;Myocardial Ischemia;Myocardium;Names;Natural regeneration;Patients;Performance;Personnel Staffing;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Proto-Oncogene Protein c-kit;Quality of life;Recovery;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Stem cells;Testing;Therapeutic;Thoracic Surgical Procedures;Time;Universities;Work;base;clinical infrastructure;cohesion;first-in-human;follower of religion Jewish;heart function;human study;implantable device;implantation;improved;in vivo;injured;insight;ischemic cardiomyopathy;left ventricular assist device;member;novel;outcome forecast;phase 1 study;phase 2 study;phase 3 study;pre-clinical research;preclinical study;programs;repaired;safety and feasibility;stem cell population;stem cell therapy;success

public_health_relevance:
We have conducted preclinical studies of stem cells for several years. In 2009 we started SCIPIO the first in-human study of c-kit+ cardiac stem cells and one that demonstrates the ability of our Center to carry out Phase l/ll studies of cell therapy in humans effectively and successfully. This application builds on SCIPIO and on the superb program in advanced heart failure at Jewish Hospital. The results may pave the way for the use of novel cell-based therapies (CD34+cells and/or VSELs) in patients with ischemic cardiomyopathy.


application_id: 9434350
project_number: 1R21AG058006-01
project_title: Dystrophic functions of aged astrocytes following traumatic brain injury
administering_ic: NIA
award_notice_date: 2018-09-21
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AG
serial_number: 058006
program_official: WISE, BRADLEY C
project_start_date: 2018-09-30
project_end_date: 2020-05-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The broad and long-term goals of this proposal are to form a significant knowledge-basesurrounding the role aged astrocytes in the propogation of neurodegenerative sequelae after TBI.TBI in the aged population represents a significant unmet healthcare challenge as advancedaging is the greatest risk factor for acquiring a TBI and subsequently developingneurodegenerative disease such as dementia Alzheimers- and Parkinsons disease.Cumulatively the research design takes advantage of specific inflammatory hallmarks andfunctional modulators associated with dystrophic astrocytes in an attempt to delineate theirrespective contributions to neuronal pathology and cognitive dysfunction. Ultimately we willdetermine if harnessing astrocytes via novel AAV constructs in aged TBI models is associatedwith improving neuronal and cognitive outcome measures.

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

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


application_id: 9433964
project_number: 1R21ES028911-01
project_title: Mechanisms of carcinogenic effects of nickel nanoparticles
administering_ic: NIEHS
award_notice_date: 2017-12-06
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: ES
serial_number: 028911
program_official: RAVICHANDRAN, LINGAMANAIDU V
project_start_date: 2017-12-15
project_end_date: 2019-11-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8567542
contact_pi: ZHANG, QUNWEI
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The development of nanotechnology has allowed the identification of unique properties in nanomaterials thathave in turn led to the development of commercial applications in many fields such as chemical catalysissemiconductors water purification cosmetics microelectrodes biosensors the food industry biomedicineetc. In 2009 developers generated more than $1 billion from the sale of nanomaterials and the market fornanotechnology is expected to grow to 75.8 billion by 2020 with several hundreds of thousands of jobs. Thusthe levels of human exposure to anthropogenic nanoparticles will substantially increase. As an importanttransition metal nickel nanoparticles (Nano-Ni) have wide ranging applications in the fields of batterieselectrical conductors permanent magnets magnetic fluids magnetic recording media solar energyabsorption fuel cell electrodes and catalysts. In addition due to structural and inherent chemical and physicalproperties nickel alloy nanomaterials have received special interest in biomedical applications. In thisproposal we selected Nano-Ni as a model metal nanoparticle because of its wide industrial interest andbiological and medical applications. Based on our preliminary data our working hypothesis is that Nano-Nican cause oxidative stress and DNA damage in lung epithelial cells and long-term exposure to Nano-Ni results in DNA repair deficiency by down-regulating Rad52 increased genomic instability and celltransformation through up-regulation of miR-210 and nuclear accumulation of the hypoxia induciblefactor 1 (HIF-1). The following two Specific Aims will be pursued. Specific Aim 1. Examine the role ofHIF-1 pathway in Nano-Ni-induced genotoxic effects in vitro and in vivo. We will first examine whetherexposure to Nano-Ni will induce DNA damage in normal human lung epithelial cells BEAS-2B and in mice bymeasuring the phosphorylation level of ataxia telangiectasia mutated (ATM) at Ser1981 and p53 at Ser15 andexpression level of Rad52 and phosphorylated histone H2AX (-H2AX). We will then investigate the role ofHIF-1 in Nano-Ni-induced DNA damage by using: (1) HIF-1 - specific siRNA; and (2) HIF-1 knock-outcells. Specific Aim 2. Examine whether exposure to Nano-Ni causes down-regulation of Rad52 throughup-regulation of miR-210 induced by HIF-1 activation during Nano-Ni-induced cell transformation. Wewill first determine whether long-term exposure to low doses of Nano-Ni will induce normal BEAS-2B cells totransform. We will then measure the levels of Rad52 miR-210 and HIF-1 in cells with long-term exposure toNano-Ni and in Nano-Ni-transformed cells. Finally we will explore the role of Rad52 in Nano-Ni-induced celltransformation through overexpression or knockout of Rad52.

project_terms:
8-hydroxy-2'-deoxyguanosine;Address;Alloys;Area;Biological;Biosensor;Caliber;Catalysis;Cell Proliferation;Cells;Characteristics;Chemicals;Cosmetics;DNA Damage;DNA Repair Disorder;Data;Deposition;Development;Dimensions;Dose;Down-Regulation;Electrodes;Epigenetic Process;Epithelial;Epithelial Cells;Equipment;Exposure to;Food Industry;Formulation;Free Radicals;Gases;Gelatinase A;Gelatinase B;Genetic;Genomic Instability;H2AFX gene;Hazard Identification;Human;Hypoxia Inducible Factor;In Vitro;Industrialization;Inflammatory Response;Knock-out;Knowledge;Length;Leukocytes;Light;Liquid substance;Lung;Magnetism;Measures;Medical;Metals;Microelectrodes;Modeling;Mus;Nanotechnology;Nickel;Nuclear;Occupations;Oxidative Stress;Oxygen;Particulate;Paste substance;Pathway interactions;Phosphorylation;Procedures;Process;Property;RAD52 gene;Rattus;Risk Assessment;Role;Sales;Semiconductors;Small Interfering RNA;Solar Energy;Surface;Surface Properties;TNF gene;TP53 gene;Testing;Toxic effect;Toxicology;Transition Elements;Up-Regulation;Vacuum;Water Purification;Work;absorption;anthropogenesis;ataxia telangiectasia mutated protein;base;carcinogenesis;carcinogenicity;catalyst;cell transformation;chemical property;cold temperature;commercial application;cytokine;exposed human population;genotoxicity;in vivo;interest;melting;nano;nanomaterials;nanometer;nanoparticle;nanosized;novel;overexpression;particle;peripheral blood;physical property;titanium dioxide;tool;vapor

public_health_relevance:
This project aims to clarify whether and how exposure to nickel nanoparticles causes genotoxic andcarcinogenic effects. We expect that our results will provide scientific knowledge and tools for evaluating othernanomaterials. Successful completion of this project will lead to a better understanding of the mechanisms bywhich metal nanoparticles induce genotoxic and carcinogenic effects.


application_id: 9433351
project_number: 1R03CA222449-01
project_title: Algorithms for Accurate and Scalable Identification of Isotopologues from Mass Spectrometry Data
administering_ic: NCI
award_notice_date: 2017-09-15
opportunity_number: RFA-RM-17-001
application_type: 1
activity_code: R03
ic: CA
serial_number: 222449
program_official: WITKIN, KEREN L
project_start_date: 2017-09-15
project_end_date: 2019-12-31
study_section: Special Emphasis Panel[ZRG1 BST-H (50)]
contact_pi_person_id: 9275058
contact_pi: LIU, JINZE
other_pis: HIGASHI, RICHARD M
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Clinical metabolomics using stable isotope resolved metabolomics (SIRM) for pathway tracingrepresents an important new approach to obtaining metabolic parameters in human cancersubjects in situ. Metabolic data generated by SIRM study are often enriched with isotopolgues.Identification of isotopologues is the key to interpret the metabolic pathways involved in aSIRM study but remains to be the major bottleneck in its data processing pipeline. The highvolume of data produced by mass spec instruments requires computational approaches forautomated assignment of the spectra and to analyze the data in an accurate meaningful andtimely fashion. The application tackles this challenges by proposing new algorithms to supportaccurate and scalable identification of isotopolgues from mass-spectrum data. Three aims of theproposal are : (1) A new algorithm for accurate and scalable identification of isotopologues froma single mass-spec dataset; (2) a robust alignment algorithm that leverages the recurringisotopologue relationships to in multiple replicates to align them; (3) a rigorous validationapproach to test and evaluate the proposed algorithms in both its sensitivity and scalability.

project_terms:
Algorithms;Biochemical Pathway;Bioinformatics;Biological;Biological Markers;Clinical;Computer software;Data;Data Analyses;Data Repository and Coordinating Center;Data Set;Databases;Deposition;Disease;Funding;Goals;Human;In Situ;Ions;Isotopes;Life;Literature;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metadata;Molecular;Pathway interactions;Periodicity;Testing;Time;United States National Institutes of Health;Validation;computerized data processing;experimental study;improved;instrument;mass spectrometer;metabolomics;novel;novel strategies;stable isotope;success;tool;ultra high resolution

public_health_relevance:
PROJECT NARRATIVEThis application proposes to develop a novel set of algorithms to improve the analysis ofdata generated by ultra-high resolution mass spectra data generated by SIRM studies.The success of this project will bridge the gap in bioinformatics tools to support theelucidation of the molecular pathways or biomarkers.


application_id: 9432924
project_number: 1R21AI135225-01
project_title: Zinc acquistion in Yersinia pestis
administering_ic: NIAID
award_notice_date: 2017-11-24
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 135225
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2017-11-24
project_end_date: 2019-10-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (81)]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Yersinia pestis is the causative agent of plague and has caused widespread loss of human life during threepandemics. Y. pestis is also firmly established in animal reservoirs on nearly every inhabited continent with thelargest reservoir in the southwestern United States. Each year multiple outbreaks occur resulting in 1000-5000 human cases reported worldwide (likely an underestimate). Currently there is not a FDA approvedvaccine for plague and the bacterium has a high potential for bioterrorism misuse. Consequently Y. pestis isconsidered a Tier 1 Select Agent. In order to grow Y. pestis must acquire essential biometals such as Fe Mnand Zn. However the host restricts access to these metals through nutritional immunity. Therefore Y. pestislike other pathogens has evolved high affinity metal acquisition systems that are essential for virulence. Werecently discovered that the yersiniabactin (Ybt) synthetase system not only contributes to Fe acquisition butalso to Zn acquisition in Y. pestis. Furthermore we have shown that the inner membrane permease YbtX(which is not required for Fe-Ybt acquisition) is required for Ybt synthetase-dependent Zn acquisition. Thesediscoveries have opened a new area in Ybt and Zn acquisition research. Specifically we hypothesize that Y.pestis produces a Ybt synthetase-dependent zincophore that is distinct from the Ybt siderophore. FurthermoreY. pestis uses a dedicated uptake system to reacquire this zincophore once bound to Zn. Along with ZnuABCthis new system is essential for Zn acquisition during infection. In Specific Aim 1 we will use a biochemicalapproach to purify and define the chemical structure and Zn affinity of the secreted Ybt synthetase-dependentzincophore. In Specific Aim 2 we will determine the contribution of the Ybt synthetase-dependent zincophoreto virulence using a hemochromatosis mouse model. Importantly the hemochromatosis mouse is defective inFe nutritional immunity. Thus this model will allow us to separate contributions of Ybt synthetase-dependentFe acquisition from Ybt synthetase-dependent Zn acquisition to Y. pestis virulence. Finally as Y. pestis alsoinfects fleas for transmission we will determine the contribution of Zn acquisition to colonization and survival inthe flea vector. Completion of these aims will provide a comprehensive understanding of the role of Znacquisition in Y. pestis virulence. Furthermore as Ybt is a conserved virulence factor this work will also berelevant to other bacterial pathogens that use the Ybt system.

project_terms:
Affinity;Animals;Area;Asians;Attenuated;Bacteria;Binding;Biochemical;Biology;Bioterrorism;Bubonic Plague;Case Study;Chemical Structure;Data;Disease Outbreaks;Enzymes;FDA approved;Fleas;Future;Gene Silencing;Goals;Growth;Hemochromatosis;Human;Infection;Insecta;Invaded;Iron;Life;Ligase;Manganese;Membrane;Membrane Transport Proteins;Metals;Modeling;Modification;Molecular;Mus;Nutritional Immunity;Organism;Pathogenesis;Plague;Plague Vaccine;Pneumonic Plague;Predisposition;Rattus;Research;Role;Septicemic plague;Siderophores;Southwestern United States;Structure;System;Testing;Trace Elements;Transition Elements;Up-Regulation;Virulence;Virulence Factors;Work;Yersinia pestis;Zinc;antimicrobial;defined contribution;mouse model;mutant;new therapeutic target;novel;pandemic disease;pathogen;permease;small molecule;transmission process;uptake;vector;yersiniabactin

public_health_relevance:
PROJECT NARRATIVEBacterial pathogens need to obtain essential biometals such as iron and zinc during infection and recently wehave identified a novel zinc acquisition system in Yersinia pestis the causative agent of human plague. Thisproject will characterize this system and define its role during mammalian and insect infection. As metalacquisition systems are essential for virulence they are viable targets for new therapeutics.


application_id: 9432480
project_number: 5R21AI131427-02
project_title: RNAi methods for Zika virus vector control
administering_ic: NIAID
award_notice_date: 2018-01-15
opportunity_number: PAR-16-106
application_type: 5
activity_code: R21
ic: AI
serial_number: 131427
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2017-02-14
project_end_date: 2020-01-31
study_section: ZAI1-RRS-M(J5)
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Mosquitoes transmit zika virus as well as other pathogens that cause many deadly diseases. These vectors causemore human suffering than any other group of animals and are responsible for millions of deaths worldwide. Insecticidesprays use of repellents and insecticide-treated bed nets for adult control and use of larvicides are the most common methodsused to control disease vectors. However widespread resistance development to insecticides in mosquitoes human healthand environmental concern from the residual toxicity of these chemicals are limiting the use of these strategies. Thereforethere is an urgent need to develop novel strategies to control disease vectors. Many applications of RNA interference (RNAi)are being developed for use in human health. RNAi could also help with studies in vector biology as well as in developingadvanced vector control methods. RNAi efficiency is variable among insects; works very well in coleopteran insects butnot in insects belonging to order Diptera that includes mosquitoes. One of the main challenges in the widespread use ofRNAi technology in disease vectors is the lack of efficient and reliable dsRNA delivery method. We propose to developnovel formulations of double-stranded RNA (dsRNA) composited with polymers and/or particulate cores resulting innanostructured delivery vehicles or dsRNA nanocomposites (dsRNA-NCs). The major goal of these studies is to improveRNAi efficiency in mosquitoes that transmit Zika virus for applications in basic research as well as in the development ofvector control methods. In specific Aim 1 we will prepare dsRNA-NCs and determine their properties. We hypothesize thatbiodegradable and environmentally friendly biomaterials could be used to develop prototype dsRNA-NCs that could aid inenhancing RNAi efficiency in mosquitoes. We will prepare cores of Ca3(PO4)2 coated with chitosan Poly-L-Lysine or Poly-L-histidine. Additionally Au cores will be used as an insoluble probe. A number of analytical methods will be used todetermine the properties of synthesized dsRNA-NCs. We will also perform a comparative analysis of synthesized dsRNA-NCs by studying protection of dsRNA from dsRNases its uptake tissue distribution intracellular transport includingendosomal escape and dsRNA processing in Aeg-2 cells (a cell line developed from Aedes aegypti) Ae. aegypti larvae andadults as a model vector species. In Specific Aim 2 we will determine the efficacy and non-target effects of synthesizeddsRNA-NCs in Ae. aegypti larvae and adults. We will expose Aeg-2 cells or feed Ae. aegypti larvae and adults with dsRNA-NCs and determine their efficiency in knocking down target genes and causing mortality as well as their effect on theexpression of non-target genes. This application proposes to employ novel approaches including nanotechnology to improveRNAi for use in disease vectors. The proposal uses interdisciplinary approaches to exploit modern technology forimprovement in the health of citizens. Successful completion of proposed research will provide novel tools to study thebiology of vectors of Zika and other pathogens and develop modern vector control methods.

project_terms:
Adult;Aedes;Animals;Applied Research;Attenuated;Bacterial Toxins;Basic Science;Beds;Biochemistry;Biocompatible Materials;Biological Assay;Biology;Caenorhabditis elegans;Cell Line;Cells;Cellular biology;Cessation of life;Chemicals;Chemistry;Chitosan;Colorado;Confocal Microscopy;Culicidae;Dengue;Development;Diptera;Disease;Disease Vectors;Double-Stranded RNA;Drug or chemical Tissue Distribution;Effectiveness;Encephalitis;Filarial Elephantiases;Formulation;Gene Silencing;Gene Targeting;Goals;Health;Hemiptera;Histidine;Human;Inductively Coupled Plasma Mass Spectrometry;Insect Vectors;Insecta;Insecticides;Intracellular Transport;Knock-in;Label;Laboratories;Larva;Lepidoptera;Lysine;Malaria;Measurement;Methods;Modeling;Modernization;Molecular Biology;Nanostructures;Nanotechnology;Nematoda;Order Coleoptera;Particulate;Phase;Plants;Polymers;Potato;Powder dose form;Prevention;Principal Investigator;Problem Solving;Property;RNA Interference;RNA Processing;Research;Residual state;Resistance;Resistance development;Resolution;Small Interfering RNA;Spectroscopy Fourier Transform Infrared;Technology;Time;Toxic effect;Transmission Electron Microscopy;Vector-transmitted infectious disease;Work;X ray diffraction analysis;Yellow Fever;Zika Virus;analytical method;base;chikungunya;comparative;design;disorder control;experimental study;feeding;fighting;gel electrophoresis;improved;interdisciplinary approach;knock-down;larval control;light scattering;mortality;nano;nanocomposite;nanoformulation;nanostructured;novel;novel strategies;pathogen;programs;prototype;tool;uptake;vector;vector control

public_health_relevance:
Project NarrativeMosquitoes transmit deadly diseases. The research proposed in this application will provide information and methods ofpotential importance for development of insecticides for vector control. The proposed studies will develop nano-formulations for delivery of dsRNA to improve RNAi efficiency in disease vectors. The methods developed will be usefulin both basic and applied research aimed at improving human health.


application_id: 9430319
project_number: 271201600028C-3-0-2
administering_ic: NIDA
project_start_date: 2016-09-18
project_end_date: 2021-09-17
contact_pi_person_id: 14759366
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF Development & Manufacture of Pharmaceutical Products for the Treatment of Substance Abuse Disorcer. NIDA Ref. No. N01DA-16-8926; POP: 09/18/2016 - 09/17/2021.

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

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


application_id: 9426752
project_number: 1R01GM126181-01
project_title: Chronic muscle weakness in sepsis survivors
administering_ic: NIGMS
award_notice_date: 2017-09-14
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: GM
serial_number: 126181
program_official: DUNSMORE, SARAH
project_start_date: 2017-09-15
project_end_date: 2021-08-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Animal Model;Antibiotics;Antioxidants;Atrophic;Bacterial Infections;Chronic;Defect;Development;Electron Microscopy;Exhibits;Functional disorder;Goals;Histologic;Hospitals;Incidence;Individual;Infection;Inflammation;Innate Immune Response;Kinetics;Knowledge;Life;Life Style;Liquid substance;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Multienzyme Complexes;Mus;Muscle;Muscle Proteins;Muscle Weakness;Muscular Atrophy;Mutant Strains Mice;Oxidative Stress;Oxygen Consumption;Pathology;Patients;Phase;Phenotype;Proteins;Protocols documentation;Public Health;Quality of life;Recovery;Reporting;Resuscitation;SOD2 gene;Sepsis;Skeletal Muscle;Survivors;Testing;Therapeutic;Therapeutic Intervention;Transgenic Mice;clinically relevant;effective therapy;mitochondrial dysfunction;mortality;mouse model;muscle form;novel therapeutics;oxidative damage


application_id: 9424936
project_number: 1R01NS104289-01
project_title: Validation of a Point of Care Diagnostic Test for Sports Related Concussion
administering_ic: NINDS
award_notice_date: 2017-12-01
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 104289
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2017-12-01
project_end_date: 2020-11-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: SMOOT, KYLE
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractMild traumatic brain injury (mTBI) resulting from sports related concussion (SRC) is a substantial public healthconcern with ~ 1.6  3.8 million injuries per year in the United States. Although extremes of head injury arerecognizable mTBI associated with SRC is more difficult to diagnose and is complicated by subtle physicalcognitive and emotional symptoms that may manifest up to 48 h following a concussive blow. In preliminarystudies using a rat model of mTBI and in a small clinical trial of patients with mTBI due to motor vehicleaccidents or unintentional falls we identified a novel post translationally modified marker of neuronal injuryubiquitinated visinin like protein 1 (ubVILIP-1) that is released into blood rapidly after injury. To facilitate rapidmeasurement of circulating ubVILIP-1 we developed a lateral flow device (LFD) that provides detection of thebiomarker in less than 20 min. The aim of the current proposal is determine if ubVILIP-1 levels can be used toidentify athletes with SRC by establishing baseline levels of the marker and then quantifying changes thatoccur following SRC and to correlate ubVILIP-1 levels with clinical metrics including SCAT3 measures.

project_terms:
Accident and Emergency department;Age;Assessment tool;Athletic Injuries;Awareness;Bedside Testings;Biological Assay;Biological Markers;Blood;Blood specimen;Brain Concussion;Chronic;Clinical;Clinical Data;Clinical Trials;Conscious;Craniocerebral Trauma;Data;Detection;Devices;Diagnosis;Diagnostic;Diagnostic tests;Drops;Early identification;Effectiveness;Enzyme-Linked Immunosorbent Assay;Equilibrium;Evaluation;Exertion;Fingers;Future;Glial Fibrillary Acidic Protein;Human;Injury;Kentucky;Lateral;Legal patent;Manufactured football;Measurement;Measures;Modeling;Monitor;Neurobehavioral Manifestations;Neuronal Injury;Neurons;Operative Surgical Procedures;Patients;Physicians;Play;Post-Translational Protein Processing;Proteins;Public Health;Rattus;Recording of previous events;Recovery;Research;Sampling;Seasons;Serum;Soccer;Specificity;Sports;Standardization;Symptoms;System;Tablets;Testing;Time;Training;Ubiquitination;United States;Universities;Validation;Weight;Woman;associated symptom;base;blood-based biomarker;conditioning;controlled cortical impact;emotional symptom;falls;male;men;mild traumatic brain injury;novel;novel marker;physical symptom;point-of-care diagnostics;recruit;research clinical testing;risk minimization;sensor;tau Proteins;vehicular accident;visinin

public_health_relevance:
NarrativeMild traumatic brain injury (mTBI) resulting from sports related concussion (SRC) is a substantial publichealth concern with ~ 1.6  3.8 million injuries per year in the United States. Despite considerableresearch there remains a critical need for a point of care test that can rapidly measure a maker of injuryin blood on the playing field during a clinically useful time frame. Preliminary and future studiesdescribed in this proposal aim to test the usefulness of a lateral flow device (LFD) that quantifies aspecific post-translational modification of visinin like protein 1 (VILIP-1) a neuron specific Ca2+-sensorprotein released into blood following mTBI as an objective marker of SRC.


application_id: 9424653
project_number: 5R01CA213990-02
project_title: Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer
administering_ic: NCI
award_notice_date: 2018-01-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 213990
program_official: XI, DAN
project_start_date: 2017-02-06
project_end_date: 2022-01-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
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:
Agonist;Anti-inflammatory;Arginine;Cell Survival;Cell physiology;Clinical Research;Cues;Data;Dinoprostone;Essential Amino Acids;Gene Expression;Generations;Genes;Genetic Transcription;Glucose;Glutamine;Glycolysis;Goals;Human;IRF4 gene;Immunosuppression;Immunosuppressive Agents;Immunotherapy;Infiltration;Inflammation;Interleukin-10;Interleukin-12;Leukocytes;Link;MHC Class II Genes;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitogen-Activated Protein Kinase Kinases;Modeling;Molecular;Mus;Natural Products;Neoplasm Metastasis;Network-based;Nitric Oxide;Non-Small-Cell Lung Carcinoma;PPAR gamma;PTGS2 gene;Particulate;Pathway Analysis;Pathway interactions;Patients;Phenotype;Play;Population Heterogeneity;Prostaglandin-Endoperoxide Synthase;Proto-Oncogene Proteins c-raf;Reactive Oxygen Species;Regulation;Role;Signal Transduction;System;T cell response;T-Lymphocyte;TNF gene;Testing;Transcriptional Regulation;Tumor Burden;Tumor-associated macrophages;Vascular Endothelial Growth Factors;Yeasts;arginase;bZIP Domain;base;beta-Glucans;c-myc Genes;cancer immunotherapy;chemotherapeutic agent;chemotherapy;cytokine;dectin 1;density;factor C;fibrosarcoma;inhibitor/antagonist;innovation;loss of function;macrophage;metabolic profile;metabolomics;monocyte;novel;outcome forecast;stable isotope;therapeutic target;therapy resistant;transcription factor;transcriptome;tumor;tumor microenvironment;tumor progression


application_id: 9424516
project_number: 1R01HG009914-01
project_title: Regulation of International Direct-to-Participant Genomic Research
administering_ic: NHGRI
award_notice_date: 2018-03-01
opportunity_number: PA-14-276
application_type: 1
activity_code: R01
ic: HG
serial_number: 009914
program_official: LOCKHART, NICOLE C
project_start_date: 2018-03-01
project_end_date: 2021-01-31
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: KNOPPERS, BARTHA MARIA M.
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryNew techniques for genomic research are being developed to take advantage of the ability tocontact research participants directly without utilizing physicians hospitals or biobanks.Researchers are now able to use the internet to recruit and enroll research participants ingenomic studies by using an online application and consent process. Participants send theirhealth records electronically and ship a sample of blood or saliva to the researchers. Althoughthis process has been approved by IRBs for domestic studies it is unclear whether this processis lawful for international research because of the diverse laws and policies of the countrieswhere the participants reside.This research will study the important but complex question of whether international direct-to-participant genomic research is lawful in a sample of 32 countries. It will also consider whatsteps are necessary to facilitate this efficient diversity-enhancing research while still protectingthe welfare of research participants.The project has the following three aims:Aim 1: Convene three expert working groups of researchers and IRB leaders to identify andprioritize the key issues for a standard questionnaire and template to distribute to the study's 32international experts on country-specific laws and research ethics.Aim 2: Distribute the questionnaires to the international experts consult with and advise themas they prepare their responses to the questionnaires and summaries of country-specific legaland ethical issues compile and analyze the responses and draft conclusions and policyoptions.Aim 3: Distribute the draft conclusions and policy options to the three expert working groupsinternational consultants and advisory board members and obtain their feedback; analyze theresponses and use them to prepare a final draft; write and publish articles presenting thefindings of the study; and disseminate the results in presentations to various groups ofstakeholders.

project_terms:
American;Biological;Blood specimen;Collaborations;Complex;Consent;Consult;Country;Electronic Health Record;Enrollment;Ethical Issues;Ethics;Feedback;Genetic Diseases;Genomics;Health;Hospitals;Individual;Institutional Review Boards;International;Internet;Laws;Legal;Participant;Physicians;Policies;Process;Publishing;Questionnaires;Regulation;Research;Research Ethics;Research Personnel;Saliva;Sampling;Ships;Specimen;Techniques;Writing;biobank;member;recruit;response;welfare;working group

public_health_relevance:
PROJECT NARRATIVEResearchers are now able to use the internet to recruit and enroll widely dispersedindividuals which is valuable for a wide range of research especially research involvingrare genetic disorders. With IRB approval online recruitment and enrollment ofindividuals from the same country as the researchers is permissible including obtainingbiological specimens and health information but it is unknown whether recruitment andenrollment of individuals from foreign countries would violate the laws of thosecountries. In collaboration with American stakeholders and legal experts from 32countries the investigators will analyze applicable legal provisions and provide policyoptions to enable ethical international direct-to-participant research.


application_id: 9423846
project_number: 1RF1AG057754-01
project_title: Therapeutic targeting of TREM2 for Alzheimer's disease
administering_ic: NIA
award_notice_date: 2018-03-14
opportunity_number: PA-16-160
application_type: 1
activity_code: RF1
ic: AG
serial_number: 057754
program_official: OPANASHUK, LISA A
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe identification of novel therapeutic targets for Alzheimer's disease is necessary to reach the goal of theNational Alzheimer's Project Act (NAPA) of having an effective treatment in place by 2025. Despite numerouspromising therapeutic approaches identified pre-clinically to treat Alzheimer's disease the translation of thesetherapies to the clinic have been incredibly disappointing. The vast number of population genetic studies thathave been performed for AD present an opportunity to identify disease pathways what could be targetedtherapeutically. One gene that has a strong effect on AD risk is the triggering receptor expressed on myeloidcells-2 (TREM2). As the name implies TREM2 is an innate immune receptor expressed on microglia knownto signal through DAP12 to trigger phagocytosis. TREM2 SNPs have been identified as significantly increasingrisk of AD in GWAS studies. The hypothesis for this increased risk is that there is a loss of function impairingthe innate immune system to clear amyloid deposition efficiently. We hypothesize that targeting TREM2 toactivate the receptor will modulate the neuroinflammatory response and stimulate microglia tophagocytose and clear the amyloid deposits. Furthermore we hypothesize that activating the TREM2receptor to modulate the neuroinflammatory response will ameliorate tau pathology provideneuroprotection and avoid cerebrovascular adverse events associated with A targeted therapies. Toactivate the TREM2 receptor we are using an antibody developed by Alector LLC Alector-002a thatrecognizes TREM2 and activates the receptor. We have found that the antibody show immune modulationclearance of amyloid deposits and cognitive improvement in amyloid depositing mice. We propose threespecific aims to test our hypothesis:Specific Aim 1: Determine the neuroinflammatory amyloid lowering and cognitive effects of A-002a.Specific Aim 2: Determine the tau modifying neuroprotective and cognitive effects of A-002a.Specific Aim 3: Determine the potential for cerebrovascular adverse events of A-002a.

project_terms:
APP-PS1;Abeta clearance;Acute;Adverse event;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Antibodies;Biochemistry;Cell Separation;Cerebral Amyloid Angiopathy;Chronic;Clinic;Cognition;Cognitive;Comorbidity;Deposition;Disease;Disease Pathway;Genes;Genetic Population Study;Genetic study;Goals;Histology;Hyperhomocysteinemia;Image;Immune;Immunohistochemistry;Immunologic Receptors;Immunotherapy;Impairment;Inflammatory Response;Innate Immune System;Magnetic Resonance Imaging;Mediating;Methods;Microglia;Modeling;Mus;Myeloid Cells;Names;Nerve Degeneration;Neurofibrillary Tangles;Pathology;Phagocytosis;Risk;Signal Transduction;TREM2 gene;TYROBP gene;Tauopathies;Testing;Tg2576;Therapeutic;Time;Transgenic Mice;Translations;Vascular Cognitive Impairment;aged;amyloid pathology;base;behavior test;cerebrovascular;cerebrovascular pathology;design;effective therapy;genome wide association study;immunoregulation;improved;intraperitoneal;loss of function;mouse model;nano-string;neuroinflammation;neuroprotection;new therapeutic target;novel;pre-clinical;prevent;receptor;response;risk variant;targeted treatment;tau Proteins;therapeutic target;vasogenic edema

public_health_relevance:
PROJECT NARRATIVEAlzheimer's disease remains an incurable condition in desperate need of novel disease-modifying. Geneticstudies have identified the TREM2 gene as a risk gene for Alzheimer's and we propose to test a therapeutictargeting TREM2. We have found that our approach lowers amyloid deposits and improves cognition in amouse model of amyloid pathology and we will test the effects of this approach on other aspects of Alzheimer'spathologies.


application_id: 9419265
project_number: 5R01AG047297-04
project_title: Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
administering_ic: NIA
award_notice_date: 2018-01-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 047297
program_official: ZIEMAN, SUSAN
project_start_date: 2015-02-01
project_end_date: 2019-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: FOLZ, RODNEY J
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 NURSING
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Asthma is a common chronic inflammatory disorder of the distal airways characterized by recurring symptoms airway inflammation and reversible airflow constriction. It is considered a collection of various phenotypes (characteristics) insteadof a single disease. Currently there is no comprehensive phenotyping specific to older adults with asthma that considers multiple factors relevant to this population. Divergent asthma phenotypes and exposure to unique environmental triggers may affect asthma control in the elderly. In addition factors contributing to asthma quality of life in the elderly have not been wll explored. The aims of our study are to: (1) develop and systematically implement a phenotyping algorithm in older adults with asthma; (2) longitudinally investigate the effects of asthma phenotypes and volatile organic compounds (VOCs) exposures on asthma control in older adults with asthma; and (3) develop a predictive model for asthma quality of life for older adults with asthma. Sub-aims are to explore the impact on moving from community-based to congregate living settings (e. g assisted living) on the course of asthma in older adults and to identify barriers to successful asthma medication management. One hundred ninety participants 60 years of age or older will be enrolled. Inclusion criteria are: meet standard diagnostic criteri for asthma non-smokers have no other chronic respiratory diseases do not reside in a skilled nursing facility and have not recently had a major a medical illness. At baseline participants wil complete spirometry bronchodilator responsiveness fractional exhaled nitric oxide methacholine challenge (if not completed within past 5 years) allergic sensitization Immunoglobulin E (IgE) and sputum analysis as well as standardized questionnaires to assess asthma control quality of life knowledge and self-efficacy. Within 30 days an in-home environmental assessment will be conducted to obtain data on VOCs air particulates moisture temperature humidity pests and an asthma home environment checklist. At 9 and 18 months in-home data will be collected on participants' pulmonary status asthma control and asthma quality of life. At 9-months participants will also complete the measures of medication management. At 18-months we will conduct follow-up in-home environmental assessments collecting the same data we collected at baseline. Participants who have moved to congregate living facilities will be asked open-ended questions about their perception of the effects of the move on the course of their asthma. Using factor analysis we will perform a comprehensive phenotypic characterization that will include a wide range of demographics asthma-specific knowledge and self-efficacy and biomarkers. Predictive models for asthma control and asthma quality of life will be identified using generalized linear mixed-effects modeling. The findings ofthis study will be used in future research to develop and test the efficacy of patient-centered interventions for older adults with asthma to improve asthma control and enhance quality of life.

project_terms:
4 year old;Acute;Address;Affect;Age;Age-Years;Air;Algorithms;Allergic;Area;Assisted Living Facilities;Asthma;Attention;Biological;Biological Markers;Biophysics;Bronchial Spasm;Bronchodilator Agents;Characteristics;Child;Chronic;Collection;Communities;Data;Diagnostic;Disease;Distal;Drug Interactions;Elderly;Emergency department visit;Enrollment;Environment;Environmental Exposure;Exhalation;Exposure to;Factor Analysis;Home environment;Hospitalization;Household Products;Humidity;IgE;Individual;Inflammatory;Intervention;Knowledge;Life Style;Living Arrangement;Longitudinal Studies;Lung;Lung diseases;Measures;Medical;Medication Management;Methods;Modeling;NIH Program Announcements;Nitric Oxide;Outcome;Paint;Participant;Particulate;Patient Selection;Perception;Personal Satisfaction;Pesticides;Pharmaceutical Preparations;Pharmacology;Phenotype;Physicians;Population;Prevalence;Quality of life;Questionnaires;Research;Research Personnel;Residential Facilities;Self Efficacy;Skilled Nursing Facilities;Spirometry;Sputum;Standardization;Stress;Symptoms;Temperature;Testing;Therapeutic Intervention;Visit;age group;airway inflammation;asthmatic;base;constriction;demographics;efficacy testing;experience;follow-up;improved;inclusion criteria;interest;methacholine;mortality;non-smoker;patient oriented;predictive modeling;public health relevance;residence;response;volatile organic compound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study will develop a method of categorizing asthma in older adults longitudinally investigate the effects of these categorizations on asthma control and identify factors such as environmental exposures and type of living arrangements that impact asthma quality of life for older adults. As the population ages and the percentage of older adults with asthma increases the information obtained from this study is needed to develop and test patient-centered interventions that will improve asthma control and quality of life in older adults with asthma.


application_id: 9418510
project_number: 5R01HD075783-05
project_title: Evaluating the long-term effects of Green Dot on teen dating violence prevention
administering_ic: NICHD
award_notice_date: 2018-04-19
opportunity_number: PA-09-169
application_type: 5
activity_code: R01
ic: HD
serial_number: 075783
program_official: BURES, REGINA M
project_start_date: 2013-09-06
project_end_date: 2019-11-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: FOLLINGSTAD, DIANE RUTH
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:
DESCRIPTION (provided by applicant): Our purpose is to evaluate the longer-term impact of Green Dot across the Bluegrass an active bystanding-based randomized intervention trial in 26 high schools across Kentucky designed to reduce dating and sexual violence in a cohort of seniors as they transition into young adulthood. Our central question is: Does Green Dot continues to have an effect in changing the culture of violence acceptance and reducing violence perpetration among students exposed to Green Dot relative to those not exposed as this cohort enters young adulthood? In this prospective cohort of approximately 7500 students we will measure the individual level exposure to the Green Dot program and into young adulthood allowing us to estimate the risk of dating and sexual violence victimization and perpetration. Very few studies have prospectively estimated the risk of dating and sexual violence among a cohort randomized to a primary prevention intervention and followed into young adulthood. This R01 is also unique because cohort members will be followed independent of whether they do or do not attend college. Individually following this cohort of seniors represents a significant value-added and time-sensitive opportunity because the full implementation of Green Dot began in late 2011. Only now (2013-15) would we anticipate seeing an effect of Green Dot among rising seniors on changing bystanding and potentially reducing violence. Aim 1. Prospectively determine whether and how the Green Dot intervention reduces rates of teen dating and sexual violence into young adulthood by (a) changing social norms of violence acceptance (b) increasing active bystanding and (c) diffusing the intervention through peer networks. Approximately 7500 high school seniors who attended Kentucky high schools randomized to the Green Dot intervention (n~3750) or control schools (n~3750) will be followed 42 months into young adulthood. Aim 2. To determine the potentially modifying effects of participants' post-high school life experience on the association between exposure to the Green Dot intervention and bystanding actions teen dating and sexual violence incidence. Post-high school experience will be categorized as attending any form of college or university versus no additional education. Specific life stressors such as relationship status pregnancy military deployment family and peer violence and substance abuse will also be explored. This cohort study is appropriately powered (90%) to address both aims. Comparisons will be made at 6-month intervals and across the 42-month follow-up and the interaction of intervention by time will be evaluated. Generalized Estimating Equations will be used to test the impact of Green Dot over time while taking clustering of high schools and correlation among repeated measurements among individual students into account and adjusting for confounders. This prospective cohort builds upon a large population-based and promising primary prevention intervention designed to reduce dating and sexual violence among high school students and provides an important test of the longer-term efficacy of this program into young adulthood.

project_terms:
Address;Adolescent;Adult;Climacteric;Cohort Studies;Collection;Data;Data Analyses;Diffuse;Education;Educational Status;Elements;Equation;Evaluation;Exposure to;Family Violence;Frequencies;Funding;High School Student;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Length;Life;Life Experience;Long-Term Effects;Measurement;Measures;Military Personnel;Outcome;Participant;Poa plant;Population;Pregnancy;Prevention program;Preventive Intervention;Primary Prevention;Prospective cohort;Randomized;Risk Estimate;Schools;Social Change;Spouses;Students;Substance abuse problem;Teen Dating Violence;Testing;Time;Training;Universities;Violence;base;cohort;college;dating violence;dating violence prevention;design;emerging adult;experience;follow-up;high risk population;high school;innovation;member;novel;partner violence;peer;peer networks;peer violence;population based;programs;prospective;public health relevance;randomized trial;recruit;sexual violence;social norm;stressor;therapy design;twelfth grade;violence perpetration;violence prevention;violence victimization;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Because teen dating and sexual violence rates remain high tests of promising primary prevention interventions with sufficient lengths of follow-up to detect changes in violence are needed. We propose a cohort study of high school seniors (n=7500) followed for up to 42 months who participated in a high school based randomized intervention trial of an active bystanding prevention program.


application_id: 9417955
project_number: 5R01HD064993-09
project_title: Aging and Dementia in Down Syndrome: Connectivity Inflammation and Cerebrovascular Contributions
administering_ic: NICHD
award_notice_date: 2018-02-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: PARISI, MELISSA
project_start_date: 2009-09-30
project_end_date: 2020-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: HEAD, ELIZABETH
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1) WM structural integrity (Aim 1) and CVF improvements (Aim 2) and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signsof dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.

project_terms:
Adult;Age;Age-Years;Aging;Alzheimer's Disease;Amyloid beta-Protein;Antigen-Antibody Complex;Attenuated;Autopsy;Behavior;Biological Markers;Blood;Brain;Case Series;Cerebrovascular Disorders;Chromosomes Human Pair 21;Classification;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive aging;Data;Dementia;Dependence;Development;Diagnosis;Diffuse;Down Syndrome;Encephalitis;Event;Future;Genes;Genetic Diseases;Goals;Human;Image;Impaired cognition;Individual;Inflammation;Inflammatory;Intellectual functioning disability;Intervention Studies;Link;Liquid substance;Longitudinal cohort;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Mediating;Molecular;Molecular Target;Nerve Degeneration;Neurobiology;Neurofibrillary Tangles;Outcome;Parietal Lobe;Pathology;Pathway interactions;Pattern;Phenotype;Plasma;Play;Predisposition;Proteins;Quality of life;RNA;Recovery;Reporting;Research;Research Design;Role;Senile Plaques;Signal Transduction;Spin Labels;Syndrome;Testing;United States;United States National Institutes of Health;abeta accumulation;abeta deposition;age related;aging brain;brain tissue;cerebrovascular;cerebrovascular pathology;cognitive function;cohort;functional decline;imaging modality;improved;individual variation;middle age;neurobiological mechanism;neuroinflammation;neuropathology;novel;prevent;public health relevance;recruit;virtual;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed study will identify early changes in brain inflammation cerebrovascular dysfunction and white matter integrity losses that signal changes in cognition behavior and functioning reflecting Alzheimer disease (AD) in adults with Down syndrome (DS). Identifying the earliest signs of dementia and indicators of individual variation incognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration. .


application_id: 9416917
project_number: 5R21AI130437-02
project_title: Exploring neurotropism in a food borne model of listeriosis
administering_ic: NIAID
award_notice_date: 2017-12-15
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 130437
program_official: BAQAR, SHAHIDA
project_start_date: 2017-01-25
project_end_date: 2019-12-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Systemic listeriosis is one of the most deadly foodborne bacterial diseases in North America as evidencedby recent outbreaks caused by contaminated cantaloupes (2011; 21% mortality) and cold cuts (2008; 39%mortality). After Listeria monocytogenes (Lm) spread to the brain it is difficult to eradicate the infectionand many patients die even while receiving aggressive antibiotic treatment. Two different types of braininfections are observed in humans: a diffuse meningitis/meningoencephalitis typically seen in the elderlyand other immune-compromised individuals; and a more focal infection localized in the brainstem(rhombencephalitis) that occurs in otherwise healthy adults. The central hypothesis of this proposal is thatmeningitis occurs via hematogenous spread primarily due to a failure of the immune system to limitoverwhelming growth of Lm in peripheral tissues while rhombencephalitis occurs when neurotropic strainsof Lm invade cranial nerves and spread to the brain by axonal migration. Progress in understanding braininfections has been limited by the lack of an appropriate small animal model to study the two proposedroutes of dissemination and by the technical limitation that very few bacteria are needed to causesymptomatic disease in the brain. In Aim 1 of this proposal bacterial colonization patterns in the brain(focal vs. diffuse) will be identified in mice given food contaminated with either neurotropic Lm (humanrhombencephalitis and sheep brain isolates) or non-neurotropic Lm (veterinary strains isolated from theliver). In Aim 2 an innovative approach will define the pathway used by neurovirulent Lm to disseminate tothe brain. Lm will be engineered to secrete Cre recombinase during intracellular growth and then used toinfect mice with a floxed GFP gene allowing for permanent identification of all cells in the body thatharbored intracellular Lm during any point of the infection. A key strength of this proposal is theinterdisciplinary approach resulting from a collaboration between microbiologists in the DOrazio lab withextensive expertise in manipulating Lm and studying host responses to infection and neuroscientists inthe Gensel lab who have the expertise to perform high resolution imaging of the nerves and brainstems ofmice. Working together this group will advance the field by revealing how Lm disseminate to the brainfollowing natural foodborne transmission and will develop a set of tools that may be used in future studiesto identify the features of neurotropic Lm strains that promote brain infection.

project_terms:
Adult;Affect;Animal Model;Antibiotic Therapy;Axon;Bacteremia;Bacteria;Bacterial Infections;Biological Models;Blood;Blood - brain barrier anatomy;Brain;Brain Stem;Cantaloupes;Cells;Cerebellum;Cerebrum;Cheese;Clinical;Collaborations;Cranial Nerves;Cytosol;Data;Diffuse;Disease;Disease Outbreaks;Eating;Elderly;Engineering;Enterobacteria phage P1 Cre recombinase;Facial nerve structure;Failure;Fatality rate;Focal Infection;Food;Food Contamination;Future;Gastrointestinal tract structure;Genes;Goals;Growth;Hematogenous Spread;Human;Immune;Immune response;Immune system;Immunodeficient Mouse;Incidence;Individual;Infant;Infection;Inflammation;Inflammatory;Ingestion;Inhalation;Injections;Intestines;Invaded;Left;Listeria monocytogenes;Listeriosis;Liver;LoxP-flanked allele;Meat;Meninges;Meningitis;Meningoencephalitis;Modeling;Morbidity - disease rate;Mus;Nerve;Neurologic Deficit;Neurons;Neurotropism;North America;Oral cavity;Pathway interactions;Patients;Pattern;Peripheral;Phagocytes;Process;Recombinants;Route;Ruminants;Sheep;Source;Spleen;Time;Tissues;Treatment Efficacy;Virulence Factors;Work;base;cell type;foodborne;foodborne pathogen;high resolution imaging;high risk population;innovation;interdisciplinary approach;migration;mortality;mouse model;neurotropic;neurovirulence;novel;sciatic nerve;therapeutic target;tool;transmission process;virtual

public_health_relevance:
Project Narrative:Ingestion of ready-to-eat foods (such as deli meat cheeses and produce) that are contaminated withListeria monocytogenes can cause serious infections of the brain that result in lingering neurologicaldeficits in otherwise healthy people and a high fatality rate (20-30%) in high risk groups such as infantsand the elderly. The goal of this proposal is to understand the pathways used by the bacteria to spreadfrom the intestinal tract to the brain with a long-term goal of developing an effective therapeutic that mightblock this process.


application_id: 9416143
project_number: 5R01ES024771-04
project_title: Community-Engaged Research and Action to Reduce Respiratory Disease in Appalachia
administering_ic: NIEHS
award_notice_date: 2018-01-18
opportunity_number: PA-12-153
application_type: 5
activity_code: R01
ic: ES
serial_number: 024771
program_official: FINN, SYMMA
project_start_date: 2015-04-15
project_end_date: 2020-01-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 1939811
contact_pi: BROWNING, STEVEN R
other_pis: SCHOENBERG, NANCY E.
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:
DESCRIPTION (provided by applicant): Rural Appalachian residents experience the nation's highest rates of serious respiratory illnesses with Appalachian Kentuckians twice as likely to be diagnosed with adult asthma and chronic obstructive pulmonary disease as their national counterparts. In response to community concern and to address the critical need to reduce respiratory health disparities in Appalachia we draw on our decade-long community-academic partnership to undertake three aims and activities: (1) to investigate the extent nature and source of respiratory health inequities we will implement a community-engaged assessment of environmental and individual-level exposures; (2) to enhance community knowledge about respiratory illness and refine a culturally appropriate environmental public health action strategy(EPHAS) we will disseminate results from the epidemiologic assessment and gather input to refine the EPHAS; and (3) to test the efficacy of the EPHAS we will implement and evaluate a three arm RCT involving self-management and home modification. Outcomes include appropriate health care use; improvement in quality of life pulmonary function respiratory illness knowledge and self-efficacy; extent of community participation; and programmatic satisfaction. The proposed application is responsive to "Research to Action: Assessing and Addressing Community Exposures to Environmental Contaminants" (PA-12-153) encouraging "community-engagement projects designed to investigate the potential health risks of environmental exposures of concern to a community and to implement an environmental public health action plan based on research findings." The proposed community-academic effort represents the first of its kind to undertake a comprehensive environmental behavioral and social determinants assessment leading to a community-endorsed environmental public health action strategy to rectify Appalachian respiratory health inequities.

project_terms:
Address;Adult;Adult asthma;Affect;Age;Air Pollutants;Appalachian Region;Area;Asthma;Back;Behavioral;Chronic Obstructive Airway Disease;Coal Mining;Collaborations;Communities;Community Participation;Data;Development;Diagnosis;Diet;Environmental Exposure;Environmental Pollution;Environmental Risk Factor;Epidemiology;Evaluation;Exposure to;Gender;Goals;Health;Health education;Healthcare;Home environment;Individual;Intervention;Kentucky;Knowledge;Lung diseases;Measurement;Measures;Modification;Nature;Neighborhoods;Occupations;Outcome;Outcome Assessment;Physical activity;Population;Process;Public Health;Quality of life;Randomized;Reporting;Research;Research Design;Research Personnel;Risk;Risk Factors;Role;Rural;Self Efficacy;Self Management;Smoking;Source;Symptoms;Testing;Voice;arm;base;community partnership;design;efficacy testing;environmental justice;epidemiology study;experience;health disparity;improved;innovation;low socioeconomic status;meetings;member;public health relevance;pulmonary function;residence;respiratory;respiratory health;response;satisfaction;social

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Residents of Rural Appalachia have the nation's highest rates of respiratory disease (asthma chronic obstructive pulmonary disease etc.). This project is the first to (1) study the many factors-environmental social and behavioral- that may account for this health inequity and (2) test an innovative approach to improve respiratory health. We draw on our long standing partnerships with several community groups-- a community research organization a community coalition/advisory board local media and health education and faith organizations- to do an epidemiologic assessment share the results and then implement and evaluate an environmental public health strategy.


application_id: 9415578
project_number: 1P20GM125504-01
project_title: Alterations and Renovations
administering_ic: NIGMS
award_notice_date: 2018-02-28
opportunity_number: PAR-16-415
application_type: 1
activity_code: P20
ic: GM
serial_number: 125504
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8248
contact_pi_person_id: 6411256
contact_pi: KING, WILLIAM W
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: 2018-03-01
budget_end_date: 2019-02-28
project_abstract:
AbstractFunds are requested to create the Germ-Free and Gnotobiotic Mouse Facility (GMF) to support the FunctionalMicrobiomics Core (FMC) the individual projects described in this COBRE as well as planned and future studiesrequiring the use of axenic and gnotobiotic animal models. Although the space included in the planned GMFtotals 933 ft2 the projected strategy involves only minor physical modifications to the existing Clinical andTranslational Research Vivarium (CTRV). The CTRV is located in the basement of the building housing many ofthe investigators described in this application and provides access to numerous ongoing research capabilitiesincluding multiple imaging modalities. Renovations include constructing a wall/door to create a more biologicallyand physically secured entryway (approximately 81 ft2) to the GMF providing centrally-distributed gases foranaerobic culture chambers which will installed in a dedicated Microbiota Preparation Room and installation ofisolators and individually-ventilated caging systems for dedicated germ-free and gnotobiotic rooms respectively.The project exploits existing infrastructure including animal procedure and housing room design that meets strictrequirements for rodent barriers emergency power in-room connections to existing HVAC systems individualroom electronic security and available bulk autoclave capacity. Once completed this facility will provide thenecessary infrastructure for investigators to obtain and manage germ-free rodents generate specifically-definedmicrobiota for inoculation and thereby create gnotobiotic animals for further study.

project_terms:
Anaerobic Bacteria;Animal Model;Animals;Axenic Animal;Biological;Centers of Research Excellence;Clinical Research;Emergency Situation;Funding;Future;Gases;Germ-Free;Gnotobiotic;Goals;Housing;Individual;Inflammation;Minor;Modification;Mus;Pathogenicity;Preparation;Procedures;Research;Research Infrastructure;Research Personnel;Rodent;Secure;Security;System;Translational Research;Universities;design;equipment acquisition;imaging modality;meetings;microbiome research;microbiota


application_id: 9415577
project_number: 1P20GM125504-01
administering_ic: NIGMS
award_notice_date: 2018-02-28
opportunity_number: PAR-16-415
application_type: 1
activity_code: P20
ic: GM
serial_number: 125504
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8247
contact_pi_person_id: 10329001
contact_pi: STEINBACH-RANKINS, JILL
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: 2018-03-01
budget_end_date: 2019-02-28
funding_mechanism: Research Centers
project_title:
Understanding the Host-Microbiome-Therapeutic Triad: Implications for Designing Alternative Intravaginal

project_abstract:
ABSTRACTBacterial vaginosis (BV) is a prominent dysbiotic condition resulting from the disruption of the diverse microbialcommunities that maintain host homeostasis and innate defense in the female reproductive tract. BV infection and recurrenceaffects over 30% of women imparting detrimental effects to female reproductive health by increasing the susceptibility toadverse pregnancy outcomes postsurgical infections and sexually transmitted infections (STIs). Current treatment optionsprimarily comprised of orally- or topically-applied antibiotics are initially efficacious; however frequent relapse isprevalent contributing to recurrent BV infections and adverse side effects. New therapeutic options including prebiotics(e.g. lactic acid glycogen) and probiotics have been utilized to recruit and stabilize indigenous normal Lactobacilli tocounterbalance the predominant BV-associated bacterial pathogen Gardnerella vaginalis (G.v.). However significant gapsremain in our understanding of host-microbiome-therapeutic interactions contributing to the difficulty in attaining a long-term effective method of protection and treatment. These widespread pandemic effects underscore the urgent need todevelop more effective BV treatment strategies and to improve our understanding of host-microbiome-therapeuticinteractions that contribute to efficacy.In this project we seek to develop new therapies to alter BV pathogenesis while advancing the understanding of host-microbiome-therapeutic interactions. To achieve these goals we will optimize the design of a novel delivery platformcomprised of core-shell polymeric electrospun fibers (EFs) that deliver pre- and probiotics test their efficacy in vitro andassess the effectiveness of these fibers in a murine model of BV infection. These studies will provide the foundation forimproved therapeutic outcomes while providing new insight into the effects of combined pre- and probiotic fibers on thevaginal microbiome host inflammatory response and BV disease markers and progression. While we will initially applythis delivery approach to target and understand the implications to BV pathogenesis we envision the research outcomeswill have a significant impact on the development of future multipurpose platforms to prevent and treat broader morecomplex interactions between bacterial and viral pathogens in the female reproductive tract.

project_terms:
Adherence;Adverse effects;Affect;Antibiotics;Bacterial Infections;Bacterial Vaginosis;Chronic;Coculture Techniques;Complex;Cream;Development;Disease Marker;Disease Progression;Dosage Forms;Ecosystem;Effectiveness;Encapsulated;Epithelial;Female;Fiber;Formulation;Foundations;Future;Gardnerella vaginalis;Glycogen;Glycolates;Goals;HIV-1;Homeostasis;Human Herpesvirus 2;In Vitro;Income;Indigenous;Infection;Inflammation;Inflammatory Response;Lactic acid;Lactobacillus;Measures;Mediating;Methods;Microbial Biofilms;Modeling;Mucous Membrane;Mus;Oral;Outcome Study;Outcomes Research;Pathogenesis;Pathogenicity;Patients;Physiological;Polymers;Predisposition;Probiotics;Recurrence;Regimen;Relapse;Reproductive Health;Sexually Transmitted Diseases;System;Tablets;Testing;Therapeutic;Time;Tissue Model;Topical application;Treatment Efficacy;Triad Acrylic Resin;Vagina;Viral;Woman;Work;adverse pregnancy outcome;antimicrobial;base;chemokine;cytokine;design;dysbiosis;host microbiome;improved;in vivo;insight;microbial community;microbiome;microbiome alteration;microbiome research;microbiome therapeutics;mouse model;nanoparticle;novel;novel therapeutics;oral biofilm;pandemic disease;pathogen;prebiotics;prevent;recruit;reproductive tract;residence;response;scaffold;success;therapy outcome;treatment strategy;vaginal microbiome;vaginal microbiota


application_id: 9415576
project_number: 1P20GM125504-01
project_title: Modulation of respiratory melioidosis inflammation
administering_ic: NIGMS
award_notice_date: 2018-02-28
opportunity_number: PAR-16-415
application_type: 1
activity_code: P20
ic: GM
serial_number: 125504
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8246
contact_pi_person_id: 10426217
contact_pi: WARAWA, JONATHAN MARK
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: 2018-03-01
budget_end_date: 2019-02-28
project_terms:
Acute;Alveolar Macrophages;Antibiotic Resistance;Bacteria;Bolus Infusion;Burkholderia pseudomallei;Cells;Cessation of life;Cytoplasm;Data;Disease;Disease Outcome;Disease susceptibility;Dose;Environment;Exhibits;Flow Cytometry;Foundations;Genome;Immune;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Inhalation;Innate Immune Response;Interferon Type II;Interferon-alpha;Interleukin-12;Life Style;Lung;Mediating;Melioidosis;Methods;Microspheres;Modification;Morbidity - disease rate;Mus;Myelogenous;Natural Killer Cells;Neutrophil Infiltration;Organ;Outcome;Pathogenesis;Pathogenicity;Phagocytes;Population;Production;Prophylactic treatment;Resolution;Route;Secondary to;Sepsis;Stains;Sterility;Supporting Cell;System;Systemic disease;T-Lymphocyte;Testing;Therapeutic;Tissues;Treatment Efficacy;Tropism;Vaccines;cell type;combat;cytokine;cytokine release syndrome;disorder control;immunoregulation;improved outcome;inflammatory lung disease;insight;lung microbiota;macrophage;microbiome research;microbiota;mortality;novel;novel therapeutics;particle;pathogen;recruit;respiratory;response;tool


application_id: 9415573
project_number: 1P20GM125504-01
project_title: Novel synthetic analogue of microbial metabolite Urolithin A mitigates inflammatory bowel diseases
administering_ic: NIGMS
award_notice_date: 2018-02-28
opportunity_number: PAR-16-415
application_type: 1
activity_code: P20
ic: GM
serial_number: 125504
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8243
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
budget_end_date: 2019-02-28
project_terms:
Acids;Acute;Affect;Anti-inflammatory;Bacteria;Benzopyrans;Berry;Biological;Biological Availability;Cells;Chemopreventive Agent;Chronic;Clinical;Colitis;Crohn's disease;Data;Development;Diet;Dietary Intervention;Dietary Practices;Disease;Disease model;Dose;Down-Regulation;Ellagi-Tannins;Ellagic Acid;Epithelial;Epithelial Cells;Erythroid;Event;Exhibits;Functional disorder;Glycols;Goals;Heme;Homeostasis;Human;Ileitis;Immune;In Vitro;Indigenous;Individual;Individual Differences;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Bowel Diseases;Interleukin-1;Interleukin-6;Intestinal permeability;Lipopolysaccharides;Measures;Mediating;Modeling;Molecular;Mus;Nuclear;Oral Administration;Oxygenases;Parents;Pathogenicity;Pathway interactions;Phenotype;Phytochemical;Pilot Projects;Pomegranate;Pre-Clinical Model;Probiotics;Production;Proteins;Risk;Role;Sampling;Sodium Dextran Sulfate;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic;Therapeutic Uses;Tight Junctions;Time;Treatment Efficacy;Trinitrobenzenesulfonic Acid;Ulcerative Colitis;Variant;analog;bacterial metabolism;base;chemokine;comparative efficacy;dysbiosis;gut bacteria;gut microbiota;in vivo;in vivo Model;inter-individual variation;microbial;microbiome research;microbiota metabolites;molecular targeted therapies;novel;protective effect


application_id: 9415572
project_number: 1P20GM125504-01
project_title: Functional Microbiomics Core-Bodduluri
administering_ic: NIGMS
award_notice_date: 2018-02-28
opportunity_number: PAR-16-415
application_type: 1
activity_code: P20
ic: GM
serial_number: 125504
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
subproject_number: 8242
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
budget_end_date: 2019-02-28
project_terms:
Address;Adopted;Anaerobic Bacteria;Area;Attention;Award;Bioinformatics;Biological;Biomedical Research;Centers of Research Excellence;Clinical;Communities;Continuing Education;Core Facility;Data Analyses;Development;Dietary Intervention;Disease;Equipment;Extramural Activities;Fee-for-Service Plans;Fostering;Funding;Generations;Genomic DNA;Genomics;Germ-Free;Gnotobiotic;Goals;Health;Housing;Human Resources;Incubators;Individual;Infection;Inflammation;Inflammation Mediators;Institution;Kentucky;Laboratories;Mentors;Metagenomics;Methodology;Mission;Mono-S;Mus;Outcome;Pathogenesis;Pathogenicity;Phase;Pilot Projects;Process;Protocols documentation;Research;Research Personnel;Research Support;Resources;Ribosomal RNA;Sampling;Services;Sterility;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;animal facility;base;biosafety level 3 facility;experimental study;fecal transplantation;histopathological examination;inflammatory marker;innovation;interest;investigator training;meetings;member;metabolomics;microbial;microbiome;microbiome research;microbiota;mouse model;pathogen;programs;protocol development;rRNA Genes;social health determinants;success;tool


application_id: 9415570
project_number: 1P20GM125504-01
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2018-02-28
opportunity_number: PAR-16-415
application_type: 1
activity_code: P20
ic: GM
serial_number: 125504
program_official: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C1)]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Anaerobic Bacteria;Anti-inflammatory;Area;Autistic Disorder;Autoimmune Diseases;Basic Science;Bioinformatics;Biological Assay;Biometry;Centers of Research Excellence;Chronic;Colorectal Cancer;Communities;Complex;Dentistry;Development;Disease;Distant;Ecology;Education;Engineering;Ensure;Environment;Equilibrium;Evaluation;Extramural Activities;Faculty;Funding;Germ-Free;Goals;Health;Health Sciences;Homeostasis;Human;Human Microbiome;Immune response;Immune system;Immunologist;Immunology;Indigenous;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interdisciplinary Study;International;Lead;Location;Mentors;Methods;Microbe;Microbiology;Monitor;Mucous Membrane;Natural Immunity;Normal tissue morphology;Outcomes Research;Parkinson Disease;Pathogenicity;Pathology;Pathway interactions;Periodontitis;Physiology;Pilot Projects;Play;Positioning Attribute;Postdoctoral Fellow;Process;Recovery;Renaissance;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resources;Rheumatoid Arthritis;Role;Scientist;Services;Shapes;Site;Specificity;Structure;Surface;System;Talents;Teacher Professional Development;Therapeutic Agents;Time;Tissues;Training;Universities;animal facility;bioimaging;career development;chronic infection;dysbiosis;graduate student;host-microbe interactions;immune system function;inflammatory marker;intercellular communication;medical schools;microbial;microbial community;microbiome;microbiome research;microbiome sequencing;microbiota;multidisciplinary;nervous system disorder;novel;novel therapeutics;pathogen;programs;recruit;response;tool


application_id: 9415469
project_number: 5R01ES024478-04
project_title: The role of chromatin structural and epigenetic changes in arsenic-induced gene expression
administering_ic: NIEHS
award_notice_date: 2018-02-06
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 024478
program_official: TYSON, FREDERICK L
project_start_date: 2015-04-07
project_end_date: 2020-01-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 10313148
contact_pi: FONDUFE-MITTENDORF, YVONNE NSOKIKA
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): Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Arsenic is a ubiquitous environmental toxic metalloid that leads to carcinogenesis. The World Health Organization estimates that over 100 million people worldwide are at risk to drinking arsenic contaminated water. Recent studies indicate that arsenic alters gene expression leading to tumorigenesis. Proper gene regulation is essential for normal growth development and etiology of diseases such as cancer. Eukaryotic DNA stored as chromatin whose basic repeating unit is the nucleosome plays an integral role in gene regulation. Previously we (and others) showed that nucleosome locations within promoters play critical roles in chromatin accessibility thus controlling gene activity. Consequently chromatin accessibility is an essential component in gene regulation yet is not fully understood. Chromatin accessibility appears to be modulated by several key epigenetic factors: histone post-translational modifications (PTMs) DNA methylation nucleosome position/occupancy transcription factors and chromatin architectural proteins (CAPs). Recent studies now indicate that changes in DNA methylation and histone PTMs influence gene expression in response to arsenic: Thus it is critically important to understand how these key epigenetic modulators integrate and interrelate to regulate the chromatin state and gene expression during arsenic exposure. This project will determine the functional changes in gene regulation chromatin composition structure and dynamics genome-wide due to arsenic in normal and iAs- transformed cells. We hypothesize that iAs-induced alterations in nucleosome position and occupancy histone PTMs and CAP occupancy all combine to dynamically restructure chromatin resulting in differential expression of key genes resulting in a failure to ensure proper gene regulation and cancer. We propose in this application the following Specific Aims: (1) determine the effect of iAs on in vivo nucleosome positioning and/occupancy during iAs-induced transformation. (2) Determine the impact of iAs- triggered modulation of CAPs-chromatin structure to impact gene expression. (3) Determine the mechanisms whereby iAs-provoked changes in chromatin composition structure and dynamics control TF occupancy. Our interdisciplinary broad approach will establish unique comprehensive functional and mechanistic data that will provide a detailed understanding of the interplay between arsenic-induced epigenetic changes and chromatin in the mammalian cell. We have developed novel systems that will provide an unprecedented and unique opportunity to discover the functional and mechanistic roles of the epigenome in toxin-induced diseases.

project_terms:
Adhesions;Affect;Architecture;Arsenic;Binding;Biochemical;Bioinformatics;Biophysics;Cell Adhesion;ChIP-seq;Chromatin;Chromatin Structure;Cues;DNA;DNA Binding;DNA Methylation;DNA Sequence;Data;Development;Diagnostic;Disease;Ensure;Epigenetic Process;Etiology;Eukaryotic Cell;Exposure to;Expression Profiling;Failure;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Structure;Generations;Genes;Genetic Transcription;Genome;Goals;Growth and Development function;Health;Heavy Metals;Histones;Human;ITGB4 gene;In Vitro;Integrins;Lead;Location;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Mediating;Modification;Molecular Target;NCAM1 gene;Neoplasm Metastasis;Nucleosomes;Organism;Outcome;Pathogenesis;Play;Positioning Attribute;Post-Translational Protein Processing;Prevention;Process;Proteins;Reactive Oxygen Species;Research;Risk;Role;Site;Specific qualifier value;Stimulus;Structure;System;To specify;Toxin;Transcriptional Regulation;World Health Organization;Zinc Fingers;base;carcinogenesis;carcinogenicity;cell transformation;chromatin protein;chromatin remodeling;clinical biomarkers;clinical development;contaminated water;differential expression;drinking;epigenome;epigenomics;epithelial to mesenchymal transition;genome-wide;in vivo;insight;metaplastic cell transformation;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;pollutant;promoter;public health relevance;response;single-molecule FRET;targeted treatment;tool;transcription factor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Proper regulation of gene expression is essential to the development and health of all organisms. The DNA in each eukaryotic cell found as chromatin plays an integral part in this gene regulation. Indeed where nucleosomes are located is important in our understanding of gene regulation. Furthermore knowing how chromatin structure responds to particular stimuli to control the on and off state of genes would be helpful in the development of new diagnostic and therapeutic tools.


application_id: 9415389
project_number: 5R01ES025515-04
project_title: Oxidative stress Cr(VI) carcinogenesis and prevention
administering_ic: NIEHS
award_notice_date: 2018-01-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 025515
program_official: REINLIB, LESLIE J
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: ZHANG, ZHUO
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): Cr(VI) is well known environmental carcinogen. Its mechanism of action or prevention remains to be investigated. Our preliminary studies have shown that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) generates reactive oxygen species (ROS) which are responsible for Cr(VI)-induced cell transformation. After transformation these cells exhibit constitutive expressions of Nrf2 and its target antioxidant proteins resulting in decreased ROS generation. The constitutive expression of Nrf2 activates Bcl-2 through binding of Nrf2 to antioxidant responsive element (ARE) of Bcl-2 gene promoter leading to increased survival and tumorigenicity of these transformed cells. These preliminary studies indicate that in non-transformed cells activation of Nrf2 may decrease ROS generation thus inhibit Cr(VI)-induced cell transformation. In contrast in Cr(VI)-transformed cells inactivation of constitutive expression of Nrf2 may decrease Bcl-2 and increase ROS leading to inhibitions of survival and tumorigenicity of transformed cells. We have screened various natural compounds attempting to select those with two properties: (a) to activate Nrf2 and decrease ROS in non- transformed cells to prevent Cr(VI)-induced cell transformation and (b) to inhibit constitutive expression of Nrf2 and enhance ROS and apoptosis in Cr(VI)-transformed cells to prevent tumorigenesis. We have found that luteolin a natural compound has such dual properties. The central hypothesis is that luteolin protects Cr(VI)- induced carcinogenesis both by inducing transient activation of Nrf2 in non-transformed cells resulting in inhibition of Cr(VI-induced cell transformation and by inactivating constitutive expression of Nrf2 in Cr(VI)- transformed cells resulting in inhibitions of survival and tumorigenesi of Cr(VI)-transformed cell and angiogenesis. Aim 1 will study prevention of luteolin against Cr(VI)-induced cell transformation. We will study luteolin-induced activations of Nrf2 and its target antioxidant genes and decreases of Cr(VI)-generated ROS. The integration of these molecular events is likely to be responsible for protection of luteolin against Cr(VI)- induced cells transformation. Aim 2 will demonstrate that in Cr(VI)-transformed cells luteolin is able to inhibit constitutive expressions of Nrf2 increase ROS level and decrease survival and tumorigenicity of Cr(VI)- transformed cells. The protection of luteolin against Cr(VI)-induced angiogenesis in animal exposed to Cr(VI) via drinking water will also be investigated. Aim 3 will investigate protection o luteolin against Cr(VI)-induced carcinogenicity in CD1 mice using a recently established animal model of "whole-life" chronic metal exposure. The animals will be exposed to Cr(VI) in the presence and absence of luteolin via drinking water in the whole life time from breeding to adulthood. The roles of Nrf2 and its key target will be studied. Tumors will be assessed in the offspring up to 2 years of adulthood. The proposed study will not only gain novel mechanistic insight in Cr(VI) carcinogenesis but also have potential translational impact of using chemopreventive compounds targeting Nrf2 signaling pathway to combat Cr(VI)-induced carcinogenicity.

project_terms:
2 year old;Adult;Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding;Breeding;Cell Death;Cells;Chemopreventive Agent;Chronic;Data;Development;Diet;Elements;Environmental Carcinogens;Enzymes;Epithelial;Event;Exhibits;Exposure to;Female;Gene Expression;Gene Targeting;Generations;Genes;Lactation;Life;Literature;Lung;Luteolin;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metal exposure;Molecular;Mus;Nutritional;Occupational;Oncogenic;Oxidative Stress;Pathway interactions;Pregnancy;Premalignant;Prevention;Prevention strategy;Property;Proteins;Reactive Oxygen Species;Resistance;Role;Signal Pathway;Signal Transduction;Source;Stress;Superoxide Dismutase;Time;Tumor Tissue;Tumorigenicity;Up-Regulation;angiogenesis;cancer cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;combat;drinking water;epidemiology study;exposed human population;in vivo;insight;male;malignant state;novel;offspring;pregnant;prevent;promoter;public health relevance;translational impact;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    NARRATIVE The study will show that luteolin protects Cr(VI) carcinogenesis by activation of inducible Nrf2 in pre-malignant stage to prevent cell transformation and by inactivation of constitutive expression of Nrf2 in later stage to prevent tumorigenesis. The expected results will demonstrate the roles of oxidative stress and Nrf2 in the mechanism of Cr(VI) carcinogenesis and the strategy for prevention.


application_id: 9414933
project_number: 5U01MD010556-03
administering_ic: NIMHD
award_notice_date: 2017-12-15
opportunity_number: RFA-MD-15-010
application_type: 5
activity_code: U01
ic: MD
serial_number: 010556
program_official: DAGHER, RADA K
project_start_date: 2016-04-26
project_end_date: 2020-12-31
study_section: ZMD1-DRI(03)
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
project_title:
Appalachians Together Restoring the Eating Environment (Appal-TREE): Advancing Sustainable CBPR Interventions to Improve Healthy Diet in Rural Appalachian Children

project_abstract:
DESCRIPTION (provided by applicant):The National Institutes of Health has acknowledged that residents of rural Appalachia experience among the nation's worst health and economic profiles including disability and premature mortality stemming from elevated rates of heart disease and stroke various cancers diabetes all of which are closely associated with suboptimal dietary intake obesity and overweight. Community members are particularly concerned about their children who have among the highest rates of obesity overweight and suboptimal dietary intake in the nation. Eliminating these health disparities requires scientificaly informed community-engaged research to develop and evaluate innovative and sustainable programs and policies. For the proposed application our community-research team will (1) use an innovative information technology CBPR method - Structured Public Involvement - to refine and tailor a package of pilot tested healthy eating interventions; (2) conduct and evaluate this package of interventions that were found to be feasible culturally consonant and promising during R24MD008018 and (3) build community capacity in social marketing an innovative approach to enhance sustainability of the intervention. Our partners include the Community Farm Alliance local school districts the Cooperative Extension Service and other community organizations. For the first aim the innovative CBPR approach Structured Public Involvement will allow us to tailor the intervention while maintaining project fidelity. For the second aim wewill administer and evaluate three interrelated interventions to transform access to and intake of healthy foods for Appalachian children; (1) a school-based water campaign to decrease sugar sweetened beverage consumption (2) healthy cooking classes to encourage healthy cooking on a budget; and (3).a farmer's market-based healthy summer feeding program. Finally in Aim 3 we will administer a CBPR-oriented approach social marketing to enhance sustainability a challenge for all behavioral interventions. Through the schools we will train teachers and administrators to teach social marketing to students who will be encouraged to develop marketing campaigns supporting healthy diets. All of these efforts will be developed implemented and evaluated in conjunction with our Community Advisory Boards. As one of our local stakeholders told us "If you really are what you eat it's no wonder so many of us are unhealthy." By developing sustainable evidence-based programming we aim to transform consumption patterns and the eating environment so the next generation of rural residents can overcome pernicious health disparities.

project_terms:
Administrator;Appalachian Region;Area;Behavior Therapy;Budgets;Child;Clinic;Communities;Community Health;Community Participation;Consumption;County;Diabetes Mellitus;Diet;Diet Habits;Dietary Intervention;Dietary intake;Disease;Eating;Educational workshop;Elements;Environment;Equilibrium;Evidence based program;Farming environment;Food;Food Services;Future;Health;Health Food;Health Priorities;Healthy Eating;Heart Diseases;Heart Rate;Home environment;Improve Access;Information Technology;Intake;Intervention;Kentucky;Lead;Life;Malignant Neoplasms;Marketing;Methods;Nutritional;Obesity;Outcome;Overweight;Parents;Pattern;Pilot Projects;Policies;Premature Mortality;Program Sustainability;Public Housing;Research;Research Personnel;Rural;Rural Health;Schools;Science;Services;Social Marketing;Specific qualifier value;Stroke;Structure;Students;Teacher Professional Development;Techniques;Technology;Testing;To specify;Trainers Training;Trees;U-Series Cooperative Agreements;United States National Institutes of Health;Water;Youth;base;behavior change;community intervention;community organizations;cooking;design;disability;evidence base;experience;farmers markets;feeding;good diet;health disparity;health economics;improved;information gathering;innovation;innovative technologies;insight;meetings;member;multidisciplinary;next generation;novel;outreach;preference;prevent;programs;public health relevance;rural underserved;school district;service programs;skills;social;stem;sugar;sweetened beverage;teacher;theories;user-friendly

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Appalachians Together Restoring the Eating Environment (Appal-TREE) uses a new CBPR technology to solicit community input delivers a tested package of healthy diet interventions (water promotion cooking classes and expansion of the Summer Food Service Program via farmers markets) to Appalachian communities. Social marketing techniques will be taught to area youth as a means of promoting sustainable support for this intervention.


application_id: 9414018
project_number: 5R01DC014658-04
project_title: Repair of mechano-electrical transduction in mammalian auditory hair cells
administering_ic: NIDCD
award_notice_date: 2018-01-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 014658
program_official: FREEMAN, NANCY
project_start_date: 2015-02-15
project_end_date: 2020-01-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
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:
DESCRIPTION (provided by applicant): It is presumed that the mechanosensory machinery in the stereocilia bundles of the inner ear hair cells is very vulnerable to intense mechanical stimulation. Yet we still do not know what exactly is damaged within the transduction machinery and whether these damages can be repaired. However it may represent a significant component in noise-induced hearing loss. The ability of the hair cell to repair these damages may determine whether the noise-induced temporary shift of hearing thresholds would recover or progress into permanent hearing loss. Interestingly damage to the actin core of stereocilia has been known as a hallmark of permanent noise-induced hearing loss for more than two decades. However little is known on how this damage develops or repairs. We have recently initiated a systematic study of the effects of mechanical overstimulation on the mechano-electrical transduction and the ultrastructure of stereocilia bundle in young postnatal cochlear hair cells. An anticipated effect of overstimulation is the loss of tip links that are known to regenerate. Using a novel immunogold scanning electron microscopy technique we have discovered that the tip link regeneration may involve a two-step molecular remodeling that includes formation of the temporary links with protocadherin-15 at both ends of the link and then replacing them with the more mature links containing protocadherin-15 and cadherin-23. Specific Aim 1 of the proposed project will explore regeneration of the tip links in mechanically damaged cochlear inner hair cells and determine whether molecular remodeling occurs in regenerating tip links. Our preliminary data also show that mechanical overstimulation does not abolish all tip links in the cochlear hair cells; many of them withstand overstimulation. However the remaining mechanotransducer current loses slow adaptation and has no evidence of the tension within the transduction machinery that is normally present at rest. Specific Aim 2 will explore the mechanisms of re-tensioning of the transduction apparatus in mechanically damaged cochlear inner hair cells. Investigating Ca2+ entry into individual stereocilia we found that the cochlear inner hair cells regulate resting tension within the transduction apparatus via anovel extremely slow Ca2+-dependent process. This regulation is likely to be affected in mechanically damaged hair cells. Specific Aim 3 will determine the mechanisms of this slow regulation and its potential disruption by intense deflections of the hair bundle. Finally we foun that overstimulation causes small nanometer-scale gaps in the actin core of stereocilia similar to the ones that we previously observed in degenerating stereocilia lacking gamma-actin. Specific Aim 4 will explore whether the hair cells can repair these gaps and whether gap formation or repair depends on gamma-actin. We believe that our study is a long-awaited step in exploring the potential mechanisms of the noise-induced hearing loss.

project_terms:
Actins;Affect;Auditory;CDH23 gene;Cells;Data;Deafness;Exposure to;Freeze Substitution;Freezing;Genes;Hair;Hair Cells;Hearing;Human;Immunogold Technics;Impairment;Individual;Inner Hair Cells;Knock-in Mouse;Labyrinth;Link;Mechanical Stimulation;Mechanics;Modeling;Molecular;Mus;Mutation;Myosin ATPase;Natural regeneration;Noise;Noise-Induced Hearing Loss;PCDH15 gene;Point Mutation;Predisposition;Probability;Process;Public Health;Recovery;Regulation;Research;Rest;Role;Sampling;Scanning Electron Microscopy;Techniques;Time;Transmission Electron Microscopy;experimental study;extracellular;gamma Actin;hearing impairment;mouse model;nanoscale;novel;overexpression;postnatal;public health relevance;repaired;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research is relevant to the public health because it investigates the basic mechanisms of noise-induced hearing loss a leading cause of hearing impairment in the US and worldwide. The proposal is unique because it explores largely uninvestigated effects of mechanical damage to the mechano-sensory apparatus of the inner ear hair cells.


application_id: 9413354
project_number: 5R01HD075829-04
project_title: The development of emotion processing in infancy
administering_ic: NICHD
award_notice_date: 2018-02-15
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 075829
program_official: ESPOSITO, LAYLA E
project_start_date: 2015-04-01
project_end_date: 2020-02-29
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 8534513
contact_pi: BHATT, RAMESH S
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Emotion processing is a critical component of social functioning. Adults derive a considerable amount of emotion information from body posture and movement. In some circumstances bodies are better sources of emotion cues than faces. Yet virtually nothing is known about the development of emotion processing from body gestures. This is in contrast to a great number of studies that have examined facial emotion processing. The proposed studies are aimed at filling this gap. They will examine predictions from models of body knowledge development emotion processing and action understanding while documenting the nature of development in early infancy and examining mechanisms that drive development. Slaughter and Heron's model of body knowledge development proposes that visuospatial body knowledge is minimal early in life and slow to develop in comparison to facial knowledge. In contrast other models of body knowledge development and theories of action understanding and emotion processing envision early development of knowledge about bodies and emotions signaled by them. One set of studies will contrast these predictions. Another set of studies will address a significant debate in the emotion literature concerning whether knowledge about basic categories of emotions is available early in life. A third set of proposed studies will test the hypothesis that visual exploration capacities contribute to the development of body emotion knowledge. Another group of studies will examine the proposition that motor experience and development are associated with body emotion knowledge development. The fifth set of proposed studies originates from empirical findings and theoretical propositions suggesting that learning plays a significant role in the development of object and social perception. We will test the hypothesis that body emotion knowledge development is facilitated by learning induced by observing exemplars of emotional behavior and correlations between bodily facial and vocal emotional expressions. Thus the proposed studies will document the development of body emotion knowledge in infancy examine the role of visual exploration as an underlying mechanism of development and investigate whether motor development and observational learning contribute to this development. Many developmental disorders such as Autism are at least in part based on deficits in emotion processing. The proposed research will contribute to the analyses and treatment of such disorders by documenting the nature of emotion processing from body information in infancy and the manner in which it normally develops early in life.

project_terms:
Address;Adult;Affect;Age-Months;Age-Years;Anger;Autistic Disorder;Awareness;Behavior;Categories;Conduct Disorder;Cues;Development;Disease;Emotional;Emotions;Exposure to;Face;Feeling;Fright;Gestures;Human;Human body;Infant;Infant Development;Intention;Knowledge;Learning;Life;Literature;Mental disorders;Modality;Modeling;Motor;Movement;Nature;Organism;Perception;Perceptual learning;Persons;Play;Posture;Psychopathology;Research;Role;Scanning;Signal Transduction;Social Functioning;Social Interaction;Social Perception;Source;Testing;Visual;Visuospatial;Walkers;Work;autism spectrum disorder;base;cognitive function;developmental disease;emotional behavior;experience;infancy;negative affect;object perception;predictive modeling;public health relevance;research study;showing emotion;social engagement;theories;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Many disorders such as Autism Spectrum Disorder and Conduct Disorder are at least in part based on deficits in emotion processing. Some of these disorders manifest themselves quite early in life while the psychopathology associated with others may be caused by developmental deficits. It is thus important to understand the development of emotion processing. The proposed research will contribute to the analysis and treatment of psychological disorders by documenting the nature of emotion processing from body information in infancy and the manner in which it normally develops early in life.


application_id: 9412826
project_number: 5R21DA041755-02
project_title: Social Cues and Drug Relapse
administering_ic: NIDA
award_notice_date: 2018-01-19
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: DA
serial_number: 041755
program_official: MOORE, HOLLY MARIE
project_start_date: 2017-02-01
project_end_date: 2021-01-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY One of the most difficult problems facing drug abuse practitioners is the continuing high rate of relapsefollowing treatment. While there are multiple internal states and external cues that may trigger relapse onecommon factor is to re-associate with drug-using social peers. Although some recent preclinical work hasexamined the role of social influence on acquisition and maintenance of drug self-administration there isessentially no information about the role of social cues in reinstatement of drug seeking. The overall hypothesisof this project is that self-administering social peers will serve as a cue to induce drug seeking in a controlledpreclinical laboratory setting. Separate from discrete cues (light tone) and contextual cues (tactile and visualcues time of day) these studies will determine if social peers also are able to reinstate extinguishedresponding for drug. In addition these studies will provide definitive information about the potential interactiveeffects of social and contextual cues in reinstatement. Two specific aims are proposed. First we willdetermine if there are sex differences in discriminative social cue-induced reinstatement and if social cuespotentiate the ability of contextual cues to reinstate drug seeking. Second in these of behavioral experimentsc-Fos protein immunoreactive cells will be quantitated in various brain regions to determine if neural activationfollowing social cues differs between males and females or if activation by social cues differs from contextualcues. If social cues prove to be a trigger for drug seeking this would provide evidence that informspsychosocial treatments which emphasize skill-building to avoid deviant peers.

project_terms:
Beer;Behavioral;Brain;Brain Diseases;Brain region;Cells;Chronic;Cocaine;Cues;Discrimination;Drug abuse;Drug usage;Environment;Exposure to;Extinction (Psychology);FOS Protein;FOS gene;Female;Goals;Individual;Intervention;Laboratories;Light;Lighting;Measures;Modeling;National Institute of Drug Abuse;Odors;Patient Self-Report;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Play;Pre-Clinical Model;Predisposing Factor;Prevention strategy;Procedures;Process;Rattus;Relapse;Reporting;Role;Saline;Self Administration;Self-Administered;Sex Characteristics;Syringes;System;Tactile;Testing;Time;Training;Treatment Efficacy;Visual;Work;cocaine use;community setting;craving;deviant;disorder later incidence prevention;drug abuser;drug maintenance;drug relapse;experimental study;immunoreactivity;male;peer;pre-clinical;psychosocial;relating to nervous system;response;skills;social;treatment program

public_health_relevance:
Relapse rates following drug treatment programs continue to be high. Treatment seeking individuals oftenreport that interacting with drug-using peers is a trigger for relapse. While exposure to discrete cues (syringecrack pipe beer bottle) or contextual cues (drug environment) are known to trigger craving and relapse thecurrent application will use a preclinical model to determine if social cues also trigger relapse.


